|
1
|
Gurovich AN. From the Swimming Pool to Precision Cardiovascular Physical Therapy: What a Journey! Cardiopulm Phys Ther J 2024; 35:126-134. [PMID: 39372518 PMCID: PMC11451943 DOI: 10.1097/cpt.0000000000000260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/08/2024]
Affiliation(s)
- Alvaro N Gurovich
- Department of Physical Therapy and Movement Science, The University of Texas at El Paso, El Paso, TX
| |
Collapse
|
|
2
|
Suzuki K, Yamada H, Fujii R, Munetsuna E, Yamazaki M, Ando Y, Ohashi K, Ishikawa H, Mizuno G, Tsuboi Y, Hashimoto S, Hamajima N. Circulating microRNA-27a and -133a are negatively associated with incident hypertension: A five-year longitudinal population-based study. Biomarkers 2022; 27:496-502. [DOI: 10.1080/1354750x.2022.2070281] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Affiliation(s)
- Koji Suzuki
- Department of Preventive Medical Sciences, Fujita Health University School of Medical Sciences, Toyoake, Japan
| | - Hiroya Yamada
- Department of Hygiene, Fujita Health University School of Medicine, Toyoake, Japan
| | - Ryosuke Fujii
- Department of Preventive Medical Sciences, Fujita Health University School of Medical Sciences, Toyoake, Japan
| | - Eiji Munetsuna
- Department of Biochemistry, Fujita Health University School of Medicine, Toyoake, Japan
| | - Mirai Yamazaki
- Faculty of Health Sciences, Kagawa Prefectural University of Health Sciences, Takamatsu, Japan
| | - Yoshitaka Ando
- Department of Informative Clinical Medicine, Fujita Health University School of Medical Sciences, Toyoake, Japan
| | - Koji Ohashi
- Department of Informative Clinical Medicine, Fujita Health University School of Medical Sciences, Toyoake, Japan
| | - Hiroaki Ishikawa
- Department of Informative Clinical Medicine, Fujita Health University School of Medical Sciences, Toyoake, Japan
| | - Genki Mizuno
- Department of Medical Technology, Tokyo University of Technology School of Health Sciences, Tokyo, Japan
| | - Yohiski Tsuboi
- Department of Preventive Medical Sciences, Fujita Health University School of Medical Sciences, Toyoake, Japan
| | - Shuji Hashimoto
- Department of Hygiene, Fujita Health University School of Medicine, Toyoake, Japan
| | - Nobuyuki Hamajima
- Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan
| |
Collapse
|
|
3
|
Nanoparticles in Medicine: A Focus on Vascular Oxidative Stress. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:6231482. [PMID: 30356429 PMCID: PMC6178176 DOI: 10.1155/2018/6231482] [Citation(s) in RCA: 93] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 07/26/2018] [Accepted: 08/19/2018] [Indexed: 01/16/2023]
Abstract
Nanotechnology has had a significant impact on medicine in recent years, its application being referred to as nanomedicine. Nanoparticles have certain properties with biomedical applications; however, in some situations, they have demonstrated cell toxicity, which has caused concern surrounding their clinical use. In this review, we focus on two aspects: first, we summarize the types of nanoparticles according to their chemical composition and the general characteristics of their use in medicine, and second, we review the applications of nanoparticles in vascular alteration, especially in endothelial dysfunction related to oxidative stress. This condition can lead to a reduction in nitric oxide (NO) bioavailability, consequently affecting vascular tone regulation and endothelial dysfunction, which is the first phase in the development of cardiovascular diseases. Therefore, nanoparticles with antioxidant properties may improve vascular dysfunction associated with hypertension, diabetes mellitus, or atherosclerosis.
Collapse
|
|
4
|
Nguyen Dinh Cat A, Antunes TT, Callera GE, Sanchez A, Tsiropoulou S, Dulak-Lis MG, Anagnostopoulou A, He Y, Montezano AC, Jaisser F, Touyz RM. Adipocyte-Specific Mineralocorticoid Receptor Overexpression in Mice Is Associated With Metabolic Syndrome and Vascular Dysfunction: Role of Redox-Sensitive PKG-1 and Rho Kinase. Diabetes 2016; 65:2392-403. [PMID: 27207514 DOI: 10.2337/db15-1627] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Accepted: 04/09/2016] [Indexed: 11/13/2022]
Abstract
Mineralocorticoid receptor (MR) expression is increased in adipose tissue from obese individuals and animals. We previously demonstrated that adipocyte-MR overexpression (Adipo-MROE) in mice is associated with metabolic changes. Whether adipocyte MR directly influences vascular function in these mice is unknown. We tested this hypothesis in resistant mesenteric arteries from Adipo-MROE mice using myography and in cultured adipocytes. Molecular mechanisms were probed in vessels/vascular smooth muscle cells and adipose tissue/adipocytes and focused on redox-sensitive pathways, Rho kinase activity, and protein kinase G type-1 (PKG-1) signaling. Adipo-MROE versus control-MR mice exhibited reduced vascular contractility, associated with increased generation of adipocyte-derived hydrogen peroxide, activation of vascular redox-sensitive PKG-1, and downregulation of Rho kinase activity. Associated with these vascular changes was increased elastin content in Adipo-MROE. Inhibition of PKG-1 with Rp-8-Br-PET-cGMPS normalized vascular contractility in Adipo-MROE. In the presence of adipocyte-conditioned culture medium, anticontractile effects of the adipose tissue were lost in Adipo-MROE mice but not in control-MR mice. In conclusion, adipocyte-MR upregulation leads to impaired contractility with preserved endothelial function and normal blood pressure. Increased elasticity may contribute to hypocontractility. We also identify functional cross talk between adipocyte MR and arteries and describe novel mechanisms involving redox-sensitive PKG-1 and Rho kinase. Our results suggest that adipose tissue from Adipo-MROE secrete vasoactive factors that preferentially influence vascular smooth muscle cells rather than endothelial cells. Our findings may be important in obesity/adiposity where adipocyte-MR expression/signaling is amplified and vascular risk increased.
Collapse
Affiliation(s)
- Aurelie Nguyen Dinh Cat
- Cardiovascular Research and Medical Sciences Institute, University of Glasgow, Glasgow, U.K.
| | - Tayze T Antunes
- Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
| | - Glaucia E Callera
- Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
| | - Ana Sanchez
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense, Madrid, Spain
| | - Sofia Tsiropoulou
- Cardiovascular Research and Medical Sciences Institute, University of Glasgow, Glasgow, U.K
| | - Maria G Dulak-Lis
- Cardiovascular Research and Medical Sciences Institute, University of Glasgow, Glasgow, U.K
| | | | - Ying He
- Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
| | - Augusto C Montezano
- Cardiovascular Research and Medical Sciences Institute, University of Glasgow, Glasgow, U.K
| | - Frederic Jaisser
- INSERM Unit 1138 Team 1, Centre de Recherche des Cordeliers, University Pierre and Marie Curie, Paris, France INSERM, Clinical Investigation Centre 1430, APHP, Henri Mondor Hospital, Pole VERDI, Paris East University, Creteil, France
| | - Rhian M Touyz
- Cardiovascular Research and Medical Sciences Institute, University of Glasgow, Glasgow, U.K. Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
| |
Collapse
|
|
5
|
Lluch P, Segarra G, Medina P. Asymmetric dimethylarginine as a mediator of vascular dysfunction in cirrhosis. World J Gastroenterol 2015; 21:9466-9475. [PMID: 26327755 PMCID: PMC4548108 DOI: 10.3748/wjg.v21.i32.9466] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Revised: 06/05/2015] [Accepted: 07/18/2015] [Indexed: 02/06/2023] Open
Abstract
Cirrhosis is associated with marked abnormalities in the circulatory function that involve a reduction in systemic vascular resistance. An important cause of this vasodilatation is the increased production or activity of nitric oxide (NO) in the splanchnic circulation. During portal hypertension and cirrhosis an increased endothelial NO synthase (eNOS) activity is demonstrated in splanchnic vessels. In contrast, the activity of eNOS in the cirrhotic liver is decreased, which suggests a different regulation of eNOS in the liver and in the splanchnic vessels. Asymmetric dimethylarginine (ADMA) is an endogenous NO inhibitor and higher plasma levels of ADMA are related to increased cardiovascular risk in both the general population and among patients with cirrhosis. It has been demonstrated that the liver is a key player in the metabolism of ADMA. This observation was further supported by investigations in human patients, showing a close correlation between ADMA plasma levels and the degree of hepatic dysfunction. ADMA is degraded to citrulline and dimethylamine by dimethylarginine dimethylaminohydrolases (DDAHs). DDAHs are expressed as type 1 and 2 isoforms and are widely distributed in various organs and tissues, including the liver. In this review, we discuss experimental and clinical data that document the effects of dimethylarginines on vascular function in cirrhosis. Our increasing understanding of the routes of synthesis and metabolism of methylarginines is beginning to provide insights into novel mechanisms of liver disease and allowing us to identify potential therapeutic opportunities.
Collapse
|
|
6
|
Nethi SK, Veeriah V, Barui AK, Rajendran S, Mattapally S, Misra S, Chatterjee S, Patra CR. Investigation of molecular mechanisms and regulatory pathways of pro-angiogenic nanorods. NANOSCALE 2015; 7:9760-9770. [PMID: 25963768 PMCID: PMC4724197 DOI: 10.1039/c5nr01327e] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Angiogenesis, a process involving the growth of new blood vessels from the pre-existing vasculature, plays a crucial role in various pathophysiological conditions. We have previously demonstrated that europium hydroxide [Eu(III)(OH)3] nanorods (EHNs) exhibit pro-angiogenic properties through the generation of reactive oxygen species (ROS) and mitogen activated protein kinase (MAPK) activation. Considering the enormous implication of angiogenesis in cardiovascular diseases (CVDs) and cancer, it is essential to understand in-depth molecular mechanisms and signaling pathways in order to develop the most efficient and effective alternative treatment strategy for CVDs. However, the exact underlying mechanism and cascade signaling pathways behind the pro-angiogenic properties exhibited by EHNs still remain unclear. Herein, we report for the first time that the hydrogen peroxide (H2O2), a redox signaling molecule, generated by these EHNs activates the endothelial nitric oxide synthase (eNOS) that promotes the nitric oxide (NO) production in a PI3K (phosphoinositide 3-kinase)/Akt dependent manner, eventually triggering angiogenesis. We intensely believe that the investigation and understanding of the in-depth molecular mechanism and signaling pathways of EHNs induced angiogenesis will help us in developing an effective alternative treatment strategy for cardiovascular related and ischemic diseases where angiogenesis plays an important role.
Collapse
Affiliation(s)
- Susheel Kumar Nethi
- Biomaterials Group, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, India
- Academy of Scientific and Innovative Research (AcSIR), 2 Rafi Marg, New Delhi, India
| | - Vimal Veeriah
- Vascular Biology Lab, Life Sciences Division, AU-KBC Research Centre, Anna University, Chennai, Tamil Nadu, India
| | - Ayan Kumar Barui
- Biomaterials Group, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, India
- Academy of Scientific and Innovative Research (AcSIR), 2 Rafi Marg, New Delhi, India
| | - Saranya Rajendran
- Vascular Biology Lab, Life Sciences Division, AU-KBC Research Centre, Anna University, Chennai, Tamil Nadu, India
| | - Saidulu Mattapally
- Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, India
| | - Sanjay Misra
- Vascular and Interventional Radiology Translational Laboratory, Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA
| | - Suvro Chatterjee
- Vascular Biology Lab, Life Sciences Division, AU-KBC Research Centre, Anna University, Chennai, Tamil Nadu, India
- Department of Biotechnology, Anna University, Chennai, India
| | - Chitta Ranjan Patra
- Biomaterials Group, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, India
- Academy of Scientific and Innovative Research (AcSIR), 2 Rafi Marg, New Delhi, India
| |
Collapse
|
|
7
|
Liman N, Alan E, Beyaz F, Gürbulak K. Endothelial and inducible nitric oxide synthase (NOS) immunoreactivity and NOS-associated NADPH-diaphorase histochemistry in the domestic cat (Felis catus) testis. Theriogenology 2013; 80:1017-32. [DOI: 10.1016/j.theriogenology.2013.07.030] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2013] [Revised: 07/24/2013] [Accepted: 07/24/2013] [Indexed: 12/18/2022]
|
|
8
|
Diers AR, Broniowska KA, Hogg N. Nitrosative stress and redox-cycling agents synergize to cause mitochondrial dysfunction and cell death in endothelial cells. Redox Biol 2013; 1:1-7. [PMID: 24024132 PMCID: PMC3757685 DOI: 10.1016/j.redox.2012.11.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2012] [Revised: 11/28/2012] [Accepted: 11/30/2012] [Indexed: 02/07/2023] Open
Abstract
Nitric oxide production by the endothelium is required for normal vascular homeostasis; however, in conditions of oxidative stress, interactions of nitric oxide with reactive oxygen species (ROS) are thought to underlie endothelial dysfunction. Beyond canonical nitric oxide signaling pathways, nitric oxide production results in the post-translational modification of protein thiols, termed S-nitrosation. The potential interplay between S-nitrosation and ROS remains poorly understood and is the focus of the current study. The effects of the S-nitrosating agent S-nitrosocysteine (CysNO) in combination with redox-cycling agents was examined in bovine aortic endothelial cells (BAEC). CysNO significantly impairs mitochondrial function and depletes the NADH/NAD+ pool; however, these changes do not result in cell death. When faced with the additional stressor of a redox-cycling agent used to generate ROS, further loss of NAD+ occurs, and cellular ATP pools are depleted. Cellular S-nitrosothiols also accumulate, and cell death is triggered. These data demonstrate that CysNO sensitizes endothelial cells to redox-cycling agent-dependent mitochondrial dysfunction and cell death and identify attenuated degradation of S-nitrosothiols as one potential mechanism for the enhanced cytotoxicity.
Collapse
Key Words
- BAEC, Bovine aortic endothelial cells
- BSO, Buthioninesulphoximine
- CysNO, S-nitrosocysteine
- DMNQ, 2,3-dimethoxy-1,4-naphthoquinone
- DMSO, Dimethyl sulfoxide
- DPBS, Dulbecco’s phosphate buffered saline
- DTPA, Diethylenetriaminepentaacetic acid
- DTT, Dithiothreitol
- GAPDH, Glyceraldehyde-3-phosphate dehydrogenase
- GSHee, Glutathione Ethyl Ester
- LDH, Lactate Dehydrogenase
- Mitochondria
- N.D., Not detectable
- NAC, N-acetyl cysteine
- NOS, Nitric oxide synthase
- Nitric oxide
- OCR, Oxygen consumption rate
- ROS, Reactive oxygen species
- Reactive oxygen species
- S-nitrosation
- S-nitrosylation
- SEM, Standard error of the mean.
- Thiol
- cGMP, Cyclic guanosine monophosphate
Collapse
Affiliation(s)
- Anne R Diers
- Department of Biophysics, Redox Biology Program, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226 USA
| | | | | |
Collapse
|
|
9
|
Francis SH, Busch JL, Corbin JD, Sibley D. cGMP-dependent protein kinases and cGMP phosphodiesterases in nitric oxide and cGMP action. Pharmacol Rev 2010; 62:525-63. [PMID: 20716671 PMCID: PMC2964902 DOI: 10.1124/pr.110.002907] [Citation(s) in RCA: 736] [Impact Index Per Article: 49.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
To date, studies suggest that biological signaling by nitric oxide (NO) is primarily mediated by cGMP, which is synthesized by NO-activated guanylyl cyclases and broken down by cyclic nucleotide phosphodiesterases (PDEs). Effects of cGMP occur through three main groups of cellular targets: cGMP-dependent protein kinases (PKGs), cGMP-gated cation channels, and PDEs. cGMP binding activates PKG, which phosphorylates serines and threonines on many cellular proteins, frequently resulting in changes in activity or function, subcellular localization, or regulatory features. The proteins that are so modified by PKG commonly regulate calcium homeostasis, calcium sensitivity of cellular proteins, platelet activation and adhesion, smooth muscle contraction, cardiac function, gene expression, feedback of the NO-signaling pathway, and other processes. Current therapies that have successfully targeted the NO-signaling pathway include nitrovasodilators (nitroglycerin), PDE5 inhibitors [sildenafil (Viagra and Revatio), vardenafil (Levitra), and tadalafil (Cialis and Adcirca)] for treatment of a number of vascular diseases including angina pectoris, erectile dysfunction, and pulmonary hypertension; the PDE3 inhibitors [cilostazol (Pletal) and milrinone (Primacor)] are used for treatment of intermittent claudication and acute heart failure, respectively. Potential for use of these medications in the treatment of other maladies continues to emerge.
Collapse
Affiliation(s)
- Sharron H Francis
- Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, 2215 Garland Avenue, Nashville, TN 37232-0615, USA.
| | | | | | | |
Collapse
|
|
10
|
Csányi G, Taylor WR, Pagano PJ. NOX and inflammation in the vascular adventitia. Free Radic Biol Med 2009; 47:1254-66. [PMID: 19628034 PMCID: PMC3061339 DOI: 10.1016/j.freeradbiomed.2009.07.022] [Citation(s) in RCA: 109] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2008] [Revised: 07/10/2009] [Accepted: 07/14/2009] [Indexed: 02/07/2023]
Abstract
Vascular inflammation has traditionally been thought to be initiated at the luminal surface and progress through the media toward the adventitial layer. In recent years, however, evidence has emerged suggesting that the vascular adventitia is activated early in a variety of cardiovascular diseases and that it plays an important role in the initiation and progression of vascular inflammation. Adventitial fibroblasts have been shown to produce substantial amounts of NAD(P)H oxidase-derived reactive oxygen species (ROS) in response to vascular injury. Additionally, inflammatory cytokines, lipids, and various hormones, implicated in fibroblast proliferation and migration, lead to recruitment of inflammatory cells to the adventitial layer and impairment of endothelium-dependent relaxation. Early in the development of vascular disease, there is clear evidence for progression toward a denser vasa vasorum which delivers oxygen and nutrients to an increasingly hypoxic and nutrient-deficient media. This expanded vascularization appears to provide enhanced delivery of inflammatory cells to the adventitia and outer media. Combined adventitial fibroblast and inflammatory cell-derived ROS therefore are expected to synergize their local effect on adventitial parenchymal cells, leading to further cytokine release and a feed-forward propagation of adventitial ROS production. In fact, data from our laboratory and others suggest a broader paracrine positive feedback role for adventitia-derived ROS in medial smooth muscle cell hypertrophy and neointimal hyperplasia. A likely candidate responsible for the adventitia-derived paracrine signaling across the vessel wall is the superoxide anion metabolite hydrogen peroxide, which is highly stable, cell permeant, and capable of activating downstream signaling mechanisms in smooth muscle cells, leading to phenotypic modulation of smooth muscle cells. This review addresses the role of adventitial NAD(P)H oxidase-derived ROS from a nontraditional, perivascular vantage of promoting vascular inflammation and will discuss how ROS derived from adventitial NAD(P)H oxidases may be a catalyst for vascular remodeling and dysfunction.
Collapse
Affiliation(s)
- Gábor Csányi
- Department of Pharmacology & Chemical Biology and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA
| | - W. Robert Taylor
- Departments of Medicine and Biomedical Engineering, Emory University and the Atlanta VA Medical Center, Atlanta, GA
| | - Patrick J. Pagano
- Department of Pharmacology & Chemical Biology and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA
| |
Collapse
|
|
11
|
Riego JA, Broniowska KA, Kettenhofen NJ, Hogg N. Activation and inhibition of soluble guanylyl cyclase by S-nitrosocysteine: involvement of amino acid transport system L. Free Radic Biol Med 2009; 47:269-74. [PMID: 19409484 PMCID: PMC2704003 DOI: 10.1016/j.freeradbiomed.2009.04.027] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2008] [Revised: 03/13/2009] [Accepted: 04/22/2009] [Indexed: 02/07/2023]
Abstract
In this study the mechanism by which S-nitrosocysteine (CysNO) activates soluble guanylyl cyclase (sGC) has been investigated. CysNO is the S-nitrosated derivative of the amino acid cysteine and has previously been shown to be transported into various cell types by amino acid transport system L. Here we show, using both neuroblastoma and pulmonary artery smooth muscle cells, that CysNO stimulates cGMP formation at low concentrations, but this effect is lost at higher concentrations. Stimulation of cGMP accumulation occurs only after its transport into the cell and subsequent flavoprotein reductase-mediated metabolism to form nitric oxide (NO). Consequently, CysNO can be regarded as a cell-targeted NO-releasing agent. However, CysNO also functions as an NO-independent thiol-modifying agent and can compromise cellular antioxidant defenses in a concentration-dependent manner. The observed biphasic nature of CysNO-dependent cGMP accumulation seems to be due to these two competing mechanisms. At higher concentrations, CysNO probably inactivates guanylyl cyclase through modification of an essential thiol group on the enzyme, either directly or as a result of a more generalized oxidative stress. We show here that higher concentrations of CysNO can increase cellular S-nitrosothiol content to nonphysiological levels, deplete cellular glutathione, and inhibit cGMP formation in parallel. Although the inhibition of sGC by S-nitrosation has been suggested as a mechanism of nitrovasodilator tolerance, in the case of CysNO, it seems to be more a reflection of a generalized oxidative stress placed upon the cell by the nonphysiological levels of intracellular S-nitrosothiol generated upon CysNO exposure.
Collapse
Affiliation(s)
- Joseph A Riego
- Department of Biophysics and Free Radical Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | | | | | | |
Collapse
|
|
12
|
Mohamadin AMA, Hammad LNA, El-Bab MF, Gawad HSA. CAN NITRIC OXIDE-GENERATING COMPOUNDS IMPROVE THE OXIDATIVE STRESS RESPONSE IN EXPERIMENTALLY DIABETIC RATS? Clin Exp Pharmacol Physiol 2007; 34:586-93. [PMID: 17581213 DOI: 10.1111/j.1440-1681.2007.04622.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
1. The present study was designed to evaluate the protective effects of the nitric oxide (NO)-generating compounds L-arginine (L-Arg) and sodium nitroprusside (SNP) on oxidative stress markers in streptozotocin (STZ)-diabetic rats. 2. Diabetes was induced after a single intraperitoneal injection of STZ (60 mg/kg). Rats were divided into non-diabetic (control), diabetic and treated diabetic groups. The treated diabetic groups were supplemented with L-Arg (300 mg/kg), SNP (3 mg/kg per day) or glibenclamide (0.6 mg/kg per day) orally for 4 weeks. 3. At the end of the experiment, fasted rats were killed by cervical decapitation. Blood was collected for estimation of glucose, haemoglobin, glycosylated haemoglobin (HbA(1c)), total cholesterol, high-density lipoprotein-cholesterol and triglycerides. Thiobarbituric acid-reactive substances (TBARS; an index of lipid peroxidation), superoxide dismutase, glutathione peroxidase, catalase, nitrate/nitrite (NO(x)) and reduced glutathione (GSH) were estimated in liver and kidney homogenates. 4. A significant increase was observed in plasma glucose levels and HbA(1c), with a concomitant decrease in haemoglobin levels, in diabetic rats. These alterations reverted back to near normal after treatment with the NO-generating compounds. A loss of bodyweight, polydipsia, polyphagia and elevated levels of serum cholesterol and triglycerides were observed in diabetic rats. Hyperglycaemia was accompanied by a significant increase in tissue TBARS and a decrease in NO(x), GSH and anti-oxidant enzymes, whereas, supplementation with L-Arg and SNP significantly reduced TBARS levels and increased GSH and anti-oxidant enzyme activities. Linear regression analysis indicated that blood glucose and TBARS had a significant positive correlation with HbA(1c), whereas a negative correlation was observed between GSH and NO(x). 5. It is concluded that NO-generating compounds improve most of the biochemical abnormalities and anti-oxidant levels in diabetic rats. The beneficial effects of NO-generating compounds can be attributed to the generation of NO and/or enhanced anti-oxidant enzyme activities.
Collapse
Affiliation(s)
- Ahmed M A Mohamadin
- Biochemistry Department and Tumor Marker Oncology Research Unit, Faculty of Pharmacy Boy, Al-Azhar University, Cairo, Egypt.
| | | | | | | |
Collapse
|
|
13
|
Puglia GD, Freeman LM, Rush JE, King RGP, Crawford SL. Use of a flow-mediated vasodilation technique to assess endothelial function in dogs. Am J Vet Res 2006; 67:1533-40. [PMID: 16948597 DOI: 10.2460/ajvr.67.9.1533] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To develop and assess the reproducibility of a protocol to noninvasively test endothelial function in dogs on the basis of the flow-mediated vasodilation (FMD) procedure used in humans. ANIMALS 5 healthy spayed female dogs. PROCEDURES Luminal arterial diameter and blood flow velocity in the brachial and femoral arteries were measured with ultrasonography. The within-dog reproducibility of these ultrasonographic measurements was tested. An occlusion period of 1, 3, or 5 minutes with an inflatable cuff was used to create the FMD response. Measurements made at 15, 30, and 60 seconds following release of the occlusion were compared with measurements made immediately prior to each occlusion to assess the FMD response. RESULTS Within-dog reproducibility of measurements revealed moderate to high correlations. Change from baseline in luminal arterial diameter was most substantial when measured at 30 seconds following release of occlusion, whereas blood flow velocity changes were maximal when measured at 15 seconds following release. The brachial imaging site provided a larger number of significant FMD responses than the femoral site. The 3-minute occlusion period provided equal or better responses than the 5-minute occlusion period. CONCLUSIONS AND CLINICAL RELEVANCE Ultrasonographic measurement of the FMD responses was a feasible and reproducible technique and significant changes from baseline were detected. The FMD responses in dogs were most substantial when performed at the brachial artery with blood flow velocity and luminal arterial diameter changes from baseline measured at 15 and 30 seconds, respectively, following release of a 3-minute occlusion period.
Collapse
Affiliation(s)
- Gary D Puglia
- Department of Clinical Sciences, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA 01536, USA
| | | | | | | | | |
Collapse
|
|
14
|
Sand A, Andersson E, Fried G. Nitric oxide donors mediate vasodilation in human placental arteries partly through a direct effect on potassium channels. Placenta 2006; 27:181-90. [PMID: 16338463 DOI: 10.1016/j.placenta.2004.12.013] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2004] [Revised: 12/14/2004] [Accepted: 12/22/2004] [Indexed: 10/25/2022]
Abstract
We have investigated the involvement of potassium channels in the NO-induced relaxation of small ET-1 precontracted arteries from placentas of normal pregnancies in the presence of the potassium channel modulating agents charybdotoxin, 4-AP, glibenclamide, TEA and the blocker of soluble guanylyl cyclase, ODQ, respectively. We have studied the effect of the NO-donor S-nitroso-N-acetylpenicillamine (SNAP) in vessels precontracted by different concentrations of potassium and we have also investigated the presence of BK(Ca) channels in placental arteries by immunohistochemistry and immunoblotting. Our results show that charybdotoxin, an inhibitor of large- and intermediate-conductance Ca(2+)-activated potassium channels, inhibits relaxation in placental arteries. In presence of both charybdotoxin and ODQ, the inhibition of relaxation was significantly stronger, which indicates that NO-induced relaxation of human placental arteries is partly mediated through cGMP, and partly through a direct effect on potassium channels of the BK(Ca) type. The NO-donor SNAP preferentially relaxes contractions induced by 75 mM K(+) as compared to 100 mM K(+). This effect profile is a unique feature of drugs acting by K(+) channel opening. The immunohistochemistry shows that BK(Ca) channels are located both in smooth muscle and in endothelium in placental arteries.
Collapse
Affiliation(s)
- A Sand
- Department of Women and Child Health, Division of Obstetrics and Gynaecology, Karolinska Institute and Hospital, S-171 76 Stockholm, Sweden.
| | | | | |
Collapse
|
|
15
|
Hummel SG, Fischer AJ, Martin SM, Schafer FQ, Buettner GR. Nitric oxide as a cellular antioxidant: a little goes a long way. Free Radic Biol Med 2006; 40:501-6. [PMID: 16443165 PMCID: PMC2258411 DOI: 10.1016/j.freeradbiomed.2005.08.047] [Citation(s) in RCA: 94] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2005] [Revised: 08/08/2005] [Accepted: 08/30/2005] [Indexed: 11/24/2022]
Abstract
Nitric oxide (NO*) is an effective chain-breaking antioxidant in free radical-mediated lipid oxidation (LPO). It reacts rapidly with peroxyl radicals as a sacrificial chain-terminating antioxidant. The goal of this work was to determine the minimum threshold concentration of NO* required to inhibit Fe2+ -induced cellular lipid peroxidation. Using oxygen consumption as a measure of LPO, we simultaneously measured nitric oxide and oxygen concentrations with NO* and O2 electrodes. Ferrous iron and dioxygen were used to initiate LPO in docosahexaenoic acid-enriched HL-60 and U937 cells. Bolus addition of NO* (1.5 microM) inhibited LPO when the NO* concentration was greater than 50 nM. Similarly, using (Z)-1-[N-(3-ammoniopropyl)-N-(n-propyl)amino]diazen-1-ium-1,2-diolate as a NO* donor we found that an average steady-state NO* concentration of at least 72 +/- 9 nM was required to blunt LPO. As long as the concentration of NO* was above 13 +/- 8 nM the inhibition was sustained. Once the concentration of NO* fell below this value, the rate of lipid oxidation accelerated as measured by the rate of oxygen consumption. Our model suggests that a continuous production of NO* that would yield a steady-state concentration of only 10-20 nM is capable of inhibiting Fe2+ -induced LPO.
Collapse
Affiliation(s)
- Stephen G. Hummel
- Free Radical and Radiation Biology & ESR Facility, The University of Iowa, Iowa City, IA 52242-1101
| | - Anthony J. Fischer
- Free Radical and Radiation Biology & ESR Facility, The University of Iowa, Iowa City, IA 52242-1101
| | - Sean M. Martin
- Free Radical and Radiation Biology & ESR Facility, The University of Iowa, Iowa City, IA 52242-1101
| | - Freya Q. Schafer
- Free Radical and Radiation Biology & ESR Facility, The University of Iowa, Iowa City, IA 52242-1101
| | - Garry R. Buettner
- Free Radical and Radiation Biology & ESR Facility, The University of Iowa, Iowa City, IA 52242-1101
| |
Collapse
|
|
16
|
Tousoulis D, Antoniades C, Stefanadis C. Nitric oxide in coronary artery disease: effects of antioxidants. Eur J Clin Pharmacol 2006; 62:101-107. [DOI: 10.1007/s00228-005-0019-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
|
|
17
|
Sulica R, Dinh HV, Dunsky K, Fuster V, Poon M. The acute hemodynamic effect of IV nitroglycerin and dipyridamole in patients with pulmonary arterial hypertension: comparison with IV epoprostenol. ACTA ACUST UNITED AC 2005; 11:139-44; quiz 145-6. [PMID: 15947535 DOI: 10.1111/j.1527-5299.2005.03885.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Nitroglycerin and dipyridamole are two commonly available and well tolerated vasoactive medications. Their acute hemodynamic effects in patients with pulmonary arterial hypertension are not well defined in the current literature. The authors retrospectively analyzed the acute hemodynamic effects of IV nitroglycerin, dipyridamole, and epoprostenol in 59 patients with pulmonary arterial hypertension as determined by changes from baseline in systemic and pulmonary hemodynamic parameters. Statistical analysis was performed using the independent sample t test. A p value <0.05 was considered significant. Nitroglycerin is predominantly a vasodilator of the pulmonary vasculature with moderate systemic vasodilator effect, while dipyridamole is primarily a positive inotropic agent. Epoprostenol is a potent vasodilator of both pulmonary and systemic vessels and a strong positive inotropic agent. Nitroglycerin and dipyridamole may be useful in the acute management of pulmonary arterial hypertension.
Collapse
Affiliation(s)
- Roxana Sulica
- Zena and Michael A. Wiener Cardiovascular Institute, Marie-Josee and Henry R. Kravis Center for Cardiovascular Health, Mount Sinai School of Medicine, New York, NY, USA
| | | | | | | | | |
Collapse
|
|
18
|
Rascado RR, Bendhack LM. Activation of alpha2-adrenoceptors is necessary to induce nitric oxide release in isoprenaline-induced relaxation. Vascul Pharmacol 2005; 42:63-8. [PMID: 15722251 DOI: 10.1016/j.vph.2005.01.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2004] [Accepted: 01/19/2005] [Indexed: 10/25/2022]
Abstract
The aim of this study was to investigate the role of the contractile agent on the relaxation induced by isoprenaline and the contribution of nitric oxide (NO) and cGMP to this relaxation. These studies were conducted in intact endothelium or denuded aortas contracted with the EC50 of norepinephrine (NE) or phenylephrine (Phe), and the relaxation induced by isoprenaline (non-selective beta-adrenoceptor agonist) or forskolin (activator of adenylyl-cyclase) was studied. The maximum effect (Emax) and pD2 were analysed. Isoprenaline and forskolin-induced relaxation were not changed by the endothelium removal in both NE and Phe-contracted aortas. However, L-NAME reduced the relaxation induced by isoprenaline (Emax from 94.48+/-2.30%, n=7 to 66.17+/-11.73%, n=7; pD2 from 7.56+/-0.10 to 6.08+/-0.15) only in NE-contracted aortas. The pD2 of isoprenaline was also reduced by ODQ (6.57+/-0.13), but not the Emax. The inhibitory effects of L-NAME and ODQ were reversed by yohimbine. L-NAME, ODQ and oxyhemoglobin had no effect on the relaxation induced by isoprenaline in Phe-contracted aortas. Taken together, these results suggest that norepinephrine, a non-selective alpha-adrenoceptor agonist can also activate alpha2-adrenoceptors sensitive to yohimbine in the endothelial cells, activating the NO-synthase and cGMP production which would potentiate the relaxation induced by isoprenaline. However, this pathway is not activated with Phe, the selective alpha1-adrenoceptors agonist.
Collapse
Affiliation(s)
- Ricardo R Rascado
- Laboratório de Farmacologia, Dept. Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil
| | | |
Collapse
|
|
19
|
Tousoulis D, Charakida M, Stefanadis C. Inflammation and endothelial dysfunction as therapeutic targets in patients with heart failure. Int J Cardiol 2005; 100:347-353. [PMID: 15837076 DOI: 10.1016/j.ijcard.2004.05.030] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2003] [Revised: 03/16/2004] [Accepted: 05/05/2004] [Indexed: 01/09/2023]
Abstract
Evidence suggests that vascular endothelium plays key role in the regulation of vascular tone, in the process of inflammation and in the thrombotic mechanisms. Recent studies indicate that it is an important component of the pathophysiological mechanisms of heart failure. Heart failure may induce endothelial dysfunction by different mechanisms, such as reduced synthesis and release of nitric oxide (NO), increased degradation of NO or by increased production of endothelin-1. In addition, endothelial dysfunction has been associated with the progression of heart failure. Alterations in neurotransmitters, hormones and also in physiological stimuli are present in heart failure and affect the vascular endothelium. Treatments with beneficial effects on endothelial dysfunction may also improve prognosis in patients with heart failure.
Collapse
Affiliation(s)
- Dimitris Tousoulis
- Cardiology Unit, Hippokration Hospital, Athens University Medical School, S. Karagiorga Street 69, 166 75 Glifada Athens, Greece.
| | | | | |
Collapse
|
|
20
|
Görür S, Bağdatoğlu OT, Polat G. Protective effect of L-carnitine on renal ischaemia-reperfusion injury in the rat. Cell Biochem Funct 2005; 23:151-5. [PMID: 15386530 DOI: 10.1002/cbf.1159] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
This study was designed to investigate the effect of L-carnitine in ischaemia and reperfusion of the rat kidney. Rats were randomly allocated into three groups. Group I (control group; n = 6) received no treatment. Group II (isotonic saline group; n = 6), received 2 ml of isotonic saline 15 min before the renal ischaemia, and group III (carnitine group; n = 6) received L-carnitine hydrochloride (100 mg kg(-1)) intraperitoneally. At the end of the reperfusion period, rats were sacrificed. Tissue malondialdehyde level (MDA), myeloperoxidase (MPO) activity, and nitrite/nitrate (NO) level of renal tissue were measured to evaluate the lipid peroxidation, neutrophil function, and nitric oxide metabolism, respectively. The tissue levels of MDA, MPO and NO were lower in group III (71.8 +/- 8.4, 172.1 +/- 27.4 U g(-1) tissue, 76.3 +/- 29.7 micromol l(-1) respectively) than levels in groups I (103.4 +/- 13.4 nmol g(-1), 325.9 +/- 20.2 U g(-1) tissue, 144.5 +/- 39.2 micromol l(-1), respectively) and II (103.5 +/- 11.4 nmol g(-1), 317.1 +/- 41.5 U g(-1) tissue, 148.9 +/- 23.9 micromol l(-1), respectively). It is shown that carnitine protects kidney tissue against ischaemia-reperfusion injury.
Collapse
Affiliation(s)
- Sadik Görür
- Department of Urology, Kadirli Devlet Hastanesi, Turkey.
| | | | | |
Collapse
|
|
21
|
Polat G, Talas DU, Polat A, Nayci A, Atiş S, Bağdatoğlu O, Cömelekoğlu U, Atik U. Effects of triazolopyrimidine on lipid peroxidation and nitric oxide levels in the corticosteroid-impaired healing of rat tracheal anastomoses. Cell Biochem Funct 2004; 23:39-45. [PMID: 15386539 DOI: 10.1002/cbf.1126] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Corticosteroids are used to reduce the oedema and prevent scar tissue formation of the upper airways by their ability to inhibit influx of inflammatory cells, limit capillary permeability and block collagen synthesis in the early stages of wound healing. Triazolopyrimidine (Trapidil) is an antiplatelet agent that acts in part as a phosphodiesterase inhibitor and as a competitive inhibitor of the platelet-derived growth factor (PDGF) receptor. Trapidil, with its vasodilator and NO releasing effect may have some potential to diminish the tissue injury. This study was carried out to evaluate the effects of trapidil (triazolopyrimidine) on lipid peroxidation and nitric oxide in the corticosteroid-impaired healing of tracheal anastomoses. Thirty-four adult Wistar rats were divided into five groups. The animals underwent tracheal transection and primary anastomoses. The groups were assigned as follows: group I, control, (GI, n = 6); group II, sham, (GII, n = 6); group III, dexamethasone, 0.1 mg kg(-1) twice daily intramuscularly, (GIII, n = 8); group IV, trapidil, 6 mg kg(-1) twice daily intraperitoneally (GIV, n = 7); group V, dexamethasone, 0.1 mg kg(-1) plus trapidil, 6 mg kg(-1) twice daily (GV, n = 7), for 1 week. After 1 week, anastomotic healing was assessed by measurement of bursting pressure, evaluation of histopathology, measurement of MDA and nitrite/nitrate levels. In GIII, GIV and GV bursting pressures resulted in significantly reduced anastomotic strength compared to the controls (p < 0.001 for all groups). The difference between bursting pressures of GIII and GIV was not found to be statistically significant (p = 0.966). In regard to fibroblast proliferation and collagen content, a significant difference was found between GIII and GI (p < 0.01), A significant difference was also found when GIV and GV were compared to GIII (p < 0.01). MDA and nitrite/nitrate levels were found to be higher in GIII when compared to all other groups. MDA levels of GIV and GV rats were found to be lower than GIII (p < 0.001, for both groups). The nitrite/nitrate levels of GIV and GV rats were found to be lower than GIII (p < 0.05), and higher than GI (p < 0.001). Trapidil may be useful for its preventive effects on lipid peroxidation and possible increases in NO in cases with corticosteroid-impaired healing of trachea anastomoses.
Collapse
Affiliation(s)
- Gürbüz Polat
- Department of Biochemistry, Mersin University, Medical Faculty, Mersin, Turkey.
| | | | | | | | | | | | | | | |
Collapse
|
|
22
|
Gessler P, Pfenninger J, Pfammatter JP, Carrel T, Baenziger O, Dahinden C. Plasma levels of interleukin-8 and expression of interleukin-8 receptors on circulating neutrophils and monocytes after cardiopulmonary bypass in children. J Thorac Cardiovasc Surg 2003; 126:718-25. [PMID: 14502144 DOI: 10.1016/s0022-5223(03)00685-8] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
OBJECTIVE Cardiopulmonary bypass induces a systemic inflammatory response that causes substantial clinical morbidity. This study sought to determine cellular and humoral variables of inflammation. We hypothesized that chemokines are a major source of stimulation of neutrophils and monocytes in pediatric cardiac surgery. METHODS We performed an observational prospective clinical study of 20 pediatric patients before and after cardiopulmonary bypass. Plasma levels of interleukin-6, interleukin-8, myeloperoxidase, and nitric oxide were measured by immunoassays. Expression of interleukin-8 receptors (CXCR1, CXCR2) and CD14 of circulating neutrophils and monocytes was assessed by flow cytometry. Clinical evaluations included length of inotropic support and mechanical ventilation as well as oxygenation. RESULTS Two hours after cardiopulmonary bypass, plasma levels of interleukin-6 and interleukin-8 were strongly increased (P =.0001 and P =.0032, respectively). Interleukin-6 and interleukin-8 concentrations correlated with the length of inotropic support, as well as with the length of mechanical ventilation (r >.70, P </=.0006), and were inversely related to the ratio of arterial oxygen tension to fraction of inspired oxygen. There was a strong association between the postoperative levels of interleukin-6 and nitric oxide, as well as between interleukin-6 and CD14 expression on monocytes (r >.62, P </=.0031). The expression of CXCR2 but not CXCR1 on neutrophils and monocytes correlated negatively with the levels of interleukin-8 and myeloperoxidase. CONCLUSIONS After cardiopulmonary bypass, impairment of cardiovascular and respiratory function correlated with the levels of interleukin-6 and interleukin-8 as mediators of an inflammatory response. The negative correlation of CXCR2 expression with interleukin-8 and myeloperoxidase indicates that myeloid cells were stimulated by CXC chemokines with Glu-Leu-Arg (ELR) motif and thereby contributed to tissue damage, leading to impairment of cardiovascular and respiratory function.
Collapse
Affiliation(s)
- Peter Gessler
- University Children's Hospital, Steinweisstrasse 75, CH 8032 Zurich, Switzerland.
| | | | | | | | | | | |
Collapse
|
|
23
|
Pingle SC, Sanchez JF, Hallam DM, Williamson AL, Maggirwar SB, Ramkumar V. Hypertonicity inhibits lipopolysaccharide-induced nitric oxide synthase expression in smooth muscle cells by inhibiting nuclear factor kappaB. Mol Pharmacol 2003; 63:1238-47. [PMID: 12761333 DOI: 10.1124/mol.63.6.1238] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
The expression of inducible nitric-oxide synthase (iNOS) in vascular smooth muscle cells leads to prolonged vasorelaxation in vivo and contributes to the profound vasodilation induced by bacterial lipopolysaccharide (LPS) in septic shock. This induction of iNOS depends, in large part, on activation of nuclear factor (NF)-kappaB. Hypertonicity regulates the activity of NF-kappaB in different cell lines; as such, we propose that it should also regulate the expression of iNOS. Thus, the goal of this study was to determine whether hypertonicity regulates iNOS expression and function in smooth muscle cells and to elucidate the mechanism(s) underlying this process. Treatment of hamster ductus deferens (DDT1MF-2) cells and porcine aortic smooth muscle cells with either mannitol (50 mM) or NaCl (50 mM) reduced LPS-stimulated iNOS expression and nitric oxide release. Both of these agents also reduced the activation of NF-kappaB induced by LPS, tumor necrosis factor-alpha and interleukin-1beta in smooth muscle cells. This inhibitory action was caused by suppression of IkappaB-alpha phosphorylation, a prerequisite for ubiquitination and degradation of this protein, and showed additivity with N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal (MG-132), an inhibitor of proteasomal degradation of IkappaB-alpha. Furthermore, exposure to mannitol inhibited the activity of IkappaB kinase, an enzyme involved in phosphorylation of IkappaB-alpha. Mannitol was unable to affect the induction of iNOS produced by overexpression of RelA in DDT1MF-2 cells, suggesting that this agent does not have additional downstream inhibitory actions on this activated NF-kappaB subunit. Taken together, these data suggest that these hypertonic solutions may prove useful as anti-inflammatory agents, especially against conditions associated with increased NF-kappaB activity.
Collapse
Affiliation(s)
- Sandeep C Pingle
- Department of Pharmacology, Southern Illinois University School of Medicine, Box 19230, Springfield, IL 62974-1222, USA
| | | | | | | | | | | |
Collapse
|
|
24
|
Kjeldsen TH, Rivier C, Lee S, Hansen EW, Christensen JD, Moesby L. Inducible nitric oxide synthase is responsible for nitric oxide release from murine pituicytes. J Neuroendocrinol 2003; 15:250-5. [PMID: 12588513 DOI: 10.1046/j.1365-2826.2003.00985.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
This study investigated whether pituicytes were able to produce and release nitric oxide (NO), and which type of nitric oxide synthase (NOS) would be responsible for this phenomenon. Lipopolysaccharide (LPS) 1 micro g/ml was used as inflammatory mediator. Because pituicytes are known to secrete interleukin (IL)-6 upon stimulation with LPS, this parameter was also investigated. Cultured pituicytes, from 4-week-old male mice, were stimulated with LPS for 6 h or 24 h. At 24 h, there was a significant increase in accumulated nitrite indicating NO formation. In contrast, IL-6 release was already significantly higher 6 h after stimulation and further increased at 24 h. The correlation between accumulated nitrite and secreted IL-6 was 0.84 after 24 h of incubation with LPS. The expression of inducible NOS (iNOS) mRNA in the pituicytes was significantly higher than the control level after 6 h and 24 h of exposure to LPS, with levels at 6 h being significantly higher than those at 24 h. There was no detected expression of endothelial NOS or neuronal NOS mRNA. Cultured pituicytes were also subjected to immunocytochemistry for iNOS protein at 6, 12, and 24 h after stimulation with LPS. Most cells were positive for iNOS, but there were no observable differences with the time points that we used. Collectively, these results show that pituicytes are able to produce NO, and that the inducible form of NOS is responsible for this production. Furthermore, there is a weak correlation between NO and IL-6 released from pituicytes after 24 h of stimulation with LPS.
Collapse
Affiliation(s)
- T H Kjeldsen
- Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, CA, USA.
| | | | | | | | | | | |
Collapse
|
|
25
|
Zhao L, Mason NA, Strange JW, Walker H, Wilkins MR. Beneficial effects of phosphodiesterase 5 inhibition in pulmonary hypertension are influenced by natriuretic Peptide activity. Circulation 2003; 107:234-7. [PMID: 12538421 DOI: 10.1161/01.cir.0000050653.10758.6b] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Phosphodiesterase type 5 (PDE5) inhibitors (eg, sildenafil) are a novel, orally active approach to the treatment of pulmonary arterial hypertension. The role of natriuretic peptides in the response to sildenafil was examined in mice lacking NPR-A, a guanylyl cyclase-linked natriuretic peptide receptor, in which pulmonary hypertension was induced by hypoxia. METHODS AND RESULTS Mice homozygous for NPR-A (NPR-A+/+) and null mutants (NPR-A-/-) were studied. Sildenafil inhibited the pressor response to acute hypoxia in the isolated perfused lungs of both genotypes. This effect was greater in the presence of atrial natriuretic peptide in the perfusate in NPR-A+/+ mice but not NPR-A-/- animals. In vivo, NPR-A mutants had higher basal right ventricular (RV) systolic pressures (RVSPs) than did NPR-A+/+ mice, and this was not affected by 3 weeks of treatment with sildenafil (25 mg x kg(-1) x d(-1)). Both genotypes exhibited a rise in RVSP and RV weight with chronic hypoxia (10% O2 for 21 days); RVSP and RV weight were reduced by continuous sildenafil administration in NPR-A+/+ mice, but only RVSP showed evidence of a response to the drug in NPR-A-/- mice. The effect of sildenafil on hypoxia-induced pulmonary vascular muscularization and cyclic GMP levels was also blunted in NPR-A-/- mice. CONCLUSIONS The natriuretic peptide pathway influences the response to PDE5 inhibition in hypoxia-induced pulmonary hypertension, particularly its effects on RV hypertrophy and vascular remodeling.
Collapse
MESH Headings
- 3',5'-Cyclic-GMP Phosphodiesterases
- Animals
- Atrial Natriuretic Factor/metabolism
- Blood Pressure/drug effects
- Cyclic GMP/metabolism
- Cyclic Nucleotide Phosphodiesterases, Type 5
- Disease Models, Animal
- Guanylate Cyclase/deficiency
- Guanylate Cyclase/genetics
- Homozygote
- Hypertension, Pulmonary/drug therapy
- Hypertension, Pulmonary/etiology
- Hypertension, Pulmonary/physiopathology
- Hypertrophy, Right Ventricular/etiology
- Hypertrophy, Right Ventricular/prevention & control
- Hypoxia/complications
- Hypoxia/physiopathology
- In Vitro Techniques
- Lung/blood supply
- Lung/drug effects
- Lung/physiopathology
- Mice
- Mice, Mutant Strains
- Perfusion
- Phosphodiesterase Inhibitors/pharmacology
- Phosphoric Diester Hydrolases/drug effects
- Phosphoric Diester Hydrolases/metabolism
- Piperazines/pharmacology
- Purines
- Receptors, Atrial Natriuretic Factor/deficiency
- Receptors, Atrial Natriuretic Factor/genetics
- Respiration, Artificial
- Sildenafil Citrate
- Sulfones
- Ventricular Function, Right/drug effects
Collapse
Affiliation(s)
- Lan Zhao
- Section on Clinical Pharmacology, Imperial College School of Science, Technology and Medicine, Hammersmith Hospital, London, England
| | | | | | | | | |
Collapse
|
|
26
|
Burns CP, Kelley EE, Wagner BA, Buettner GR. Role of nitric oxide and membrane phospholipid polyunsaturation in oxidative cell death. Subcell Biochem 2002; 36:97-121. [PMID: 12037992 DOI: 10.1007/0-306-47931-1_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/25/2023]
Affiliation(s)
- C Patrick Burns
- Department of Medicine, University of Iowa College of Medicine, Iowa City, IA, USA
| | | | | | | |
Collapse
|
|
27
|
Miri R, Niknahad H, Vesal G, Shafiee A. Synthesis and calcium channel antagonist activities of 3-nitrooxyalkyl, 5-alkyl 1,4-dihydro-2,6-dimethyl-4-(1-methyl-5-nitro-2-imidazolyl)-3, 5-pyridinedicarboxylates. FARMACO (SOCIETA CHIMICA ITALIANA : 1989) 2002; 57:123-8. [PMID: 11902654 DOI: 10.1016/s0014-827x(01)01183-1] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
A group of racemic 3-[(2-nitrooxyethyl), (3-nitrooxypropyl), (4-nitrooxybutyl) or (1,3-dinitrooxy-2-propyl)], 5-methyl (ethyl or propyl) 1,4-dihydro-2,6-dimethyl-4-(1-methyl-5-nitro-2-imidazolyl)-3,5-pyridinedicarboxylates (18-29) were synthesized using modified Hantzsch reaction that involved the condensation of 2-nitrooxyethyl (8), 3-nitrooxypropyl (9), 4-nitrooxybutyl (10) or 1,3-dinitrooxy-2-propyl (13) acetoacetate with methyl (14), ethyl (15) or isopropyl (16) 3-aminocrotonate and 1-methyl-5-nitroimidazole-2-carboxaldehyde (17). In vitro calcium channel antagonist activities were determined using a guinea pig ileum longitudinal smooth muscle assay. Compounds 18-29 exhibited superior, or equipotent, calcium antagonist activity (IC50= 10(11) - 10(-13) M range) relative to the reference drug nifedipine (IC50 = 1.07 +/- 0.12 x 10(-11) M), which could serve as potential probes to investigate the in vivo release of nitric oxide which induces vascular muscle relaxation.
Collapse
Affiliation(s)
- Ramin Miri
- Department of Medicinal Chemistry, Faculty of Pharmacy, Shiraz University of Medical Science, Iran.
| | | | | | | |
Collapse
|
|
28
|
Zhao L, Mason NA, Morrell NW, Kojonazarov B, Sadykov A, Maripov A, Mirrakhimov MM, Aldashev A, Wilkins MR. Sildenafil inhibits hypoxia-induced pulmonary hypertension. Circulation 2001; 104:424-8. [PMID: 11468204 DOI: 10.1161/hc2901.093117] [Citation(s) in RCA: 312] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND This study investigated the effect of the phosphodiesterase 5 inhibitor sildenafil on the pulmonary vascular response to hypoxia in humans and mice. METHODS AND RESULTS In a randomized, double-blind study, sildenafil 100 mg or placebo was given orally to 10 healthy volunteers 1 hour before breathing 11% O(2) for 30 minutes. Pulmonary artery pressure (PAP) was measured with an indwelling right heart catheter. The acute 56% increase in mean PAP produced by hypoxia during placebo treatment (mean PAP [mean+/-SD mm Hg]: normoxia 16.0+/-2.1 versus hypoxia 25.0+/-4.8) was almost abolished by sildenafil (normoxia 16.0+/-2.1 versus hypoxia 18.0+/-3.6), with no significant effect on systemic blood pressure. In the isolated perfused lung of wild-type and endothelial nitric oxide synthase (eNOS)-deficient mice, sildenafil markedly blunted acute hypoxic pulmonary vasoconstriction. Wild-type mice dosed orally with the drug (25 mg. kg(-1). d(-1)) throughout 3 weeks of exposure to hypoxia (10% O(2)) exhibited a significant reduction in right ventricular systolic pressure (placebo versus sildenafil: 43.3+/-9.9 versus 29.9+/-9.7 mm Hg, P<0.05) coupled with a small reduction in right ventricular hypertrophy and inhibition of pulmonary vascular remodeling. In eNOS mutant mice, sildenafil attenuated the increase in right ventricular systolic pressure but without a significant effect on right ventricular hypertrophy or vascular remodeling. CONCLUSIONS Sildenafil attenuates hypoxia-induced pulmonary hypertension in humans and mice and offers a novel approach to the treatment of this condition. The eNOS-NO-cGMP pathway contributes to the response to sildenafil, but other biochemical sources of cGMP also play a role. Sildenafil has beneficial pulmonary hemodynamic effects even when eNOS activity is impaired.
Collapse
Affiliation(s)
- L Zhao
- Section on Clinical Pharmacology, Imperial College School of Medicine, Hammersmith Hospital, London, UK
| | | | | | | | | | | | | | | | | |
Collapse
|
|
29
|
Miri R, McEwen, CA, Knaus EE. Synthesis and calcium channel modulating effects of modified Hantzsch nitrooxyalkyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(pyridinyl or 2-trifluoromethylphenyl)-5-pyridinecarboxylates. Drug Dev Res 2001. [DOI: 10.1002/ddr.3] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
|
|
30
|
Lin JH, Wang MX, Wei A, Zhu W, Diwan AD, Murrell GA. Temporal expression of nitric oxide synthase isoforms in healing Achilles tendon. J Orthop Res 2001; 19:136-42. [PMID: 11332610 DOI: 10.1016/s0736-0266(00)00019-x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
We investigated the temporal expressions of the three nitric oxide synthase (NOS) isoforms by semi-quantitative polymerase chain reaction (PCR) assays and by immunoblot analysis, following Achilles tendon transection in rats. Four days after injury, there were increases in the steady-state levels of mRNA for all three NOS isoforms, with peaks for the inducible isoform (iNOS) (23-fold increase) at day 4, the endothelial isoform (eNOS) (24-fold increase) at day 7 and the neuronal isoform (bNOS) (seven-fold increase) at day 21. The temporal expression of NOS isoforms at a protein level was consistent with the results at the mRNA level. We have previously shown a five-fold increase in the NOS activity, as detected by 3H-arginine to 3H-citrulline conversion, at day 7 postinjury. These findings indicate that all three NOS isoforms are expressed during tendon healing with differential expression patterns during the various phases of tendon healing. These findings may prove clinically relevant with respect to strategies for regulating tendon healing.
Collapse
Affiliation(s)
- J H Lin
- Orthopaedic Research Institute, St. George Hospital Campus, University of New South Wales, Sydney, Australia
| | | | | | | | | | | |
Collapse
|
|
31
|
Abstract
Nitric oxide is formed from the N-guanido terminal of the amino acid L-arginine and from molecular oxygen by nitric oxide synthase enzymes. L-arginine administration improves the coronary blood flow response to acetylcholine in patients with normal coronary arteries and hypercholesterolemia, reverses the defective endothelium-dependent vasodilation associated with an elevated plasma low-density lipoprotein level or hypercholesterolemia, dilates coronary epicardial arteries and stenoses, enhances nitric oxide generation, and inhibits lesion formation after balloon angioplasty. Stimulation of endogenous nitric oxide production could inhibit atherogenesis, and therefore may be of benefit in patients with risk factors for atherosclerosis.
Collapse
Affiliation(s)
- C Tentolouris
- Cardiology Unit, Hippokration Hospital, Athens University Medical School, Athens, Greece
| | | | | | | | | | | |
Collapse
|
|
32
|
Grifoni SC, Bendhack LM. Relaxation induced by histamine is not endothelium dependent in tail arteries of L-NAME-treated rats. GENERAL PHARMACOLOGY 2000; 34:435-41. [PMID: 11483293 DOI: 10.1016/s0306-3623(01)00081-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
The present study was carried out to evaluate the relaxation induced by histamine in tail arteries of rats after chronic inhibition of nitric oxide (NO) synthesis with the inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) compared to tail arteries of control rats. The maximum relaxation induced by histamine was greater in control (88.09% +/-5.50, n=6) than in L-NAME arteries (47.33% +/-6.40, n=6), although pD(2) values were not different between the two groups (control: 4.89+/-0.08; L-NAME: 4.81+/-0.10). After incubation with 100 microM L-NAME in vitro, the maximum relaxation induced by histamine was only reduced in the control arteries (44.93% +/-2.35, n=6), whereas it had no effect on aortas of rats pretreated with this inhibitor. The incubation with 100 microM L-NAME had the same effect as endothelium removal in both arterial groups. Furthermore, the relaxation induced by histamine was unaffected by indomethacin. The combination of L-NAME and the histamine antagonist cimetidine completely abolished the relaxation induced by histamine in both arterial groups. These results show that when NO synthesis is impaired, the relaxation induced by histamine is endothelium independent, and when NO-synthase is active, the relaxation involves both NO released from endothelial cells and an endothelium-independent mechanism that is sensitive to cimetidine.
Collapse
Affiliation(s)
- S C Grifoni
- Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café s/no., SP-14040-903, Ribeirão Preto, Brazil
| | | |
Collapse
|
|
33
|
Kelley EE, Wagner BA, Buettner GR, Burns CP. Nitric oxide inhibits iron-induced lipid peroxidation in HL-60 cells. Arch Biochem Biophys 1999; 370:97-104. [PMID: 10496982 DOI: 10.1006/abbi.1999.1386] [Citation(s) in RCA: 47] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Nitric oxide ((*)NO) can protect cells against the detrimental effects of reactive oxygen species. Using low-density lipoprotein as well as model systems, it has been demonstrated that (*)NO can serve as a chain-breaking antioxidant to blunt lipid peroxidation. To test the hypothesis that (*)NO can serve as a chain-breaking antioxidant in cell membranes, we examined the effect of (*)NO on iron-induced lipid peroxidation in human leukemia cells. We exposed HL-60 cells to an oxidative stress (20 microM Fe(2+)) and monitored the consumption of oxygen as a measure of lipid peroxidation. Oxygen consumption was arrested by the addition of (*)NO as a saturated aqueous solution. The duration of inhibition of oxygen consumption by (*)NO was concentration-dependent in the 0.4-1.8 microM range. The inhibition ended upon depletion of (*)NO. The addition of (*)NO prior to initiation of peroxidation delayed the onset of peroxidation; the nearer in time it was before Fe(2+) addition, the longer the inhibition. Depletion of cellular glutathione levels by d, l-buthionine-S,R-sulfoximine prior to Fe(2+) addition resulted in a more rapid initial rate of oxygen depletion and a shorter time for the (*)NO-induced inhibition of oxygen consumption. Complementary studies of this iron-induced lipid peroxidation, using thiobarbituric acid reactive substances as a marker, also demonstrated the protective effects of (*)NO. This protection of cells against lipid peroxidation also manifested itself as a reduction in trypan blue uptake, an observation demonstrating the protective effects of (*)NO on membrane integrity. We conclude that (*)NO protects HL-60 human leukemia cells from lipid peroxidation and that this protection ameliorates the toxicity of the oxidation processes initiated by Fe(2+) and dioxygen.
Collapse
Affiliation(s)
- E E Kelley
- Department of Medicine, The University of Iowa College of Medicine, Iowa City, Iowa, 52242, USA
| | | | | | | |
Collapse
|
|
34
|
Khan MA, Thompson CS, Emsley AM, Mumtaz FH, Mikhailidis DP, Angelini GD, Morgan RJ, Jeremy JY. The interaction of homocysteine and copper markedly inhibits the relaxation of rabbit corpus cavernosum: new risk factors for angiopathic erectile dysfunction? BJU Int 1999; 84:720-4. [PMID: 10510122 DOI: 10.1046/j.1464-410x.1999.00253.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVES To explore whether homocysteine (HCy), an independent risk factor for atherosclerosis (the angiopathic effect of which occurs through the generation of superoxide anions and hydrogen peroxide, augmented by copper, the superoxide anions reacting with nitric oxide, NO, to produce peroxynitrite, a highly angiopathic free radical) and copper contribute to erectile dysfunction (ED) through similar mechanisms, by assessing their interactive effects on the relaxation of corpus cavernosum using organ-bath techniques. MATERIALS AND METHODS Cavernosal smooth muscle strips were obtained from adult New Zealand White rabbits and mounted in organ baths. After precontraction with phenylephrine (100 micromol/L), relaxation responses to carbachol or sodium nitroprusside (SNP) were assessed in the presence or absence of HCy and copper. The effects of HCy and copper in the presence of superoxide dismutase or catalase were also investigated. RESULTS HCy alone inhibited carbachol-stimulated (NO-dependent) but not SNP-stimulated relaxations (NO-independent). This effect of HCy was significantly augmented by copper, which alone had no effect. The combined effect of HCy and copper was significantly (P<0.05) reversed by superoxide dismutase or catalase. CONCLUSIONS HCy inhibited NO-mediated cavernosal smooth muscle relaxation, an effect that was potentiated by copper and reversed by superoxide dismutase or catalase. It is therefore proposed that the effect of HCy on cavernosal smooth muscle relaxation is mediated by an interaction between NO and superoxide anions. Moreover, HCy may constitute a new risk factor for angiopathic ED.
Collapse
Affiliation(s)
- M A Khan
- Department of Urology, Royal Free and University College Medical School (University College London), Royal Free Campus & The Royal Free Hampstead NHS Trust, London, UK
| | | | | | | | | | | | | | | |
Collapse
|
|
35
|
Seki T, Naruse M, Naruse K, Yoshimoto T, Tanabe A, Seki M, Tago K, Imaki T, Demura R, Demura H. Induction of heme oxygenase produces load-independent cardioprotective effects in hypertensive rats. Life Sci 1999; 65:1077-86. [PMID: 10499875 DOI: 10.1016/s0024-3205(99)00338-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Although heme oxygenase (HO) has been suggested to be involved in the regulation of cardiovascular function through production of carbon monoxide (CO), the pathophysiological significance of HO in hypertensive organ damage remains unknown. We examined the effects of inducing HO-1 mRNA by stannous chloride (SnCl2) on cardiac hypertrophy in stroke-prone spontaneously hypertensive rats (SHR-SP/Izm). Chronic administration of SnCl2 resulted in a significant decrease in left ventricular (LV) weight/body weight ratio and LV brain natriuretic peptide (BNP) mRNA levels as a marker of cardiac hypertrophy and a significant increase in LV HO-1 mRNA levels and LV cGMP contents in SHR-SP/Izm, while there was no significant change in systemic blood pressure. These results provide the first evidence that induction of HO in the heart attenuates cardiac hypertrophy in load-independent mechanism in genetically hypertensive rats.
Collapse
Affiliation(s)
- T Seki
- Department of Medicine, Institute of Clinical Endocrinology, Tokyo Women's Medical University, Japan
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Abstract
Nitric oxide (NO) is a short-lived molecule with messenger and cytotoxic functions in nervous, cardiovascular, and immune systems. Nitric oxide synthase (NOS), the enzyme responsible for NO synthesis, exists in three different forms: the neuronal (nNOS), present in discrete neuronal populations; the endothelial (eNOS), present in vascular endotheliun, and the inducible isoform (iNOS), expressed in various cell types when activated, including macrophages and glial cells. In this study, we have investigated the possible involvement of NO in Wallerian degeneration and the subsequent regeneration occurring after sciatic nerve ligature, using histochemistry and immunocytochemistry for the three NOS isoforms, at different postinjury periods. Two days after lesion, the three NOS isoforms are overexpressed, reaching their greatest expression during the second week. nNOS is upregulated in dorsal root ganglion neurons, centrifugally transported and accumulated in growing axons. eNOS is overexpressed in vasa nervorum of the distal stump and around ligature, and iNOS is induced in recruited macrophages. These findings indicate that different cellular sources contribute to maintain high levels of NO at the lesion site. The parallelism between NOS inductions and well-known repair phenomena suggests that NO, acting in different ways, may exert a beneficial effect on nerve regeneration.
Collapse
Affiliation(s)
- T González-Hernández
- Department of Cell Biology and Anatomy, School of Medicine, The University of North Carolina at Chapel Hill, USA.
| | | |
Collapse
|
|
37
|
Ziegler JW, Ivy DD, Wiggins JW, Kinsella JP, Clarke WR, Abman SH. Effects of dipyridamole and inhaled nitric oxide in pediatric patients with pulmonary hypertension. Am J Respir Crit Care Med 1998; 158:1388-95. [PMID: 9817684 DOI: 10.1164/ajrccm.158.5.9710117] [Citation(s) in RCA: 71] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Inhaled nitric oxide (iNO) causes selective pulmonary vasodilation by increasing pulmonary vascular levels of cyclic guanosine monophosphate (cGMP). Dipyridamole, a drug with several putative vasodilator mechanisms, is an inhibitor of cGMP-specific phosphodiesterases (PDE5); it therefore has the potential to increase pulmonary vascular cGMP levels, lower pulmonary vascular resistance, augment iNO-induced pulmonary vasodilation, and attenuate excessive pulmonary vasoreactivity. To test dipyridamole in the pulmonary circulation, we studied pediatric patients undergoing cardiac catheterization who had severe resting pulmonary hypertension (Group 1; n = 11) or exaggerated acute hypoxia-induced pulmonary vasoconstriction (Group 2; n = 4). In Group 1, we compared the effects of iNO (20 ppm), dipyridamole (0.6 mg/kg), and combined treatments (iNO + dipyridamole) on pulmonary and systemic hemodynamics. In Group 2 we measured the pulmonary and systemic effects of dipyridamole while the patients were breathing room air and hypoxic gas mixtures (FIO2 = 0.16). One patient in Group 1 had a hypotensive response to dipyridamole and was exluded from study. In the remaining 12 studies done on 10 patients, iNO caused a selective decrease in mean pulmonary artery pressure (Ppa) and indexed pulmonary vascular resistance (PVRI) without affecting mean aortic pressure (Pao) or indexed systemic vascular resistance (SVRI). Dipyridamole decreased PVRI to similar values as did iNO, but this effect was primarily due to an increase in cardiac index (CI), and was not associated with any change in Ppa, and was associated with a decrease in Pao and SVRI. In comparison with individual treatments, combined therapy (iNO + dipyridamole) did not augment pulmonary vasodilation in the group as a whole; however, in 50% of patients, combined therapy decreased PVRI by 20% more than did iNO or dipyridamole alone. In Group 2, Ppa and the pulmonary-to-systemic resistance ratio (Rp/Rs) increased to suprasystemic levels during acute hypoxia. Pretreatment with dipyridamole blunted the increase in Ppa and Rp/Rs during repeat hypoxia, keeping Ppa at a subsystemic level and Rp/Rs < 1. We conclude that: (1) dipyridamole nonselectively reduces PVRI, primarily through an increase in CI; (2) in combination with iNO, dipyridamole augments the decrease in PVRI in some patients; and (3) dipyridamole blunts the severity of acute hypoxic pulmonary vasoconstriction in children with exaggerated hypoxic pressor responses.
Collapse
Affiliation(s)
- J W Ziegler
- Department of Pediatrics, University of Colorado School of Medicine, and Children's Hospital, Denver, Colorado, USA.
| | | | | | | | | | | |
Collapse
|
|
38
|
Ravalli S, Albala A, Ming M, Szabolcs M, Barbone A, Michler RE, Cannon PJ. Inducible nitric oxide synthase expression in smooth muscle cells and macrophages of human transplant coronary artery disease. Circulation 1998; 97:2338-45. [PMID: 9639378 DOI: 10.1161/01.cir.97.23.2338] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND The inducible isoform of the nitric oxide synthase (iNOS) produces large amounts of nitric oxide in response to cytokine stimulation. Previous investigations have demonstrated iNOS expression in the setting of acute and chronic rejection in experimental cardiac transplant models. The goal of this study was to investigate whether iNOS is upregulated in human transplant coronary artery disease (TCAD), a major cause of late mortality after cardiac transplantation. METHODS AND RESULTS We studied 15 patients with TCAD and 10 with normal coronary arteries. In situ hybridization and immunohistochemistry were used in tissue sections to localize iNOS mRNA and protein, respectively. The presence of peroxynitrite was indirectly assessed by immunostaining with an anti-nitrotyrosine antibody. Normal coronary arteries had no evidence of iNOS expression. In contrast, 30 of 36 coronary artery segments with TCAD (83%) were immunostained by the iNOS antibody. The presence of iNOS mRNA was demonstrated in these vessels by in situ hybridization. Specific cell markers identified iNOS-positive cells as neointimal macrophages and smooth muscle cells. Nitrotyrosine immunoreactivity colocalized with iNOS expression in arteries with TCAD, distributed in macrophages and smooth muscle cells. CONCLUSIONS iNOS mRNA and protein are expressed in human arteries with TCAD, where they are associated with extensive nitration of protein tyrosines. These findings indicate that the high-output nitric oxide pathway and possibly the oxidant peroxynitrite might be involved in the process leading to the development of TCAD.
Collapse
Affiliation(s)
- S Ravalli
- Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA
| | | | | | | | | | | | | |
Collapse
|
|
39
|
Affiliation(s)
- M K al-Ali
- University Medicine, Southampton General Hospital, U.K
| | | |
Collapse
|
|
40
|
|
|
41
|
Noguchi K, Takahashi K, Araki H, Higuchi S. Vasodilation profile of CD-832, a novel dihydropyridine derivative in rabbit aorta. GENERAL PHARMACOLOGY 1997; 29:361-6. [PMID: 9378240 DOI: 10.1016/s0306-3623(96)00813-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
1. CD-832, nifedipine and nitrendipine, but not nitroglycerin and nicorandil, inhibited the KCl-induced contraction of rabbit aortas. 2. CD-832, nitroglycerin and nicorandil, but not nifedipine and nitrendipine, inhibited the norepinephrine-induced contraction of aortas. The inhibitory effects of these agents were either potentiated or inhibited by zaprinast or methylene blue, respectively. 3. On the KCl-induced contraction, the duration of CD-832-induced vasodilation was longer than that of nifedipine. Concerning the norepinephrine-induced contraction, the duration of CD-832-induced vasodilation was longer than that of nicorandil. 4. These results suggest that the mechanism of CD-832-induced vasodilation concerns both Ca(2+)-antagonistic action and a nitratelike action. Furthermore, the vasodilation is long lasting.
Collapse
Affiliation(s)
- K Noguchi
- Pharmacology Laboratory, Taisho Pharmaceutical Co., Ltd., Saitama, Japan
| | | | | | | |
Collapse
|
|
42
|
The decomposition of S-nitrosated dithiols: A model for vicinal nitrosothiols in enzymes. Bioorg Med Chem Lett 1997. [DOI: 10.1016/s0960-894x(97)00234-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
|
|
43
|
Affiliation(s)
- J B Dattilo
- Department of Surgery, Medical College of Virginia/Virginia Commonwealth University, Richmond 23298-0108, USA
| | | |
Collapse
|
|
44
|
Khurana VG, Besser M. Pathophysiological basis of cerebral vasospasm following aneurysmal subarachnoid haemorrhage. J Clin Neurosci 1997; 4:122-31. [DOI: 10.1016/s0967-5868(97)90061-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/1995] [Accepted: 11/29/1995] [Indexed: 01/16/2023]
|
|
45
|
Kugiyama K, Ohgushi M, Sugiyama S, Motoyama T, Kawano H, Hirashima O, Yasue H. Supersensitive dilator response to nitroglycerin but not to atrial natriuretic peptide in spastic coronary arteries in coronary spastic angina. Am J Cardiol 1997; 79:606-10. [PMID: 9068517 DOI: 10.1016/s0002-9149(96)00824-7] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
It has been shown that there is the supersensitivity of the dilator effect of nitrovasodilators in the coronary arteries of patients with coronary spastic angina. This study was aimed to elucidate its mechanism(s) by examination of dilator response of spastic coronary arteries to atrial natriuretic peptide (ANP), which is known to dilate arteries by the same final common pathway through cyclic guanosine monophosphate (cGMP) as nitrovasodilators. Effects of infusion of nitroglycerin and ANP on epicardial coronary diameter of left coronary arteries were thus examined by quantitative coronary angiography in 20 patients with coronary spastic angina, who had spasm in left coronary arteries, and in 27 control subjects. Dilator response of coronary diameter to intracoronary infusion of ANP (0.5 microgram/kg) was found to be comparable between spastic coronary arteries and control arteries, whereas dilator response to nitroglycerin (250 micrograms) was enhanced in the spastic arteries compared with control arteries. The results indicate that spastic coronary arteries exhibit supersensitive dilator response to nitroglycerin but not to ANP. There is a possibility that dilator response to cGMP may be comparable between spastic and control coronary arteries and that soluble guanylate cyclase activity and/or conversion of nitric oxide bio-activity from nitroglycerin may be enhanced in spastic coronary arteries.
Collapse
Affiliation(s)
- K Kugiyama
- Division of Cardiology, Kumomoto University School of Medicine, Japan
| | | | | | | | | | | | | |
Collapse
|
|
46
|
Werner J, Rivera J, Fernandez-del Castillo C, Lewandrowski K, Adrie C, Rattner DW, Warshaw AL. Differing roles of nitric oxide in the pathogenesis of acute edematous versus necrotizing pancreatitis. Surgery 1997; 121:23-30. [PMID: 9001547 DOI: 10.1016/s0039-6060(97)90178-1] [Citation(s) in RCA: 49] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
BACKGROUND Microcirculatory changes and leukocyte-endothelial interaction are both central to the pathogenesis of acute pancreatitis. We studied the effects of nitric oxide (NO) donors (intravenous or inhaled) and NO inhibitors, which affect each of these processes, on markers of experimental mild (edematous) and severe (necrotizing) pancreatitis in rats. METHODS Mild pancreatitis was induced with intravenous cerulein (n = 100) and severe pancreatitis with intravenous cerulein and intraductal glycodeoxycholic acid (n = 100). Each group was randomly divided into five equal treatment subgroups: control, NO-synthase substrate L-arginine, NO donor sodium nitroprusside, NO-synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME), and NO-inhalation. After 6 hours edema was measured by a wet/dry weight ratio, and pancreatic injury was quantified by tissue levels of trypsinogen activation peptides (TAPs) and by histologic analysis of inflammation and necrosis. RESULTS In mild pancreatitis (1) both NO donors reduced edema formation (p < 0.001) and also reduced intrapancreatic TAPs (p < 0.03); (2) L-NAME significantly increased tissue TAPs (p < 0.03); and (3) inhaled NO had no effect. In severe pancreatitis (1) both intravenous NO donors reduced edema formation (p < 0.005) and both markedly reduced intrapancreatic TAPs (p < 0.001); (2) L-NAME did not further increase the already high tissue TAPs; and (3) inhaled NO decreased tissue TAPs (p = 0.01). Evaluation of inflammation and necrosis by histologic scoring confirmed the reduction of pancreatic injury by NO donors and worsening with NO-synthase inhibitor. CONCLUSIONS NO donors have a beneficial effect on edema formation in acute pancreatitis but confer more important protection against ectopic trypsinogen activation, which correlates with mortality, inflammation, and necrosis. Although direct microcirculatory action is likely, the salutary effect of inhaled NO in severe pancreatitis may suggest indirect action on circulating leukocytes, which are thought to potentiate tissue injury.
Collapse
Affiliation(s)
- J Werner
- Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA
| | | | | | | | | | | | | |
Collapse
|
|
47
|
Kayigil O, Atahan O, Metin A. Electromyographic Changes of Corpus Cavernosum Due to Papaverine and Nitroprusside in Veno-Occlusive Dysfunction. J Urol 1996. [DOI: 10.1016/s0022-5347(01)65577-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Onder Kayigil
- Urologic Clinics of TCDD Ankara Hospital, Ankara, Turkey
| | - Ozcan Atahan
- Urologic Clinics of TCDD Ankara Hospital, Ankara, Turkey
| | - Ahmet Metin
- Urologic Clinics of TCDD Ankara Hospital, Ankara, Turkey
| |
Collapse
|
|
48
|
Koeppel TA, Lehmann TG, Thies JC, Gehrcke R, Gebhard MM, Herfarth C, Otto G, Post S. Impact of N-acetylcysteine on the hepatic microcirculation after orthotopic liver transplantation. Transplantation 1996; 61:1397-402. [PMID: 8629304 DOI: 10.1097/00007890-199605150-00020] [Citation(s) in RCA: 54] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Recent observations showed an improvement of hepatic macro- and microhemodynamics as well as survival rates after warm ischemia of the liver following treatment with N-acetylcysteine (NAC). In this study we assessed the influence of NAC on the hepatic microcirculation after orthotopic liver transplantation (OLT) using intravital fluorescence microscopy. OLT with simultaneous arterialization was performed in 16 male Lewis rats following cold storage in University of Wisconsin solution for 24 hr. Within the experimental group (n = 8) donors received NAC (400 mg/kg) 25 min before hepatectomy. In addition, high-dose treatment of recipients with NAC (400 mg/kg) was started with reperfusion. Control animals (n = 8) received an equivalent amount of Ringer's solution. Intravital fluorescence microscopy was performed 30-90 min after reperfusion assessing acinar and sinusoidal perfusion, leukocyte-endothelium interaction, and phagocytic activity. Treatment with NAC reduced the number of nonperfused sinusoid from 52.4 +/- 0.8% to 15.7 +/- 0.5% (p = 0.0001) (mean +/- SEM). Furthermore, we achieved a significant reduction of leukocytes adhering to sinusoidal endothelium (per mm2 liver surface) from 351.9 +/- 13.0 in controls to 83.6 +/- 4.2 in the experimental group (P = 0.0001). In postsinusoidal venules, treatment with NAC decreased the number of sticking leukocytes (per mm2 endothelium) from 1098.5 +/- 59.6 to 425.9 +/- 37.7 (P = 0.0001). Moreover, bile flow was significantly increased after therapy with NAC (4.3 +/- 1.2 vs. 2.2 +/- 0.7 ml/90 min x 100g liver) (P < 0.05). Phagocytic activity was not influenced by application of NAC. We conclude that high-dose therapy with NAC in OLT attenuates manifestations of microvascular perfusion failure early after reperfusion and should be considered as a means to reduce reperfusion injury.
Collapse
Affiliation(s)
- T A Koeppel
- Department of General Surgery, University of Heidelberg, Germany
| | | | | | | | | | | | | | | |
Collapse
|
|
49
|
Hardy P, Nuyt AM, Abran D, St-Louis J, Varma DR, Chemtob S. Nitric oxide in retinal and choroidal blood flow autoregulation in newborn pigs: interactions with prostaglandins. Pediatr Res 1996; 39:487-93. [PMID: 8929870 DOI: 10.1203/00006450-199603000-00017] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
The role of nitric oxide (NO) as well as its interaction with prostaglandins (PG) in setting the limits of autoregulation of retinal blood flow (RBF) and choroidal blood flow (ChBF) were studied in newborn pigs (1-5 d old). Blood flows were measured by the microsphere technique. Low and high ocular perfusion pressures (OPP) were induced by inflating balloon-tipped catheters placed at the aortic root and isthmus, respectively. Animals were treated with the NO synthase inhibitors, NG-nitro-L-arginine methyl ester (L-NAME, 1 mg/kg followed by 50 mu g/kg/min; n = 12) or NG-monomethyl-L-arginine (L-NMMA, same dose as L-NAME; n = 3), or with saline (n = 12). In separate animals (n = 42), guanosine 3',5'-cyclic monophosphate (cGMP), the second messenger for NO, and PG were measured at an average OPP of 90 mm Hg and 125 +/- 6 mm Hg; cGMP levels served as an index of NO release. The effect of the NO donor sodium nitroprusside on choroidal vessel diameter was determined using video imaging of isolated eyecup preparations. In control animals RBF was constant only within a range of 30 to 80 mm Hg OPP (r = 0.03, p > 0.9). There was no autoregulation of ChBF which increased as a function of OPP (tau = 0.58-0.72, p < 0.01). L-NAME and L-NMMA prevented a change in RBF and ChBF from 30 to 146 mm Hg [the highest OPP studied (r < 0.3, p > 0.15)] and caused an increase in retinal as well as choroidal vascular resistance as OPP was raised; these agents did not affect ocular blood flow at OPP < 30 mm Hg. Elevated OPP caused increases in cGMP, 6-keto-PGF1alpha, and PGE2 in the choroid (a vascular tissue), which were prevented by L-NAME and L-NMMA. Sodium nitroprusside caused a dilatation of choroidal vessels in isolated eyecup preparations, which was significantly attenuated by indomethacin. Data suggest a role for NO in the autoregulation of RBF and ChBF in the newborn such that a release of NO during a rise in OPP prevents adequate constriction necessary for maintaining RBF and ChBF constant; data also suggest that the vasodilator effect of NO might in part be mediated through a release of PG.
Collapse
Affiliation(s)
- P Hardy
- Department of Pediatrics, Research Center of Hosptal St. Justine, University of Montrial, Quebec, Canada
| | | | | | | | | | | |
Collapse
|
|
50
|
Hicks RC, Golledge J, Mir-Hasseine R, Powell JT. Vasoactive effects of fibrinogen on saphenous vein. Nature 1996; 379:818-20. [PMID: 8587603 DOI: 10.1038/379818a0] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Normal plasma fibrinogen concentrations are critical to haemostasis. Higher fibrinogen concentrations are associated with increasing risk of atherosclerotic disease and with graft stenosis and occlusion after saphenous vein bypass surgery. Vein graft stenosis is characterized by the localized proliferation of intimal smooth muscle cells, causing narrowing of the graft with increased risk of thrombotic occlusion. In rabbit arteries, fibrinopeptide B is reported to have both vasoconstrictor and mitogenic properties. We report here that fibrinopeptides had no vasoactive effects on saphenous vein rings; however, fibrinogen (0-2 microM) affected an endothelium-dependent relaxation, followed by recontraction at higher concentrations. The fibrinogen-mediated relaxation was inhibited by K+-channel blockers and antibodies to ICAM-1. Coupled signalling pathways for the synthesis of vasoactive mediators and mitogens could underlie the association between fibrinogen and the development of vein graft pathology.
Collapse
Affiliation(s)
- R C Hicks
- Cardiovascular & Pulmonary Research Division, Charing Cross & Westminster Medical School, London, UK
| | | | | | | |
Collapse
|