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Shcheblykin DV, Bolgov AA, Pokrovskii MV, Stepenko JV, Tsuverkalova JM, Shcheblykina OV, Golubinskaya PA, Korokina LV. Endothelial dysfunction: developmental mechanisms and therapeutic strategies. RESEARCH RESULTS IN PHARMACOLOGY 2022. [DOI: 10.3897/rrpharmacology.8.80376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Introduction: Every year the importance of the normal functioning of the endothelial layer of the vascular wall in maintaining the health of the body becomes more and more obvious.
The physiological role of the endothelium: The endothelium is a metabolically active organ actively involved in the regulation of hemostasis, modulation of inflammation, maintenance of hemovascular homeostasis, regulation of angiogenesis, vascular tone, and permeability.
Risk factors for the development of endothelial dysfunction: Currently, insufficient bioavailability of nitric oxide is considered the most significant risk factor for endothelial dysfunction.
Mechanisms of development of endothelial dysfunction: The genesis of endothelial dysfunction is a multifactorial process. Among various complex mechanisms, this review examines oxidative stress, inflammation, hyperglycemia, vitamin D deficiency, dyslipidemia, excess visceral fat, hyperhomocysteinemia, hyperuricemia, as well as primary genetic defect of endotheliocytes, as the most common causes in the population underlying the development of endothelial dysfunction.
Markers of endothelial dysfunction in various diseases: This article discusses the main biomarkers of endothelial dysfunction currently used, as well as promising biomarkers in the future for laboratory diagnosis of this pathology.
Therapeutic strategies: Therapeutic approaches to the endothelium in order to prevent or reduce a degree of damage to the vascular wall are briefly described.
Conclusion: Endothelial dysfunction is a typical pathological process involved in the pathogenesis of many diseases. Thus, pharmacological agents with endothelioprotective properties can provide more therapeutic benefits than a drug without such an effect.
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Effect of direct renin inhibition on vascular function after long-term treatment with aliskiren in hypertensive and diabetic patients. J Hypertens 2020; 39:169-180. [PMID: 32740409 DOI: 10.1097/hjh.0000000000002595] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE We tested the hypothesis that chronic treatment with the direct renin inhibitor aliskiren improves vascular function in resistance and conduit arteries of type two diabetic and hypertensive patients. METHOD Sixteen patients with mild essential hypertension and with a previous diagnosis of noninsulin-dependent diabetes mellitus were included in the study. Patients were then randomized to aliskiren (150 mg once daily, n = 9), or ramipril (5 mg once daily, n = 7). Each patient underwent a biopsy of the subcutaneous tissue and small arteries were dissected and mounted on a pressurized micromyograph to evaluate endothelium dependent vasorelaxation in response to acetylcholine ± N omega-nitro-L-arginine methyl ester hydrochloride in vessels precontracted with norepinephrine. Endothelial function has been quantified also in large conduit arteries by flow-mediated dilation. RESULTS A similar office blood pressure-lowering effect was observed with the two drugs, although changes in DBP were not statistically significant in the ramipril group. Aliskiren significantly improved endothelium-dependent relaxation in subcutaneous resistance arteries, as well as increased flow-mediated dilation in conduit arteries, whereas the effects induced by ramipril did not reach statistical significance. Only aliskiren significantly increased the expression of p1177-endothelial nitric oxide synthase in the endothelium. Both aliskiren and ramipril had a negligible effect on markers of oxidative stress. CONCLUSION Aliskiren restored endothelial function and induced a more prompt peripheral vasodilation in hypertensive and diabetic patients possibly through the increased production of nitric oxide via the enhanced expression and function of the active phosphorylated form of endothelial nitric oxide synthase.
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Radenković M, Stojanović M, Prostran M. Calcium Channel Blockers in Restoration of Endothelial Function: Systematic Review and Meta-Analysis of Randomized Controlled Trials. Curr Med Chem 2019; 26:5579-5595. [PMID: 30009701 DOI: 10.2174/0929867325666180713144806] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2017] [Revised: 03/04/2018] [Accepted: 07/06/2018] [Indexed: 12/17/2022]
Abstract
BACKGROUND Clinical evaluation of the Endothelial Function (EF) is becoming an essential step in the quality assessment of cardiovascular risk prevention and rational pharmacotherapy of cardiovascular disorders. The existing pieces of evidence suggested that Calcium Channel Blockers (CCB) can induce positive effects on impaired EF. OBJECTIVE To evaluate the effects of CCB on EF, we performed a meta-analysis of available data from randomized and placebo-controlled or other treatment-controlled clinical studies encompassing effects of CCB on EF, as measured by Flow-Mediated Dilation (FMD) of the brachial artery. METHODS The relevant clinical studies were searched by systematic exploration of the appropriate databases until November 30, 2017. A random-effect model was conducted. The primary outcome was the percentage change in FMD between the baseline and the final levels in response to investigated drugs. RESULTS Fifteen randomized clinical studies with 33 arms were identified. CCB improved FMD more pronounced than thiazide diuretics - TD (3 studies, 157 participants, WMD=2.08%, 95% CI=0.35-3.80%; P=0.02). Oppositely, ACE Inhibitors (ACEI) and Angiotensin Receptor Blockers (ARB) notably improved FMD if compared to CCB (CCB vs. ACEI: 5 studies, 533 participants, WMD = -1.62%, 95% CI = -2.74% to -0.50%; P=0.005; and CCB vs. ARB: 9 studies, 669 participants, WMD = -1.52%, 95% CI = -2.22% to -0.81%; P=0.0001). CCB effects on EF were similar to those evoked by beta blockers or placebo. CONCLUSION CCB improved EF to a more prominent extent only if paralleled to TD, while inversely; ACEI and ARB were more effective in augmenting FMD.
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Affiliation(s)
- Miroslav Radenković
- Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Marko Stojanović
- Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Milica Prostran
- Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
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Altarejo Marin T, Machado Bertassoli B, Alves de Siqueira de Carvalho A, Feder D. The use of aliskiren as an antifibrotic drug in experimental models: A systematic review. Drug Dev Res 2019; 81:114-126. [PMID: 31605544 DOI: 10.1002/ddr.21610] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 08/21/2019] [Accepted: 09/13/2019] [Indexed: 11/12/2022]
Abstract
Aliskiren is an oral antihypertensive medication that acts by directly inhibiting renin. High levels of circulating renin and prorenin activate the pathological signaling pathway of fibrosis. This drug also reduces oxidative stress. Thus, the aim of this systematic review is to analyze experimental studies that show the actions of aliskiren on fibrosis. PubMed and LILACS databases were consulted using the keywords aliskiren and fibrosis within the period between 2005 and 2017. Fifty-three articles were analyzed. In the heart, aliskiren attenuated remodeling, hypertrophy, inflammatory cytokines, collagen deposition, and oxidative stress. In the kidneys, there was a reduction in interstitial fibrosis, the infiltration of inflammatory cells, apoptosis, proteinuria, and in the recruitment of macrophages. In diabetic models, an improvement in the albumin/creatinine relationship and in the insulin pathway in skeletal muscles was observed; aliskiren was beneficial to pancreatic function and glucose tolerance. In the liver, aliskiren reduced fibrosis, steatosis, inflammatory cytokines, and collagen deposition. In the lung and peritoneal tissues, there was a reduction in fibrosis. Many studies have reported on the beneficial effects of aliskiren on endothelial function and arterial rigidity. A reduction in fibrosis in different organs is cited by many authors, which complies with the results found in this review. However, studies diverge on the use of the drug in diabetic patients. Aliskiren has antifibrotic potential in several experimental models, interfering with the levels of fibrogenic cytokines and oxidative stress. Therefore, its use in diseases in which fibrosis plays an important pathophysiological role is suggested.
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Affiliation(s)
| | | | | | - David Feder
- Department of Phamacology, Faculdade de Medicina do ABC, Santo André, SP, Brazil
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Serhiyenko VA, Serhiyenko AA. Cardiac autonomic neuropathy: Risk factors, diagnosis and treatment. World J Diabetes 2018; 9:1-24. [PMID: 29359025 PMCID: PMC5763036 DOI: 10.4239/wjd.v9.i1.1] [Citation(s) in RCA: 124] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2017] [Revised: 12/09/2017] [Accepted: 12/29/2017] [Indexed: 02/06/2023] Open
Abstract
Cardiac autonomic neuropathy (CAN) is a serious complication of diabetes mellitus (DM) that is strongly associated with approximately five-fold increased risk of cardiovascular mortality. CAN manifests in a spectrum of things, ranging from resting tachycardia and fixed heart rate (HR) to development of "silent" myocardial infarction. Clinical correlates or risk markers for CAN are age, DM duration, glycemic control, hypertension, and dyslipidemia (DLP), development of other microvascular complications. Established risk factors for CAN are poor glycemic control in type 1 DM and a combination of hypertension, DLP, obesity, and unsatisfactory glycemic control in type 2 DM. Symptomatic manifestations of CAN include sinus tachycardia, exercise intolerance, orthostatic hypotension (OH), abnormal blood pressure (BP) regulation, dizziness, presyncope and syncope, intraoperative cardiovascular instability, asymptomatic myocardial ischemia and infarction. Methods of CAN assessment in clinical practice include assessment of symptoms and signs, cardiovascular reflex tests based on HR and BP, short-term electrocardiography (ECG), QT interval prolongation, HR variability (24 h, classic 24 h Holter ECG), ambulatory BP monitoring, HR turbulence, baroreflex sensitivity, muscle sympathetic nerve activity, catecholamine assessment and cardiovascular sympathetic tests, heart sympathetic imaging. Although it is common complication, the significance of CAN has not been fully appreciated and there are no unified treatment algorithms for today. Treatment is based on early diagnosis, life style changes, optimization of glycemic control and management of cardiovascular risk factors. Pathogenetic treatment of CAN includes: Balanced diet and physical activity; optimization of glycemic control; treatment of DLP; antioxidants, first of all α-lipoic acid (ALA), aldose reductase inhibitors, acetyl-L-carnitine; vitamins, first of all fat-soluble vitamin B1; correction of vascular endothelial dysfunction; prevention and treatment of thrombosis; in severe cases-treatment of OH. The promising methods include prescription of prostacyclin analogues, thromboxane A2 blockers and drugs that contribute into strengthening and/or normalization of Na+, K+-ATPase (phosphodiesterase inhibitor), ALA, dihomo-γ-linolenic acid (DGLA), ω-3 polyunsaturated fatty acids (ω-3 PUFAs), and the simultaneous prescription of ALA, ω-3 PUFAs and DGLA, but the future investigations are needed. Development of OH is associated with severe or advanced CAN and prescription of nonpharmacological and pharmacological, in the foreground midodrine and fludrocortisone acetate, treatment methods are necessary.
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Affiliation(s)
- Victoria A Serhiyenko
- Department of Endocrinology, Lviv National Medical University Named by Danylo Halitsky, Lviv 79010, Ukraine
| | - Alexandr A Serhiyenko
- Department of Endocrinology, Lviv National Medical University Named by Danylo Halitsky, Lviv 79010, Ukraine
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Pantzaris ND, Karanikolas E, Tsiotsios K, Velissaris D. Renin Inhibition with Aliskiren: A Decade of Clinical Experience. J Clin Med 2017; 6:jcm6060061. [PMID: 28598381 PMCID: PMC5483871 DOI: 10.3390/jcm6060061] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Revised: 05/24/2017] [Accepted: 06/03/2017] [Indexed: 11/29/2022] Open
Abstract
The renin-angiotensin-aldosterone system (RAAS) plays a key role in the pathophysiology of arterial hypertension as well as in more complex mechanisms of cardiovascular and renal diseases. RAAS-blocking agents like angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers, have long been key components in the treatment of essential hypertension, heart failure, diabetic nephropathy, and chronic kidney disease, showing benefits well beyond blood pressure reduction. Renin blockade as the first step of the RAAS cascade finally became possible in 2007 with the approval of aliskiren, the first orally active direct renin inhibitor available for clinical use and the newest antihypertensive agent on the market. In the last decade, many clinical trials and meta-analyses have been conducted concerning the efficacy and safety of aliskiren in comparison to other antihypertensive agents, as well as the efficacy and potential clinical use of various combinations. Large trials with cardiovascular and renal endpoints attempted to show potential benefits of aliskiren beyond blood pressure lowering, as well as morbidity and mortality outcomes in specific populations such as diabetics, heart failure patients, and post-myocardial infarction individuals. The purpose of this review is to present the currently available data regarding established and future potential clinical uses of aliskiren.
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Affiliation(s)
| | - Evangelos Karanikolas
- Department of Medicine, Schools of Health Sciences, University of Athens75 Mikras Asias str., Athens 11527, Greece.
| | | | - Dimitrios Velissaris
- Internal Medicine Department, University Hospital of Patras, Rio Achaia 26504, Greece.
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Su JB. Vascular endothelial dysfunction and pharmacological treatment. World J Cardiol 2015; 7:719-741. [PMID: 26635921 PMCID: PMC4660468 DOI: 10.4330/wjc.v7.i11.719] [Citation(s) in RCA: 127] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Revised: 06/23/2015] [Accepted: 09/18/2015] [Indexed: 02/06/2023] Open
Abstract
The endothelium exerts multiple actions involving regulation of vascular permeability and tone, coagulation and fibrinolysis, inflammatory and immunological reactions and cell growth. Alterations of one or more such actions may cause vascular endothelial dysfunction. Different risk factors such as hypercholesterolemia, homocystinemia, hyperglycemia, hypertension, smoking, inflammation, and aging contribute to the development of endothelial dysfunction. Mechanisms underlying endothelial dysfunction are multiple, including impaired endothelium-derived vasodilators, enhanced endothelium-derived vasoconstrictors, over production of reactive oxygen species and reactive nitrogen species, activation of inflammatory and immune reactions, and imbalance of coagulation and fibrinolysis. Endothelial dysfunction occurs in many cardiovascular diseases, which involves different mechanisms, depending on specific risk factors affecting the disease. Among these mechanisms, a reduction in nitric oxide (NO) bioavailability plays a central role in the development of endothelial dysfunction because NO exerts diverse physiological actions, including vasodilation, anti-inflammation, antiplatelet, antiproliferation and antimigration. Experimental and clinical studies have demonstrated that a variety of currently used or investigational drugs, such as angiotensin-converting enzyme inhibitors, angiotensin AT1 receptors blockers, angiotensin-(1-7), antioxidants, beta-blockers, calcium channel blockers, endothelial NO synthase enhancers, phosphodiesterase 5 inhibitors, sphingosine-1-phosphate and statins, exert endothelial protective effects. Due to the difference in mechanisms of action, these drugs need to be used according to specific mechanisms underlying endothelial dysfunction of the disease.
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Cohen-Barak E, Sah M, Kerner M, Rozenman D, Ziv M. Impact of antipsoriatic therapy on endothelial function. Br J Dermatol 2015; 173:1440-6. [DOI: 10.1111/bjd.14076] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/11/2015] [Indexed: 02/02/2023]
Affiliation(s)
- E. Cohen-Barak
- Department of Dermatology; Haemek Medical Center; Afula 18101 Israel
| | - M. Sah
- Department of Dermatology; Haemek Medical Center; Afula 18101 Israel
| | - M. Kerner
- Department of Dermatology; Haemek Medical Center; Afula 18101 Israel
| | - D. Rozenman
- Department of Dermatology; Haemek Medical Center; Afula 18101 Israel
| | - M. Ziv
- Department of Dermatology; Haemek Medical Center; Afula 18101 Israel
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Yildiz A, Soydinc S. Diastolic dysfunction and endothelial dysfunction in systemic lupus erythematosus. Rheumatol Int 2015; 35:1281-2. [PMID: 25614160 DOI: 10.1007/s00296-015-3220-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2014] [Accepted: 01/13/2015] [Indexed: 10/24/2022]
Affiliation(s)
- Ali Yildiz
- Department of Cardiology, School of Medicine, Hacettepe University, 06100, Ankara, Turkey,
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Ozeki A, Amiya E, Watanabe M, Hosoya Y, Takata M, Watanabe A, Kawarasaki S, Nakao T, Watanabe S, Omori K, Yamada N, Tahara Y, Hirata Y, Nagai R. Effect of Add-on Aliskiren to Type 1 Angiotensin Receptor Blocker Therapy on Endothelial Function and Autonomic Nervous System in Hypertensive Patients With Ischemic Heart Disease. J Clin Hypertens (Greenwich) 2014; 16:591-8. [DOI: 10.1111/jch.12366] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2014] [Revised: 05/27/2014] [Accepted: 05/28/2014] [Indexed: 12/01/2022]
Affiliation(s)
- Atsuko Ozeki
- Department of Cardiovascular Medicine; Graduate School of Medicine; the University of Tokyo; Tokyo Japan
| | - Eisuke Amiya
- Department of Cardiovascular Medicine; Graduate School of Medicine; the University of Tokyo; Tokyo Japan
| | - Masafumi Watanabe
- Department of Cardiovascular Medicine; Graduate School of Medicine; the University of Tokyo; Tokyo Japan
| | - Yumiko Hosoya
- Department of Cardiovascular Medicine; Graduate School of Medicine; the University of Tokyo; Tokyo Japan
| | - Munenori Takata
- Department of Cardiovascular Medicine; Graduate School of Medicine; the University of Tokyo; Tokyo Japan
| | - Aya Watanabe
- Department of Cardiovascular Medicine; Graduate School of Medicine; the University of Tokyo; Tokyo Japan
| | - Shuichi Kawarasaki
- Department of Cardiovascular Medicine; Graduate School of Medicine; the University of Tokyo; Tokyo Japan
| | - Tomoko Nakao
- Department of Cardiovascular Medicine; Graduate School of Medicine; the University of Tokyo; Tokyo Japan
| | - Shogo Watanabe
- Department of Pathophysiological Laboratory Sciences; Nagoya University Graduate School of Medicine; Nagoya Japan
| | - Kazuko Omori
- Department of Pathophysiological Laboratory Sciences; Nagoya University Graduate School of Medicine; Nagoya Japan
| | - Namie Yamada
- Department of Translational Research Center; the University of Tokyo; Tokyo Japan
| | - Yukiko Tahara
- Department of Translational Research Center; the University of Tokyo; Tokyo Japan
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