|
1
|
Rosenberg AJ, Fernandez A, Moody AW, Sprick JD. Remote ischemic preconditioning attenuates ischemia-reperfusion injury-induced reductions in vascular function through release of endogenous opioids. J Appl Physiol (1985) 2025; 138:571-576. [PMID: 39819103 DOI: 10.1152/japplphysiol.00913.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 12/12/2024] [Accepted: 01/10/2025] [Indexed: 01/19/2025] Open
Abstract
Remote ischemic preconditioning (RIPC) is a therapy characterized by repeated bouts of limb ischemia and reperfusion. RIPC protects against ischemia-reperfusion injury (IRI), and preclinical studies suggest that this is mediated through the release of endogenous opioids. We aimed to interrogate the role of endogenous opioids in RIPC-signaling in humans, using an arm model of IRI. We hypothesized that RIPC would attenuate IRI-induced reductions in brachial artery flow-mediated dilation (FMD) and that this would be prevented by systemic opioid receptor blockade. Eleven healthy adults (8 M/3 F, age = 28 ± 8 yr) completed three experimental visits in which IRI was induced via 20-min upper arm ischemia and 20-min reperfusion achieved via upper arm cuff inflation to 250 mmHg. FMD was measured at rest and again following IRI. During the control condition, RIPC was not performed. During the RIPC condition, RIPC was performed on the contralateral arm via four cycles of 5-min cuff inflation (250 mmHg) with 5-min reperfusion. During the opioid receptor blockade condition (naloxone), RIPC was performed in the presence of systemic opioid receptor blockade via intranasal naloxone (4 mg), which was administered during the first 5-min cycle of RIPC. The change in FMD from baseline versus post-IRI was compared between visits via a two-way repeated measures ANOVA (factor 1: time, factor 2: condition) followed by Tukey post hoc tests. IRI reduced FMD during the control (pre = 6.1 ± 2.4%, post = 3.5 ± 2.8%, P < 0.001) and naloxone (pre = 6.6 ± 2.7%, post = 3.5 ± 1.9%, P < 0.001) conditions but not during the RIPC condition (pre = 5.9 ± 2.2%, post = 4.9 ± 2.8%, P = 0.14). These findings demonstrate that RIPC provides vascular protection from IRI in humans through an opioid-dependent mechanism.NEW & NOTEWORTHY Remote ischemic preconditioning (RIPC) is a cardioprotective therapy characterized by brief cycles of limb ischemia and reperfusion. We demonstrate that a single bout of arm RIPC provides protection from ischemia-reperfusion injury-induced reductions in vascular function in healthy adults. This protection was attenuated when RIPC was administered in the presence of systemic opioid-receptor blockade via intranasal naloxone. These findings suggest that endogenous opioids contribute to RIPC-induced protection of vascular function in humans.
Collapse
Affiliation(s)
- Alexander J Rosenberg
- Department of Physiology, Midwestern University, Downers Grove, Illinois, United States
| | - Alexander Fernandez
- Department of Kinesiology, Health Promotion and Recreation, University of North Texas, Denton, Texas, United States
| | - Ayrion W Moody
- Department of Kinesiology, Health Promotion and Recreation, University of North Texas, Denton, Texas, United States
| | - Justin D Sprick
- Department of Kinesiology, Health Promotion and Recreation, University of North Texas, Denton, Texas, United States
| |
Collapse
|
|
2
|
Sirbu C. The Role of Endogenous Opioids in Cardioprotection. ADVANCES IN NEUROBIOLOGY 2024; 35:381-395. [PMID: 38874733 DOI: 10.1007/978-3-031-45493-6_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2024]
Abstract
The opioid system involves opioid receptors (OPRs) and endogenous opioid peptides.This chapter will focus on the distribution of OPRs in the cardiovascular system, the expression pattern in the heart, the activation by opioid peptides, and the effects of OPRs activation with potential relevance in cardiovascular performance. In the heart, OPRs are co-expressed with beta adrenergic receptors (β-ARs) in the G-protein-coupled receptor (GPCR) superfamily, functionally cross-talk with β-Ars and modify catecholamine-induced effects. They are involved in cardiac contractility, energy metabolism, myocyte survival or death, vascular resistance. The effects of the opioid system in the regulation of systemic circulation at both the central and peripheral level are presented. The pathways are discussed under physiological (i.e., aging) and pathological conditions (atherosclerosis, heart failure, essential hypertension, ischemic stress). Stimulation of OPRs not only inhibits cardiac excitation-contraction coupling, but also protects the heart against hypoxic and ischemic injury. An enhanced sensitivity to opioids of endocrine organs and neuronal systems is operative in hypertensive patients. The opioid system can be pharmacologically engaged to selectively mimic these responses via cardiac and nervous signaling. The clinical opportunities for the use of cardioprotective effects of opioids require future investigations to provide more specific details of the impact on cardiac performance and electrophysiological properties.
Collapse
Affiliation(s)
- Cristina Sirbu
- Department of Cardiac Surgery and Transplantation, University Hospital Nancy-Brabois, Nancy, France
| |
Collapse
|
|
3
|
Blaine AT, van Rijn RM. Receptor expression and signaling properties in the brain, and structural ligand motifs that contribute to delta opioid receptor agonist-induced seizures. Neuropharmacology 2023; 232:109526. [PMID: 37004753 PMCID: PMC11078570 DOI: 10.1016/j.neuropharm.2023.109526] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 03/10/2023] [Accepted: 03/28/2023] [Indexed: 04/03/2023]
Abstract
The δ opioid receptor (δOR) is a therapeutic target for the treatment of various neurological disorders, such as migraines, chronic pain, alcohol use, and mood disorders. Relative to μ opioid receptor agonists, δOR agonists show lower abuse liability and may be potentially safer analgesic alternatives. However, currently no δOR agonists are approved for clinical use. A small number of δOR agonists reached Phase II trials, but ultimately failed to progress due to lack of efficacy. One side effect of δOR agonism that remains poorly understood is the ability of δOR agonists to produce seizures. The lack of a clear mechanism of action is partly driven by the fact that δOR agonists range in their propensity to induce seizure behavior, with multiple δOR agonists reportedly not causing seizures. There is a significant gap in our current understanding of why certain δOR agonists are more likely to induce seizures, and what signal-transduction pathway and/or brain area is engaged to produce these seizures. In this review we provide a comprehensive overview of the current state of knowledge of δOR agonist-mediated seizures. The review was structured to highlight which agonists produce seizures, which brain regions have been implicated and which signaling mediators have been examined in this behavior. Our hope is that this review will spur future studies that are carefully designed and aimed to solve the question why certain δOR agonists are seizurogenic. Obtaining such insight may expedite the development of novel δOR clinical candidates without the risk of inducing seizures. This article is part of the Special Issue on "Opioid-induced changes in addiction and pain circuits".
Collapse
Affiliation(s)
- Arryn T Blaine
- Purdue University, Department of Medicinal Chemistry and Molecular Pharmacology, West Lafayette, IN, 47907, USA; Purdue University Interdisciplinary Life Science graduate program, West Lafayette, IN, 47907, USA
| | - Richard M van Rijn
- Purdue University, Department of Medicinal Chemistry and Molecular Pharmacology, West Lafayette, IN, 47907, USA; Purdue Institute for Integrative Neuroscience, West Lafayette, IN, 47907, USA; Purdue Institute for Drug Discovery, West Lafayette, IN, 47907, USA; Septerna Inc., South San Francisco, CA, 94080, USA.
| |
Collapse
|
|
4
|
Blaine AT, Miao Y, Yuan J, Palant S, Liu RJ, Zhang ZY, van Rijn RM. Exploration of beta-arrestin isoform signaling pathways in delta opioid receptor agonist-induced convulsions. Front Pharmacol 2022; 13:914651. [PMID: 36059958 PMCID: PMC9428791 DOI: 10.3389/fphar.2022.914651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 07/13/2022] [Indexed: 11/17/2022] Open
Abstract
The δ-opioid receptor (δOR) has been considered as a therapeutic target in multiple neurological and neuropsychiatric disorders particularly as δOR agonists are deemed safer alternatives relative to the more abuse-liable µ-opioid receptor drugs. Clinical development of δOR agonists, however, has been challenging in part due to the seizure-inducing effects of certain δOR agonists. Especially agonists that resemble the δOR-selective agonist SNC80 have well-established convulsive activity. Close inspection suggests that many of those seizurogenic δOR agonists efficaciously recruit β-arrestin, yet surprisingly, SNC80 displays enhanced seizure activity in β-arrestin 1 knockout mice. This finding led us to hypothesize that perhaps β-arrestin 1 is protective against, whereas β-arrestin 2 is detrimental for δOR-agonist-induced seizures. To investigate our hypothesis, we characterized three different δOR agonists (SNC80, ADL5859, ARM390) in cellular assays and in vivo in wild-type and β-arrestin 1 and β-arrestin 2 knockout mice for seizure activity. We also investigated downstream kinases associated with β-arrestin-dependent signal transduction. We discovered that δOR agonist-induced seizure activity strongly and positively correlates with β-arrestin 2 efficacy for the agonist, but that indirect inhibition of ERK activation using the MEK inhibitor SL327 did not inhibit seizure potency and duration. Inhibition of the PI3K/AKT/mTOR signaling with honokiol but not PQR530, attenuated SNC80 seizure duration in β-arrestin 1 knockout, but honokiol did not reduce SNC80-induced seizures in wild-type mice. Ultimately, our results indicate that β-arrestin 2 is correlated with δOR agonist-induced seizure intensity, but that global β-arrestin 1 knockout mice are a poor model system to investigate their mechanism of action.
Collapse
Affiliation(s)
- Arryn T. Blaine
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, United States
- Purdue Interdisciplinary Life Sciences Graduate Program, West Lafayette, IN, United States
| | - Yiming Miao
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, United States
| | - Jinling Yuan
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, United States
| | - Sophia Palant
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, United States
| | - Rebecca J. Liu
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, United States
| | - Zhong-Yin Zhang
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, United States
- Purdue Institute for Drug Discovery, West Lafayette, IN, United States
- Purdue University Cancer Center, West Lafayette, IN, United States
| | - Richard. M. van Rijn
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, United States
- Purdue Institute for Drug Discovery, West Lafayette, IN, United States
- Purdue University Cancer Center, West Lafayette, IN, United States
- Purdue Institute for Integrative Neuroscience, West Lafayette, IN, United States
- *Correspondence: Richard. M. van Rijn,
| |
Collapse
|
|
5
|
Naryzhnaya N, Khaliulin I, Lishmanov Y, Suleiman M, Tsibulnikov S, Kolar F, Maslov L. Participation of opioid receptors in the cytoprotective effect of chronic normobaric hypoxia. Physiol Res 2019; 68:245-253. [DOI: 10.33549/physiolres.933938] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
We studied the role of the delta, micro, and kappa opioid receptor (OR) subtypes in the cardioprotective effect of chronic continuous normobaric hypoxia (CNH) in the model of acuteanoxia-reoxygenation of isolated cardiomyocytes. Adaptation of rats to CNH was performed by their exposure to atmosphere containing 12% of O(2) for 21 days. Anoxia-reoxygenation of cardiomyocytes isolated from normoxiccontrol rats caused the death of 51 % of cells and lactate dehydrogenase (LDH) release. Adaptation of rats to CNH resulted in the anoxia/reoxygenation-induced cardiomyocyte death of only 38 %, and reduced the LDH release by 25 %. Pre-incubation of the cells with either the non-selective OR (opioid receptor) blocker naloxone (300 nM/l), the delta OR antagonist TIPP(psi) (30 nM/l), the selective delta(2) OR antagonist naltriben (1 nM/l) or the micro OR antagonist CTAP (100 nM/l) for 25 minutes before anoxia abolished the reduction of cell death and LDH release afforded by CNH. The antagonist of delta(1) OR BNTX (1 nM/l) or the kappa OR antagonist nor-binaltorphimine (3 nM/l) did not influence the cytoprotective effects of CNH. Taken together, the cytoprotective effect of CNH is associated with the activation of the delta(2) and micro OR localized on cardiomyocytes.
Collapse
Affiliation(s)
- N.V. Naryzhnaya
- Laboratory of Experimental Cardiology, Cardiology Research Institute, Tomsk National Research Medical Centre, Russian Academy of Sciences, Tomsk, Russia.
| | | | | | | | | | | | | |
Collapse
|
|
6
|
Abstract
The opioid system is activated in heart failure, which may be cardioprotective but may also be counter-regulatory. Recently, systemic proenkephalin activation has been investigated in various conditions predicting mortality and kidney injury. In acute heart failure, proenkephalin independently predicts mortality and heart failure rehospitalization in addition to traditional risk markers. It also predicts worsening renal function, increasingly recognized as an important risk predictor for poor outcome in heart failure. This article explores the role of enkephalins and delta-opioid receptors in the heart, then reviews studies measuring proenkephalin levels in the circulation and their associations with prognosis.
Collapse
Affiliation(s)
- Daniel Chu Siong Chan
- Department of Cardiovascular Sciences, NIHR Biomedical Research Centre, University of Leicester, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK
| | - Thong Huy Cao
- Department of Cardiovascular Sciences, NIHR Biomedical Research Centre, University of Leicester, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK; Department of General Internal Medicine, University of Medicine and Pharmacy, Hong Bang Street, Ward 11, District 5, Ho Chi Minh City, Vietnam
| | - Leong Loke Ng
- Department of Cardiovascular Sciences, NIHR Biomedical Research Centre, University of Leicester, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK.
| |
Collapse
|
|
7
|
da Luz VF, Otsuki DA, Gonzalez MMC, Negri EM, Caldini EG, Damaceno-Rodrigues NR, Malbouisson LMS, Viana BG, Vane MF, Carmona MJC. Myocardial protection induced by fentanyl in pigs exposed to high-dose adrenaline. Clin Exp Pharmacol Physiol 2015; 42:1098-107. [DOI: 10.1111/1440-1681.12456] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2015] [Revised: 06/30/2015] [Accepted: 07/09/2015] [Indexed: 01/02/2023]
Affiliation(s)
| | - Denise Aya Otsuki
- University of Sao Paulo Medical School; Department of Anaesthesiology; São Paulo Brazil
| | | | | | | | | | | | | | | | | |
Collapse
|
|
8
|
Chien CY, Chien CT, Wang SS. Progressive thermopreconditioning attenuates rat cardiac ischemia/reperfusion injury by mitochondria-mediated antioxidant and antiapoptotic mechanisms. J Thorac Cardiovasc Surg 2014; 148:705-13. [PMID: 24507988 DOI: 10.1016/j.jtcvs.2013.12.065] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Revised: 11/12/2013] [Accepted: 12/05/2013] [Indexed: 12/23/2022]
Abstract
OBJECTIVES Progressive thermal preconditioning (PTP) provides vascular protection with less hemodynamic fluctuations, endoplasmic reticulum (ER), and oxidative stress compared with whole body hyperthermia. We suggest PTP might efficiently diminish cardiac ischemia/reperfusion-induced apoptosis and autophagy injury. METHODS A total of 67 male Wistar rats were divided into a non-PTP control group, 24 or 72 hours after a single cycle or 3 consecutive cycles of PTP in a 42°C water bath (1-24, 1-72, 3-24, and 3-72 groups). We measured the cardiac O2(-) amount in vivo in response to left anterior descending coronary artery ligation for 2 hours and reperfusion for 3 hours. Cardiac function and injury were determined by microcirculation, electrocardiography, and infarct size. The PTP-induced protective effects on nicotinamide adenine dinucleotide phosphate oxidase gp91-mediated oxidative stress, ER stress, and apoptosis- and autophagy-related mechanisms were examined using Western blot and immunohistochemistry. RESULTS Coronary arterial ischemia/reperfusion depressed cardiac microcirculation, induced ST-segment elevation and increased infarct size in non-PTP and PTP rats. Ischemia/reperfusion enhanced the cardiac O2(-) levels by enhanced nicotinamide adenine dinucleotide phosphate oxidase gp91 expression, cytosolic cytochrome C release, and decreased mitochondrial Bcl-2 expression. Cardiac injury activated ER stress-78-kDa glucose-regulated protein expression, increased the Bax/Bcl-2 ratio, cleaved caspase 3 expression and poly-(ADP-ribose)-polymerase fragments, leading to apoptosis formation, and promoted LC3-II expression, resulting in autophagy formation. PTP treatment elevated heat shock protein 70, heat shock protein 32, Bcl-2, Bcl-xL, and manganese superoxide dismutase in the rat heart, especially in the 3-72 group. PTP treatment significantly restored cardiac microcirculation, decreased oxidative stress, ER stress, apoptosis, autophagy, and infarct size. CONCLUSIONS PTP significantly reduced cardiac ischemia/reperfusion injury by upregulating antioxidant, antiapoptotic, and antiautophagic mechanisms.
Collapse
Affiliation(s)
- Chen-Yen Chien
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan, Republic of China; Department of Surgery, Mackay Memorial Hospital and Mackay Medical College, Taipei, Taiwan, Republic of China; Mackay Medicine, Nursing and Management College, New Taipei City, Taiwan, Republic of China
| | - Chiang-Ting Chien
- Department of Biological Science, National Taiwan Normal University, Taipei, Taiwan, Republic of China.
| | - Shoei-Shen Wang
- Department of Surgery, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan, Republic of China
| |
Collapse
|
|
9
|
Dragasis S, Bassiakou E, Iacovidou N, Papadimitriou L, Andreas Steen P, Gulati A, Xanthos T. The role of opioid receptor agonists in ischemic preconditioning. Eur J Pharmacol 2013; 720:401-8. [DOI: 10.1016/j.ejphar.2013.10.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2013] [Revised: 09/20/2013] [Accepted: 10/01/2013] [Indexed: 12/24/2022]
|
|
10
|
Fuardo M, Lemoine S, Lo Coco C, Hanouz JL, Massetti M. [D-Ala2,D-Leu5]-enkephalin (DADLE) and morphine-induced postconditioning by inhibition of mitochondrial permeability transition pore, in human myocardium. Exp Biol Med (Maywood) 2013; 238:426-32. [PMID: 23436882 DOI: 10.1177/1535370212474602] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
The aim of the study was to examine the cardioprotective effect of morphine and Delta 2 opioid D-Ala2-Leu5 enkephalin(DADLE) administered, at early reoxygenation, in isolated human myocardium exposed to hypoxia–reoxygenation. Then,we tested the involvement of mitochondrial permeability transition pore in morphine and DADLE-induced postconditioning.Human right atrial trabeculae were obtained during cardiac surgery (coronary artery bypass and aortic valve replacement).Isometrically contracting isolated human right atrial trabeculae were exposed to 30-min hypoxia and 60-min reoxygenation(control group). In treatment groups, morphine 0.5 mmol, DADLE 10 nmol, DADLE 50 nmol and DADLE 100 nmol were administered during the first 15 min of reoxygenation. In two additional groups, morphine and DADLE 100 nmol were administered in the presence of atractyloside 50 mmol, the mitochondrial permeability transition pore opener. The force of contraction at the end of 60-min reoxygenation period (FoC60 expressed as % of baseline) was compared (mean+standard deviation) between the groups by an analysis of variance. Morphine (FoC60: 81+9% of baseline), DADLE50 nmol (FoC60: 76+11% of baseline) and DADLE 100 nmol (FoC60: 81+4% of baseline) increased significantly (P,0.001) the FoC60 as compared with the control group (FoC60: 53+3% of baseline). DADLE 10 nmol did not modify the FoC60 (50+9% of baseline; P ¼ 0.60 versus control group). The enhanced recovery of FoC60 induced by morphine and DADLE 100 nmol were abolished in the presence of atractyloside (FoC60: respectively 57+6% and 44+7% of baseline;P, 0.001). In conclusion, the administration of morphine and DADLE, in early reoxygenation period, protected human myocardium, in vitro, against hypoxia–reoxygenation injury, at least in part, by the inhibition of mitochondrial permeability transition pore opening.
Collapse
Affiliation(s)
- Marinella Fuardo
- Department of Surgery, Chirurgia Epatopancreatica, Fondazione IRCCS San Matteo Hospital, University of Pavia
| | | | | | | | | |
Collapse
|
|
11
|
Rungatscher A, Linardi D, Giacomazzi A, Tessari M, Menon T, Mazzucco A, Faggian G. Cardioprotective effect of δ-opioid receptor agonist vs mild therapeutic hypothermia in a rat model of cardiac arrest with extracorporeal life support. Resuscitation 2013; 84:244-8. [DOI: 10.1016/j.resuscitation.2012.06.016] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2012] [Revised: 06/11/2012] [Accepted: 06/20/2012] [Indexed: 12/22/2022]
|
|
12
|
Bouma HR, Ploeg RJ, Schuurs TA. Signal transduction pathways involved in brain death-induced renal injury. Am J Transplant 2009; 9:989-97. [PMID: 19422328 DOI: 10.1111/j.1600-6143.2009.02587.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Kidneys derived from brain death organ donors show an inferior survival when compared to kidneys derived from living donors. Brain death is known to induce organ injury by evoking an inflammatory response in the donor. Neuronal injury triggers an inflammatory response in the brain, leading to endothelial dysfunction and the release of cytokines in the circulation. Serum levels of interleukin-6, -8, -10, and monocyte chemoattractant protein-1 (MCP-1) are increased after brain death. Binding with cytokine-receptors in kidneys stimulates activation of nuclear factor-kappa B (NF-kappaB), selectins, adhesion molecules and production of chemokines leading to cellular influx. Mitogen-activated protein kinases (MAP-kinases) mediate inflammatory responses and together with NF-kappaB they seem to play an important role in brain death induced renal injury. Altering the activation state of MAP-kinases could be a promising drug target for early intervention to reduce cerebral injury related donor kidney damage and improve outcome after transplantation.
Collapse
Affiliation(s)
- H R Bouma
- Department of Clinical Pharmacology, Groningen University Institute of Drug Exploration, University Medical Center Groningen, The Netherlands
| | | | | |
Collapse
|
|
13
|
van den Brink OWV, Delbridge LM, Rosenfeldt FL, Penny D, Esmore DS, Quick D, Kaye DM, Pepe S. Endogenous cardiac opioids: enkephalins in adaptation and protection of the heart. Heart Lung Circ 2008; 12:178-87. [PMID: 16352129 DOI: 10.1046/j.1444-2892.2003.00240.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Opiates have been used for thousands of years in the form of opium for relief of pain or fever and to induce sleep. However, it was only in the 1970s that the endogenous ligands for the opiate receptors were identified and termed opioid peptides. Opioid peptides activate G protein-coupled receptors in the central and autonomic nervous system, with marked effects on the regulation of pain perception, body temperature, respiration, heart rate and blood pressure. Cardiovascular regulatory effects of endogenous opioids were initially considered to originate from neural centres in the central nervous system, facilitating a regulatory role in neuro-transmission, as demonstrated by the presynaptic co-release from sympathetic neurones of norepinephrine with enkephalin or acetylcholine with enkephalin. However, opioid peptides of myocardial origin have also recently been shown to play a key role in local regulation of the heart. This brief review highlights the key features of the enkephalin opioids in the heart and the current understanding of their role in development, ageing, cardioprotection, hypertension, hypertrophy, and heart failure.
Collapse
|
|
14
|
Drabek T, Han F, Garman RH, Stezoski J, Tisherman SA, Stezoski SW, Morhard RC, Kochanek PM. Assessment of the delta opioid agonist DADLE in a rat model of lethal hemorrhage treated by emergency preservation and resuscitation. Resuscitation 2008; 77:220-228. [PMID: 18207625 DOI: 10.1016/j.resuscitation.2007.11.020] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2007] [Revised: 11/03/2007] [Accepted: 11/12/2007] [Indexed: 10/22/2022]
Abstract
Emergency preservation and resuscitation (EPR) is a new approach for resuscitation of exsanguination cardiac arrest (CA) victims. EPR uses a cold aortic flush to induce deep hypothermic preservation during no-flow to buy time for transport and damage control surgery, followed by resuscitation with cardiopulmonary bypass (CPB). We reported previously that 20-60 min EPR in rats was associated with intact outcome, while 75 min EPR resulted in high mortality and neurological impairment in survivors. The delta opioid agonist DADLE ([D-Ala(2),D-Leu(5)]-enkephalin) was shown previously to be protective against ischemia-reperfusion injury in multiple organs, including brain. We hypothesized that DADLE could augment neurological outcome after EPR in rats. After rapid lethal hemorrhage, EPR was initiated by perfusion with ice-cold crystalloid to induce hypothermia (15 degrees C). After 75 min EPR, resuscitation was attempted with CPB. After randomization, three groups were studied (n=10 per group): DADLE 0mg/kg (D0), 4 mg/kg (D4) or 10mg/kg (D10) added to the flush and during reperfusion. Survival, overall performance category (OPC; 1=normal, 5=death), neurological deficit score (NDS; 0-10% normal, 100%=max deficit), and histological damage score (HDS) were assessed in survivors on day 3. In D0 group, 2/10 rats survived, while in D4 and D10 groups, 4/10 and 5/10 rats survived, respectively (p=NS). Survival time (h) was 26.7+/-28.2 in D0, 36.3+/-31.9 in D4 and 47.1+/-30.3 in D10 groups, respectively (p=0.3). OPC, NDS and HDS were not significantly different between groups. In conclusion, DADLE failed to confer benefit on functional or histological outcome in our model of prolonged rat EPR.
Collapse
Affiliation(s)
- Tomas Drabek
- Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, United States.
| | | | | | | | | | | | | | | |
Collapse
|
|
15
|
Rutten M, Govindaswami M, Oeltgen P, Sonneborn JS. Post-treatment with the novel deltorphin E, a delta2-opioid receptor agonist, increases recovery and survival after severe hemorrhagic shock in behaving rats. Shock 2008; 29:42-8. [PMID: 17621254 DOI: 10.1097/shk.0b013e31805cdb70] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Deltorphin E was investigated as a pharmaceutical intervention in the ischemic hemorrhagic model. To monitor the hemodynamic biomarkers mean arterial pressure (MAP) and heart rate (HR) and to facilitate i.v. injections, rats were surgically fitted with femoral artery and vein catheters under anesthesia. After removal of 48% of total blood volume (range, 12-15 mL), posthemorrhage i.v. injections of 5.5-mg/kg deltorphin E were found to significantly (P < 0.05) increase maximum MAP, pulse pressure, and survival after hemorrhage, whereas lactic acid concentration was decreased when compared with saline injections. The results for the 5.5-mg/kg deltorphin E-treated animals versus saline controls showed the following values (expressed as mean +/- SEM): maximum MAP, 58 +/- 7 vs. 35 +/- 9 mmHg, respectively; lactic acid, 6.5 +/- 1.25 vs. 8.9 +/- 0.12 mmol/L, respectively; pulse pressure, 47.9 +/- 0.55 vs. 38.3 +/- 0.44 mmHg, respectively; and at least a fourfold increase in survival, 331 +/- 18 vs. 50 +/- 8 min, respectively. Heart rate in deltorphin E-treated groups was not significantly different from that in saline-treated groups (maximum HR, 396 +/- 40 vs. 425 +/- 94 bpm, respectively). Using logistic analysis, deltorphin E did not significantly alter the baroreflex sensitivity. However, a significant deltorphin E dose-dependent correlation was found between survival time and lactic acid production. Increased pulse pressure was also correlated with survival. Glibenclamide, a potassium-sensitive adenosine triphosphate-sensitive channel blocker, did not interfere with the positive effects of deltorphin E. Only the antagonists tested, known to affect delta(2)-opioid receptors, interfered with the deltorphin E survival benefit after hemorrhage. As a conclusion, deltorphin E is an effective pharmaceutical intervention in severe hemorrhagic shock and, perhaps, in other ischemic shock scenarios when administered after the onset of stress. Therefore, deltorphin E may have clinical potential.
Collapse
Affiliation(s)
- Mikal Rutten
- Zoology and Physiology Department Graduate Program, University of Wyoming, Laramie, Wyoming 8207, USA
| | | | | | | |
Collapse
|
|
16
|
Zatta AJ, Kin H, Yoshishige D, Jiang R, Wang N, Reeves JG, Mykytenko J, Guyton RA, Zhao ZQ, Caffrey JL, Vinten-Johansen J. Evidence that cardioprotection by postconditioning involves preservation of myocardial opioid content and selective opioid receptor activation. Am J Physiol Heart Circ Physiol 2008; 294:H1444-51. [PMID: 18203844 DOI: 10.1152/ajpheart.01279.2006] [Citation(s) in RCA: 81] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Opioids introduced at reperfusion (R) following ischemia (I) reduce infarct size much like postconditioning, suggesting the hypothesis that postconditioning increases cardiac opioids and activates local opioid receptors. Anesthetized male rats subjected to 30 min regional I and 3 h R were postconditioned with three cycles of 10 s R and 10 s reocclusion at onset of R. Naloxone (NL), its peripherally restricted analog naloxone methiodide, delta-opioid receptor (DOR) antagonist naltrindole (NTI), kappa-opioid receptor antagonist norbinaltorphimine (NorBNI), and mu-opioid receptor (MOR) antagonist H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) were administered intravenously 5 min before R. The area at risk (AAR) was comparable among groups, and postconditioning reduced infarct size from 57 +/- 2 to 42 +/- 2% (P < 0.05). None of the antagonists alone altered infarct size. All antagonists abrogated postconditioning protection at higher doses. However, blockade of infarct sparing by postconditioning was lost, since tested doses of NL, NTI, NorBNI, and CTAP were lowered. The efficacy of NorBNI declined first at 3.4 micromol/kg, followed sequentially by NTI (1.1), NL (0.37), and CTAP (0.09), suggesting likely MOR and perhaps DOR participation. Representative small, intermediate, and large enkephalins in the AAR were quantified (fmol/mg protein; mean +/- SE). I/R reduced proenkephalin (58 +/- 9 vs. 33 +/- 4; P < 0.05) and sum total of measured enkephalins, including proenkephalin, peptide B, methionine-enkephalin, and methionine-enkephalin-arginine-phenylalanine (139 +/- 17 vs. 104 +/- 7; P < 0.05) compared with shams. Postconditioning increased total enkephalins (89 +/- 8 vs. 135 +/- 5; P < 0.05) largely by increasing proenkephalin (33 +/- 4 vs. 96 +/- 7; P < 0.05). Thus the infarct-sparing effect of postconditioning appeared to involve endogenously activated MORs and possibly DORs, and preservation of enkephalin precursor synthesis in the AAR.
Collapse
Affiliation(s)
- Amanda J Zatta
- Department of Cardiothoracic Surgery, Carlyle Fraser Heart Center/Crawford Long Hospital, Emory University School of Medicine, Atlanta, Georgia 30308-2225, USA
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
17
|
Abstract
Homeothermy is the result of an evolutionary process during which every increase in oxygen supply led to a consecutive increase in metabolic rate and, thus, to a new dependence on favorable ambient conditions. In response to the food scarcity of winter months, some inhabitants of temperate zones developed an ability to hibernate which is characterized by a fully thermocontrolled reduction in body temperature down to near zero values. Hibernation thus illustrates that in homeotherms, not only the body shell is poikilothermic, but also the core temperature is more variable than often assumed. However, in contrast to clinical hypothermia, natural torpidity does not consist of a cold-induced reduction in metabolic rate, but of an endogenous metabolic reduction with subsequent lowering of body temperature. As a factor of metabolic suppression, the pH has been suspected which, in hibernators, is kept constant at 7.4 by relative hypoventilation (pH-stat) which differs from its passive shift in the poikilothermic body shell (alpha-stat). In clinical hypothermia, temperature governs the metabolic rate in that, depending on the state of thermoregulation, either a cold defense reaction with an increased metabolic rate (accidental hypothermia) or a cold-induced reduction in metabolic rate (induced hypothermia) occurs. However, as can be learned from hibernators, the lower limit of hypothermia tolerance seems to be due to a uniform minimal metabolic rate rather than to the species-specific body temperature at which this metabolic limit is reached, depending on body size and basal metabolic rate. Accordingly, in judging the sequelae of hypothermia, the degree of cooling should be given less emphasis than the resulting effects on metabolic rate.
Collapse
Affiliation(s)
- D Singer
- Sektion Neonatologie und Pädiatrische Intensivmedizin, Zentrum Frauen-, Kinder- und Jugendmedizin, Universitätsklinikum Eppendorf, Martinistr. 52, 20246 Hamburg.
| |
Collapse
|
|
18
|
Pfeifer L, Gruenwald I, Welker A, Stahn RM, Stein K, Rex A. Fluorimetric characterisation of metabolic activity of ex vivo perfused pig hearts. BIOMED ENG-BIOMED TE 2007; 52:193-9. [PMID: 17408379 DOI: 10.1515/bmt.2007.036] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Autofluorescence of tissues and organs is an indicator of the physiological state of cells. The aim of the study was to investigate whether fluorimetric determination of the redox state of the ex vivo perfused pig heart can provide fast online detection of progressive changes in heart muscle tissue. Measurements on six organs perfused in a four-chamber working heart model were performed using a spectroscopic method exploiting the specific and different fluorescence lifetimes of intrinsic fluorophores such as NADH and flavins and providing a means of internal signal referencing. It was shown that the redox potential of heart muscle tissue can be assessed by fluorescence measurement. In the steady-state phase of the beating heart, spectroscopic measurements revealed a change in redox state from an initial constant level to a continuous decrease, accompanied by a decrease in heart performance and indications of changes in electrolyte equilibrium (K(+) concentration). At the same time, troponin I levels in the perfusate increased. The results indicate that fluorimetric determination of heart muscle metabolic activity yields reliable information about the functional status of the ex vivo heart and may be advantageous for the optimisation of ex vivo organ models.
Collapse
Affiliation(s)
- Lutz Pfeifer
- IOM Innovative Optische Messtechnik GmbH, Berlin, Germany.
| | | | | | | | | | | |
Collapse
|
|
19
|
Oeltgen PR, Govindaswami M, Witzke DB. 24-hour pretreatment with delta opioid enhances survival from hemorrhagic shock. Acad Emerg Med 2006; 13:127-33. [PMID: 16461748 DOI: 10.1197/j.aem.2005.08.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
OBJECTIVES Delta opioids have been shown to confer ischemic preconditioning and pharmacologic ischemic preconditioning to the myocardium. However, their role in providing extended pharmacologic ischemic preconditioning in hemorrhagic shock has not been explored. The authors examined the effects of 24-hour preinfusions of a selective delta opioid receptor agonist, Deltorphin-Dvariant (Delt-Dvar), on hemodynamic stability and duration of survival in a rat model of severe hemorrhagic shock. METHODS Conscious Sprague-Dawley rats with indwelling catheters were hemorrhaged at a rate of 3.18 mL/l00 g over 20 minutes. Twenty-four hours before hemorrhage, the control group (n = 14) was infused with 1.0 mL lactated Ringer's solution, and the Delt-Dvar-treated group (n = 22) was infused with 5.0 mg/kg Delt-Dvar in 1.0 mL lactated Ringer's solution. Rats were continuously monitored for heart rate (HR), mean arterial pressure, and four-hour survival rates. Plasma lactate levels were determined at the beginning of hemorrhage and the end of hemorrhage. RESULTS At 240 minutes, only one of 14 controls (7.1%) survived, while 16 (72.7%) of the 22 experimental rats survived. No significant differences in heart rate between controls and Delt-Dvar-treated rats were noted. Increases in mean arterial pressure of Delt-Dvar-treated rats at the beginning of hemorrhage and at the end of hemorrhage were found to be significant (p < 0.05). At 240 minutes, heart rate and mean arterial pressure were not different between the single surviving control and the Delt-Dvar group. At the end of hemorrhage, lactate levels in the Delt-Dvar-treated group were 8.5 (+/- 0.5) mmol/L versus 10.8 (+/- 0.6) mmol/L (p < 0.05) in the control group. CONCLUSIONS Twenty-four-hour pretreatment with Delt-Dvar decreases plasma lactate levels and improves hemodynamic stability and survival during hemorrhagic shock. The use of delta-specific opioids may improve survival from hemorrhagic shock and have clinical utility in providing ischemic protection in scenarios of planned ischemia.
Collapse
Affiliation(s)
- Peter R Oeltgen
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.
| | | | | |
Collapse
|
|
20
|
Oeltgen PR, Govindaswami M, Witzke DB. 24-Hour Pretreatment with δ Opioid Enhances Survival from Hemorrhagic Shock. Acad Emerg Med 2006. [DOI: 10.1111/j.1553-2712.2006.tb01660.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
|
|
21
|
Tsai BM, Wang M, March KL, Turrentine MW, Brown JW, Meldrum DR. Preconditioning: evolution of basic mechanisms to potential therapeutic strategies. Shock 2004; 21:195-209. [PMID: 14770032 DOI: 10.1097/01.shk.0000114828.98480.e0] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Preconditioning describes the phenomenon by which a traumatic or stressful stimulus confers protection against subsequent injury. Originally recognized in dog heart subjected to ischemic challenges, preconditioning has been demonstrated in multiple species, can be induced by various stimuli, and is applicable in different organ systems. Tremendous progress has been made elucidating the signal transduction cascade of preconditioning. Preconditioning represents a potent tissue-protective condition, and mechanistic understanding may allow safe clinical application. This review recalls the history of preconditioning and how it relates to the history of the investigation of endogenous adaptation; summarizes the current mechanistic understanding of acute preconditioning; outlines the signal transduction cascade leading to the development of delayed preconditioning; discusses preconditioning in noncardiac tissue; and explores the potential of using preconditioning clinically.
Collapse
Affiliation(s)
- Ben M Tsai
- Section of Cardiothoracic Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
| | | | | | | | | | | |
Collapse
|
|
22
|
Li SQ, Liang LJ, Huang JF, Li Z. Ischemic preconditioning protects liver from hepatectomy under hepatic inflow occlusion for hepatocellular carcinoma patients with cirrhosis. World J Gastroenterol 2004; 10:2580-4. [PMID: 15300911 PMCID: PMC4572168 DOI: 10.3748/wjg.v10.i17.2580] [Citation(s) in RCA: 57] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To investigate the protective effect of ischemic preconditioning (IPC) on hepatocellular carcinoma (HCC) patients with cirrhosis undergoing hepatic resection under hepatic inflow occlusion (HIO) and its possible mechanism.
METHODS: Twenty-nine consecutive patients with resectable 0HCC were randomized into two groups: IPC group: before HIO, IPC with 5 min of ischemia and 5 min of reperfusion was given; control group: no IPC was given. Liver functions, hepatic Caspase-3 activity, and apoptotic cells were compared between these two groups.
RESULTS: On postoperative days (POD) 1, 3 and 7, the aspartate transaminase (AST) and alanine transaminase (ALT) levels in the IPC group were significantly lower than those in the control group (P < 0.05). On POD 3 and 7, the total bilirubin level in the IPC group was significantly lower than that in the control group (P < 0.05). On POD 1, the albumin level in the IPC group was higher than that in the control group (P = 0.053). After 1 h of reperfusion, both hepatic Caspase-3 activity and apoptotic sinusoidal endothelial cells in the IPC group were significantly lower than those in the control group (P < 0.05).
CONCLUSION: IPC has a potential protective effect on HCC patients with cirrhosis. Its protective mechanism underlying the suppression of sinusoidal endothelial cell apoptosis is achieved by inhibiting Caspase-3 activity.
Collapse
Affiliation(s)
- Shao-Qiang Li
- Department of Hepatobiliary Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China
| | | | | | | |
Collapse
|
|
23
|
Romano MA, Seymour EM, Berry JA, McNish RA, Bolling SF. Relative contribution of endogenous opioids to myocardial ischemic tolerance1. J Surg Res 2004; 118:32-7. [PMID: 15093714 DOI: 10.1016/j.jss.2003.12.006] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/14/2003] [Indexed: 11/19/2022]
Abstract
BACKGROUND Opioid preconditioning by exogenous opioids experimentally protects the myocardium against ischemia/reflow injury. Additionally, endogenous opioid peptides released during ischemia also enhance ischemic tolerance. Promiscuous opioid receptor agonists conceal the differential contribution of the mu, delta, and kappa opioid subtypes. This study compared the impact of selective delta and kappa opioid receptor antagonists on postischemic functional and metabolic recovery. Also measured were changing levels of peptides dynorphin B and met-enkephalin during ischemia/reflow injury. MATERIALS AND METHODS Using the rabbit Langendorff model, the functional recovery of control hearts (following 2 h of global ischemia) was compared to hearts pretreated with delta antagonist NTB (1 microM) or kappa antagonist, nor-BNI (1 microM). Measures included percentage of return of isovolumetric developed pressure (LVDP), myocardial oxygen consumption (MVO(2)) and coronary flow (CF). In additional studies, untreated hearts were harvested at baseline, following ischemia, or following 5 or 45 min of reflow. Tissue concentrations of met-enkephalin and dynorphin B were measured by RIA. RESULTS After 45 min of reflow, hearts pretreated with either NTB or nor-BNI showed impaired functional recovery by a decrease in LVDP (P < 0.05); however, MVO(2) or CF were unaffected. RIA data shows that baseline levels of both peptides are similar and increase significantly during ischemia, but reflow dynorphin levels drop far below baseline, while met-enkephalin returns to baseline. CONCLUSION Antagonism of both delta and kappa opioid receptor subtypes equally contributes to impaired left ventricular function, independent of altered perfusion or metabolic rate. Endogenous kappa-receptor agonists may contribute primarily during ischemia or early reflow, since low late reflow dynorphin content did not correlate with altered functional recovery.
Collapse
Affiliation(s)
- Matthew A Romano
- Department of Cardiac Surgery, B558 MSRBII 0686, University of Michigan Medical School, Ann Arbor, MI 48105, USA
| | | | | | | | | |
Collapse
|
|
24
|
Summers RL, Li Z, Hildebrandt D. Effect of a delta receptor agonist on duration of survival during hemorrhagic shock. Acad Emerg Med 2003; 10:587-93. [PMID: 12782517 DOI: 10.1111/j.1553-2712.2003.tb00040.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
OBJECTIVES Selective delta receptor agonists have been shown to stabilize membrane physiologic processes, reduce metabolic rates, and provide protection against ischemic insults through K(ATP) channel opening in a variety of organ beds. However, their potential for affecting outcomes in states of generalized ischemia has not been explored. The authors examined the effect of the nonselective delta receptor agonist, DADLE (D-Ala2-Leu5-enkephalin), on hemodynamic stability and duration of survival in an animal model of severe hemorrhagic shock. METHODS Conscious Sprague Dawley rats with indwelling catheters were hemorrhaged at a rate of 3.25 mL/100 grams over 20 minutes after half of the group received 1% DADLE (1 mg/kg IV). Following the hemorrhage, all rats were continuously monitored for heart rate (HR), mean arterial pressure (MAP), and life signs for up to three hours (death defined as apnea, systolic blood pressure < 30 mm Hg without pulsations, and electroencephalographic silence). Survival rates and hemodynamic trends were compared between the control and DADLE-treated groups. RESULTS In the 14 rats studied (8 DADLE; 6 controls), initial hemorrhage resulted in similar hemodynamic shock (average MAP fall: 118 to 59 vs 119 to 55 mm Hg). Analysis of survival at 3.5 hours revealed statistically significant differences between the control and DADLE groups. While 50% of the DADLE group survived past the three hours, no control animals were still alive at the end of the experimental period. The MAP trended downward and the HR increased for the control group, but all hemodynamic parameters stabilized in the rats treated with DADLE. CONCLUSIONS Most current strategies for treating shock focus on the supply side of resuscitation. The coordinated various actions of DADLE have the potential to work in concert in the intact organism to improve overall survival during severe hemorrhagic shock. In an animal model of severe hemorrhagic shock, there was improvement in hemodynamic stability and a prolonged survival with DADLE treatment. Physiologic manipulation with DADLE appears to be a way to improve survival during shock with possible clinical implications.
Collapse
Affiliation(s)
- Richard L Summers
- Department of Emergency Medicine, University of Mississippi Medical Center, Jackson 39216, USA.
| | | | | |
Collapse
|
|
25
|
Abstract
This paper is the twenty-fourth installment of the annual review of research concerning the opiate system. It summarizes papers published during 2001 that studied the behavioral effects of the opiate peptides and antagonists. The particular topics covered this year include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology(Section 9); mental illness and mood (Section 10); seizures and neurologic disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration and thermoregulation (Section 16); and immunological responses (Section 17).
Collapse
Affiliation(s)
- Richard J Bodnar
- Department of Psychology and Neuropsychology Doctoral Sub-Program, Queens College, City University of New York, CUNY, 65-30 Kissena Blvd., Flushing, NY 11367, USA.
| | | |
Collapse
|