Reduction of Ischemic, Pharmacological and Remote Preconditioning Effects by an Antioxidant N-Acetyl Cysteine Pretreatment in Isolated Rat Heart

Khanna, Gitika; Diwan, Vishal; Singh, Manjeet; Singh, Nirmal; Jaggi, Amteshwar Singh

doi:10.1248/yakushi.128.469

Cited by 25 publications

(19 citation statements)

References 45 publications

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“…Clinically, NAC is indicated for the treatment of acetaminophen overdose, for the prevention of radiocontrastinduced nephropathy, and as an adjuvant in respiratory conditions with excessive and/or thick mucus production. However, there are contradictory reports on the effects of NAC in clinical (13,14) and animal studies (15)(16)(17) of myocardial IR injury. Furthermore, there are limited data specifically focused on NAC use during infancy.…”

Section: Yocardial Ischemia-reperfusion (Ir) Injury Associatedmentioning

confidence: 99%

Impact of N-Acetylcysteine on Neonatal Cardiomyocyte Ischemia-Reperfusion Injury

2011

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ABSTRACT:Reactive oxygen species (ROS) are hypothesized to play a key role in myocardial ischemia-reperfusion (IR) injury after cardiopulmonary bypass in children. Clinical studies in adults and several animal models suggest that myocardial IR injury involves cardiomyocyte apoptosis and necrosis. This study investigated a potential relationship between IR-induced ROS production and neonatal cardiomyocyte apoptosis using both in vitro and ex vivo techniques. For in vitro experiments, embryonic rat cardiomyocytes (H9c2 cells) exposed to hypoxia-reoxygenation (HR) showed a timedependent increase in gp91 phox (a marker for ROS production by NADPH oxidases), caspase-3 (a key mediator of apoptosis) expression, and a decrease in the glutathione redox ratio. N-acetylcysteine (NAC; 0.25-2 mM), a potent antioxidant, decreased gp91 phox and caspase-3 expression, inhibited apoptosis and restored the glutathione redox ratio. M yocardial ischemia-reperfusion (IR) injury associatedwith cardiopulmonary bypass and cardioplegic arrest contributes to adverse outcomes after cardiac surgery. The pathogenesis of IR injury is complex, but reactive oxygen species (ROS) generated during IR are thought to play a pivotal role leading to membrane lipid peroxidation, protein denaturation, and DNA modification, all of which may result in irreversible myocyte injury and cell death. Oxygen free radicals are cytotoxic molecules generated during reperfusion and/or reoxygenation of a previously hypoxic tissue bed. The cell damage induced by ROS can also initiate a local inflammatory response, which leads to further oxidant stressmediated tissue damage (1).Several studies have suggested that ROS are involved in the pathogenesis of perinatal asphyxia (2). Neonates, especially those born prematurely, are particularly vulnerable to ROSmediated tissue damage due, in part, to their immature native antioxidant system (3,4). Similarly, myocardial IR injury seems to be a more clinically significant problem in infants after cardiac surgery compared with adults (5-7). Several ROS-producing systems have been identified in many cell types. NADPH oxidase is reported to be a primary source of ROS production in cardiac tissue, and gp91 phox is responsible for the catalytic activity of NADPH oxidase (8,9). Increased ROS induce apoptosis in cardiomyocytes. Caspase-3 protein is a member of the cysteine-aspartic acid protease family that has been identified as being a key mediator of apoptosis in mammalian cells (10,11).N-acetylcysteine (NAC) is a thiol-containing molecule that acts as a free radical scavenger. In addition, NAC is a glutathione precursor that increases intracellular antioxidant capacity (12). Clinically, NAC is indicated for the treatment of acetaminophen overdose, for the prevention of radiocontrastinduced nephropathy, and as an adjuvant in respiratory conditions with excessive and/or thick mucus production. However, there are contradictory reports on the effects of NAC in clinical (13,14) and animal studies (15-17) of myocardial IR injury. Furthe...

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Section: Yocardial Ischemia-reperfusion (Ir) Injury Associatedmentioning

confidence: 99%

Impact of N-Acetylcysteine on Neonatal Cardiomyocyte Ischemia-Reperfusion Injury

2011

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“…Our own laboratory has documented protective eŠects of ischemic preconditioning in heart 10,11) and brain. 12,13) Moreover, pharmacological preconditioning, 14,15) remote preconditioning, 16,17) and ischemic post-conditioning 18) have been documented to produce tissue-protective eŠects. In the present investigation, stress as an insult was analogous to the ischemic insult and hence, accordingly short episodes of stress were employed before sustained restrain stress, analogous to protocols employed to investigate the protective eŠects of ischemic reconditioning.…”

Section: Discussionmentioning

confidence: 99%

“…Our own laboratory has documented the protective eŠects of ischemic preconditioning in heart 10,11) and brain. 12,13) This concept has been expanded to include pharmacological preconditioning, 14,15) remote preconditioning, 16,17) and ischemic post-conditioning. 18) The concept of ischemic and pharmacological preconditioning has been extrapolated to investigate the ameliorative role of stress preconditioning on stress-induced pathological changes and there have been reports suggesting the gastroprotective eŠects of stress preconditioning on cold, alcohol, restrain, and water immersion-induced gastric lesions in rats.…”

Section: Introductionmentioning

confidence: 99%

Studies on Effect of Stress Preconditioning in Restrain Stress-induced Behavioral Alterations

2010

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Stress preconditioning has been documented to confer on gastroprotective eŠects on stress-induced gastric ulcerations. However, the eŠects of prior exposure of stress preconditioning episodes on stress-induced behavioral changes have not been explored yet. Therefore the present study was designed to investigate the ameliorative eŠects of stress preconditioning in immobilization stress-induced behavioral alterations in rats. The rats were subjected to restrain stress by placing in restrainer (5.5 cm in diameter and 18 cm in length) for 3.5 h. Stress preconditioning was induced by subjecting the rats to two cycles of restraint and restrain-free periods of 15 min each. Furthermore, a similar type of stress preconditioning was induced using diŠerent time cycles of 30 and 45 min. The extent and severity of the stress-induced behavioral alterations were assessed using diŠerent behavioral tests such as hole-board test, social interaction test, open eld test, and actophotometer. Restrain stress resulted in decrease in locomotor activity, frequency of head dips and rearing in hole board, line crossing and rearing in openˆeld, and decreased following and increased avoidance in social interaction test. Stress preconditioning with two cycles of 15, 30 or 45 min respectively, did not attenuate stress-induced behavioral changes to any extent. It may be concluded that stress preconditioning does not seem to confer any protective eŠect in modulating restrain stress-induced behavioral alterations.

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“…Earlier report from our laboratory had suggested the peak release of LDH immediately and 30 min after reperfusion, whilst peak release of CK after 5 min of reperfusion during myocardial injury. 16,22,23) Therefore, samples of coronary effluent were collected at these time intervals to estimate the release of LDH and CK.…”

Section: Discussionmentioning

confidence: 99%

Possible Mechanism of Rottlerin Induced Modulation of Ischemia Reperfusion Injury in Isolated Rat Hearts

Kaur

Singh

et al. 2008

Biological & Pharmaceutical Bulletin

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Coronary artery diseases represent a global burden on health care resources and poised to become the leading cause of morbidity and mortality in the world by 2020. Early reperfusion is essential to salvage ischemic myocardium; however reperfusion of ischemic region is not devoid of deleterious effects. Reperfusion of ischemic myocardium is noted to produce detrimental morphological and functional changes in the form of reperfusion injury manifested as reperfusion arrhythmias, myocardial stunning, micro-vascular and endothelial dysfunction leading to impairment of reflow. 1,2)Myocardial ischemia and reperfusion lead to activation of two novel PKC iso-forms (PKCd and PKCe) which are reported to play opposing roles during myocardial ischemia and reperfusion (I/R).3,4) PKCd has been reported to mediate I/R induced myocardial injury through activation of mitochondrial pathway, 5,6) whereas PKCe has been reported to provide cardioprotection through preconditioning. 7) PKCd has been implicated in I/R induced myocardial injury by producing apoptotic and necrotic cell death. 4,5) A selective peptide inhibitor of PKCd i.e. dV1-1, has been reported to reduce I/R induced myocardial injury by inhibiting apoptotic as well as necrotic cell death. 6)Ischemia and reperfusion has also been reported to activate protein kinases such as p-38 mitogen activated protein kinase (p-38 MAPK); which further increases transcription of pro-inflammatory cytokines such as tumor necrosis factora (TNF-a).8,9) Administration of SB 203580, a selective p-38 MAPK inhibitor, has been reported to attenuate the apoptotic and necrotic cell death of cardiomyocytes.10) Rottlerin is a specific non-peptide inhibitor of PKCd,11,12) which is also reported to activate p-38 MAPK.13) Therefore, the present study was designed to investigate the modulatory effects of rottlerin, an inhibitor of PKCd and activator of p-38 MAPK on ischemia reperfusion induced myocardial injury. MATERIAL AND METHODSWistar albino, rats of either sex weighing 150-200 g maintained at standard animal diet (Kisan Feeds Ltd., Chandigarh, India) and tap water ad libitum were employed in the present study. The animals were procured from 'disease free small animal house' Chaudary Charn Singh, Haryana Agriculture University, Hisar (Haryana), India. They were exposed to 12 h cycle of light and dark. The protocol of the study was duly approved by Institutional Animal Ethics Committee and care of the animals was taken as per guidelines of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), Ministry of Environment and Forest, Govt. of India (Reg. No. 107/CPCSEA 1999).Drugs and Chemicals Rottlerin (Sigma Aldrich, St. Louis, U.S.A.) and FR-167653 (Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan) were dissolved in 1 : 5 mixtures of ethanol with normal saline and saline respectively. All other reagents used in the study were of analytic grade.Isolated Rat Heart Preparation Rats were heparinised (500 I.U., i.p.) about 20 min before sacrificing the animal by cerv...

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Reduction of Ischemic, Pharmacological and Remote Preconditioning Effects by an Antioxidant N-Acetyl Cysteine Pretreatment in Isolated Rat Heart

Cited by 25 publications

References 45 publications

Impact of N-Acetylcysteine on Neonatal Cardiomyocyte Ischemia-Reperfusion Injury

Impact of N-Acetylcysteine on Neonatal Cardiomyocyte Ischemia-Reperfusion Injury

Studies on Effect of Stress Preconditioning in Restrain Stress-induced Behavioral Alterations

Possible Mechanism of Rottlerin Induced Modulation of Ischemia Reperfusion Injury in Isolated Rat Hearts

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