Pretreatment with Sarafotoxin 6c Prior to Coronary Occlusion Protects Against Infarction and Arrhythmias via Cardiomyocyte Mitochondrial KATP Channel Activation in the Intact Rabbit Heart During Ischemia/Reperfusion
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Endothelial ETB receptor activation by exogenously administered sarafotoxin 6c(a snake venom peptide with a sequence homology to ET-1 prior to ischemia activates release of nitric oxide(NO) and previous studies have shown that NO facilitates mitochondrial KATP activation in cardiac cells and cardioprotection.
Objectives and methods
The aim of this investigation was to test whether the administration of sarafotoxin 6c(a selective ETB receptor agonist) has cardioprotective and antiarrhythmic effects against ischemia and reperfusion injury in a well-standardized model of reperfusion arrhythmias in anesthetized adult male rabbits (n = 53) subjected to 30 min occlusion of the left coronary artery followed by 120 min of reperfusion.
Pretreatment with sarafotoxin 6c (0.24 nmol/kg, i.v.) prior to the period of coronary occlusion offers significant infarct size reduction (19.1 ± 2.0% versus 39.7 ± 3.7% in the saline control group; P < 0.01) and antiarrhythmic effects. Sarafotoxin 6c treatment significantly attenuated the incidence of life-threatening arrhythmias like sustained VT (13 versus 100% in the saline control group; P < 0.005) and other arrhythmias (25 versus 100% in the saline control group; P < 0.005), and increased the number of surviving animals without arrhythmias. Pretreatment with 5-HD but not HMR 1883 abolished the beneficial effects of sarafotoxin 6c on reperfusion induced arrhythmias and cardioprotection suggesting that benefits have been achieved via the selective activation of cardiomyocyte mitochondrial KATP channels. Sarafotoxin 6c evoked NO release and selective activation of mitoKATP channels in cardiomyocytes contributes to cardioprotection and antiarrhythmic activity during ischemia-reperfusion in the anesthetized rabbit.
We conclude that the selective activation of ETB receptors by sarafotoxin 6c prior to coronary occlusion contributes to cardioprotective and antiarrhythmic properties.
Key wordsischemic preconditioning sarafotoxin 6c HMR 1883 ETB receptors sarcolemmal KATP channel mitochondrial KATP channel anesthetized rabbit coronary occlusion reperfusion arrhythmia
- 6.Gourine AV, Molosh AI, Poputnikov D, Bulhak A, Sjoquist PO, Pernow J. Endothelin-1 exerts a preconditioning-like cardioprotective effect against ischemia/reperfusion injury via the ETA receptor and the mitochondrial KATP channel in the rat in vivo. Br J Pharmacol 2005;144:331–7.CrossRefGoogle Scholar
- 13.Anonymous. Guidelines for care and use of animals in scientific research. Revised ed. Indian National Science Academy, New Delhi 2000.Google Scholar
- 20.Beutler E, Daron O, Kelly BM. Improved method for the determination of blood glutathione. J Lab Clin Med 1963;61:883–7.Google Scholar
- 22.Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with Folin phenol reagent. J Biol Chem 1951;193:256–75.Google Scholar
- 23.Bergmeyer HU (Ed): Methods of enzymatic analysis, Vols. 6–8, VCH Verlagsgesellschaft, Basel (1984–1985).Google Scholar
- 32.Crockett TR, McBride M, Ness KF, Kane KA, Wainwright CL. The effect of S6c on platelet aggregation and leukocyte free radical generation in rat blood in vitro and ex vivo.Br J Pharmacol 2000;131:162P.Google Scholar