Abstract
Endogenous H2S is synthesized mainly by cystathionine γ-lyase in the heart. The present study investigated the role of H2S in cardioprotection induced by ischemic preconditioning. We have examined the effect of endogenous H2S and exogenous application of NaHS (H2S donor) on cardiac rhythm in the isolated rat heart subjected to low-flow ischemia insults as well as cell viability and function in isolated myocytes exposed to simulated ischemia solution. Preconditioning with NaHS (SP) or ischemia (IP) for three cycles (3 min each cycle separated by 5 min of recovery) significantly decreased the duration and severity of ischemia/reperfusion-induced arrhythmias in the isolated heart while increasing cell viability and the amplitude of electrically induced calcium transients after ischemia/reperfusion in cardiac myocytes. Both IP and SP also significantly attenuated the decreased H2S production during ischemia. Moreover, decreasing endogenous H2S production significantly attenuated the protective effect of IP in both the isolated heart and isolated cardiac myocytes. Blockade of protein kinase C with chelerythrine or bisindolylmaleimide I as well as ATP-sensitive K+ (KATP) channel with glibenclamide (a nonselective KATP blocker) and HMR-1098 (1-[[5-[2-(5-Chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthiourea) (a sarcolemmal KATP channel blocker) reversed the cardioprotection induced by SP or IP. However, blockade of mitochondrial KATP channels with 5-hydroxydecanoic acid had no effect on the cardioprotection of SP, suggesting that, unlike the mechanism involved in IP, mitochondrial KATP channels most probably do not play a major role in the cardioprotection of SP. Our findings suggest that endogenous H2S contributes to cardioprotection induced by IP, which effect may involve protein kinase C and sarcolemmal KATP channels.
Footnotes
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This work was supported by Singapore Heart Foundation Grant R184000089593 and by National University of Singapore Office of Life Sciences Research Grant R184000074712. M.Y.A. was supported by the award of a graduate scholarship from the Agency for Science, Technology and Research (A*STAR).
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doi:10.1124/jpet.105.092023.
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ABBREVIATIONS: IP, ischemic preconditioning; PKC, protein kinase C; sarcKATP, sarcolemmal KATP; mitoKATP, mitochondrial KATP; CSE, cystathionine γ-lyase; SP, NaHS preconditioning; VP, vehicle preconditioning; PAG, dl-propargylglycine; BCA, β-cyano-l-alanine; VF, ventricular fibrillation; VT, ventricular tachycardia; 2-DOG, 2-deoxy-d-glucose; DMEM, Dulbecco's modified Eagle's medium; BSM, bisindolylmaleimide I; 5-HD, 5-hydroxydecanoic acid; HMR-1098, 1-[[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthiourea, sodium salt; Con, control; ROS, reactive oxygen species; APD, action potential duration.
- Received July 4, 2005.
- Accepted October 3, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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