The gaseous mediator hydrogen sulfide (H(2)S) is synthesized mainly by cystathionine γ-lyase in the heart and plays a role in the regulation of cardiovascular homeostasis. Here we first overview the state of the art in the literature on the cardioprotective effects of H(2)S in various models of cardiac injury. Subsequently, we present original data showing the beneficial effects of parenteral administration of a donor of H(2)S on myocardial and endothelial function during reperfusion in a canine experimental model of cardiopulmonary bypass. Overview of the literature demonstrates that various formulations of H(2)S exert cardioprotective effects in cultured cells, isolated hearts and various rodent and large animal models of regional or global myocardial ischemia and heart failure. In addition, the production of H(2)S plays a role in myocardial pre- and post-conditioning responses. The pathways implicated in the cardioprotective action of H(2)S are multiple and involve K(ATP) channels, regulation of mitochondrial respiration, and regulation of cytoprotective genes such as Nrf-2. In the experimental part of the current article, we demonstrate the cardioprotective effects of H(2)S in a canine model of cardiopulmonary bypass surgery. Anesthetized dogs were subjected hypothermic cardiopulmonary bypass with 60 min of hypothermic cardiac arrest in the presence of either saline (control, n=8), or H(2)S infusion (1 mg/kg/h for 2 h). Left ventricular hemodynamic variables (via combined pressure-volume-conductance catheter) as well as coronary blood flow, endothelium-dependent vasodilatation to acetylcholine and endothelium-independent vasodilatation to sodium nitroprusside were measured at baseline and after 60 min of reperfusion. Ex vivo vascular function and high-energy phosphate contents were also measured. H(2)S led to a significantly better recovery of preload recruitable stroke work (p<0.05) after 60 min of reperfusion. Coronary blood flow was also significantly higher in the H(2)S group (p<0.05). While the vasodilatory response to sodium nitroprusside was similar in both groups, acetylcholine resulted in a significantly higher increase in coronary blood flow in the H(2)S-treated group (p<0.05) both in vivo and ex vivo. Furthermore, high-energy phosphate contents were better preserved in the H(2)S group. Additionally, the cytoprotective effects of H(2)S were confirmed also using in vitro cell culture experiments in H9c2 cardiac myocytes exposed to hypoxia and reoxygenation or to the cytotoxic oxidant hydrogen peroxide. Thus, therapeutic administration of H(2)S exerts cardioprotective effects in a variety of experimental models, including a significant improvement of the recovery of myocardial and endothelial function in a canine model of cardiopulmonary bypass with hypothermic cardiac arrest.
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