Cardioprotective effects of hydrogen sulfide

The gaseous mediator hydrogen sulfide (H ₂S) 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 ₂S in various models of cardiac injury. Subsequently, we present original data showing the beneficial effects of parenteral administration of a donor of H ₂S 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 ₂S 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 ₂S plays a role in myocardial pre- and post-conditioning responses. The pathways implicated in the cardioprotective action of H ₂S 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 ₂S 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 ₂S 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 ₂S 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 ₂S 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 ₂S-treated group (p < 0.05) both in vivo and ex vivo. Furthermore, high-energy phosphate contents were better preserved in the H ₂S group. Additionally, the cytoprotective effects of H ₂S 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 ₂S 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.