Elsevier

Nitric Oxide

Volume 25, Issue 2, 1 August 2011, Pages 201-210
Nitric Oxide

Cardioprotective effects of hydrogen sulfide

https://doi.org/10.1016/j.niox.2010.11.001Get rights and content

Abstract

The gaseous mediator hydrogen sulfide (H2S) 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 H2S in various models of cardiac injury. Subsequently, we present original data showing the beneficial effects of parenteral administration of a donor of H2S on myocardial and endothelial function during reperfusion in a canine experimental model of cardiopulmonary bypass. Overview of the literature demonstrates that various formulations of H2S 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 H2S plays a role in myocardial pre- and post-conditioning responses. The pathways implicated in the cardioprotective action of H2S are multiple and involve KATP 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 H2S 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 H2S 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. H2S 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 H2S 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 H2S-treated group (p < 0.05) both in vivo and ex vivo. Furthermore, high-energy phosphate contents were better preserved in the H2S group. Additionally, the cytoprotective effects of H2S 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 H2S 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.

Introduction

For many decades the conventional view has been that hydrogen sulfide (H2S) is a toxic gas that interferes with cellular functions. This viewpoint has recently been completely revised in light of three recent discoveries. First, several lines of studies demonstrated that H2S is generated from endogenous sources and is physiologically present in blood and other tissues. Second, endogenous H2S generating enzymes have been identified in mammals. H2S is synthesized from l-cysteine in mammalian tissues by two pyridoxal-5′-phosphate-dependent enzymes, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), with the latter one being the more abundant enzyme in the heart. Third, H2S was shown to inhibit neutrophil adhesion and activation [1], [2], [3]. These data demonstrate that endogenous H2S may play a role in regulation of cardiovascular function and inflammatory/immune responses as a potential endogenous gaseous transmitter.

Similarly to the other two gaseous transmitters nitric oxide and carbon monoxide, administration of small amounts of H2S have been shown to exert beneficial effects in a number of experimental models of inflammatory and cardiovascular diseases. The beneficial effects of H2S in various models of cardiac injury are shown in Table 1. The cytoprotective effects of H2S were demonstrated in cultured cardiomyocytes in vitro [4], [5], [6], [7], [8], [9], [10], [11], [12], in isolated perfused heart preparations [13], [14], [15], [16], [17], [18] as well as in rodent models of cardiac dysfunction [5], [11], [17], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30]. Many of these studies focus on acute myocardial protection, where the beneficial effects of H2S has been demonstrated in multiple rodent models of coronary artery ligation and reperfusion, homocysteine or isoproterenol induced myocardial injury and storage of hearts prior to transplantation (Table 1). A relatively smaller number of studies investigated the effects of parenteral H2S formulations in large animal models: protection against regional myocardial ischemia–reperfusion injury [31], [32], [33] and cardiopulmonary bypass [34] have been demonstrated in recent porcine studies. The endogenous production of H2S has also been shown to be required for ischemic preconditioning and post-conditioning; blockade of endogenous H2S production has been shown to inhibit these responses [8], [35]. Some of the cardioprotective pathways of H2S identified to date are depicted in Fig. 1.

Although there is a significant body of evidence demonstrating the protective effects of H2S in various models of cardiac injury, most of the studies are focusing on focal ischemia–reperfusion (see above). Less attention has been paid to global ischemia, such as the one that occurs in conjunction to cardiopulmonary bypass. This condition, nevertheless, is highly significant, given the fact that the majority of the cardiac surgical procedures done today is performed with aortic cross-clamping and cardioplegic arrest. Despite improvements in cardioplegic techniques, ventricular dysfunction following cardioplegic arrest is a major cause of perioperative morbidity and mortality [36]. Even if cardiac dysfunction is not clinically evident, a reduction of myocardial contractility is apparent, as demonstrated in humans by the measurement of pressure–volume relationships [36], [37]. In addition, coronary endothelial and peripheral vascular dysfunction may further complicate the postoperative course [38], [39]. Extracorporal circulation is also known to induce a systemic inflammatory reaction with free radical release leading to secondary organ injury [39]. The aim of the experimental component of the present study was to test the hypothesis that H2S improves myocardial and endothelial function after hypothermic cardioplegic arrest and reperfusion in a clinically relevant canine model of cardiopulmonary bypass.

Section snippets

Animals

Twenty dogs (foxhounds) weighing 19–34 kg were used in this experiment. In four animals without cardiopulmonary bypass the hearts were explanted and the coronary arteries were prepared for in vitro isolated vessel experiments (controls without cardiopulmonary bypass). Sixteen animals were used for the cardiopulmonary bypass studies, which were conducted according to our previously described experimental protocols [40], [41], [42]. All animals received humane care in compliance with the

Effect of H2S in a canine model of cardiopulmonary bypass

The infusion of the H2S donor did not lead to any changes of hemodynamic parameters before CPB (data nor shown). Heart rate, mean arterial pressure, cardiac output and coronary blood flow are shown in Table 2. Baseline heart rate tended to be higher in the treatment groups without reaching the level of significance, otherwise no differences were noted. Mean arterial pressure showed a decreasing tendency in both groups after CPB, without reaching the level of significance. Cardiac output showed

Discussion

In the experimental section of the current article, the benefit of the therapeutic supplementation of the endogenous gaseotransmitter H2S was assessed after cardioplegic arrest and reperfusion in a canine model of cardiopulmonary bypass. In accordance with the literature [36], [37], hypothermic cardioplegic arrest and reperfusion resulted in a decline in ventricular contractile and endothelial function. We showed for the first time in a clinically relevant large animal model that therapeutic

Acknowledgments

The contribution of Paul Hill (Ikaria Inc., Seattle, WA) in producing the injectable formulation of hydrogen sulfide used in the current study is appreciated. We thank Ms. Karin Sonnenberg and Lutz Hoffman for their excellent technical assistance. Work in the laboratory of C.S. is supported by a grant from the National Institutes of Health (NIH R01 GM060915) and by a grant from the Shriners Burns Hospitals (#8661).

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