Hydrogen sulfide therapy attenuates the inflammatory response in a porcine model of myocardial ischemia/reperfusion injury

Abstract

Introduction: Hydrogen sulfide is produced endogenously in response to myocardial ischemia and thought to be cardioprotective. The mechanism underlying this protection has yet to be fully elucidated, but it may be related to sulfide's ability to limit inflammation. This study investigates the cardioprotection provided by exogenous hydrogen sulfide and its potential anti-inflammatory mechanism of action.

Methods: The mid left anterior descending coronary artery in 14 Yorkshire swine was acutely occluded for 60 minutes, followed by reperfusion for 120 minutes. Controls (n = 7) received placebo, and treatment animals (n = 7) received sulfide 10 minutes before and throughout reperfusion. Hemodynamic and functional measurements were obtained. Evans blue and triphenyl tetrazolium chloride staining identified the area at risk and infarction. Coronary microvascular reactivity was assessed. Tissue was assayed for myeloperoxidase activity and proinflammatory cytokines.

Results: Pre-ischemia/reperfusion hemodynamics were similar between groups, whereas post-ischemia/reperfusion mean arterial pressure was reduced by 28.7 +/- 5.0 mm Hg in controls versus 6.7 +/- 6.2 mm Hg in treatment animals (P = .03). Positive first derivative of left ventricular pressure over time was reduced by 1325 +/- 455 mm Hg/s in controls versys 416 +/- 207 mm Hg/s in treatment animals (P = .002). Segmental shortening in the area at risk was better in treatment animals. Infarct size (percent of area at risk) in controls was 41.0% +/- 7.8% versus 21.2% +/- 2.5% in the treated group (P = .036). Tissue levels of interleukin 6, interleukin 8, tumor necrosis factor-alpha, and myeloperoxidase activity decreased in the treatment group. Treated animals demonstrated improved microvascular reactivity.

Conclusions: Therapeutic sulfide provides protection in response to ischemia/reperfusion injury, improving myocardial function, reducing infarct size, and improving coronary microvascular reactivity, potentially through its anti-inflammatory properties. Exogenous sulfide may have therapeutic utility in clinical settings in which ischemia/reperfusion injury is encountered.

Figure 1

Regional LV function (% segmental shortening) was preserved to a greater extent in sulfide treated animals in the (A) longitudinal axis, whereas no differences were observed in the (B) horizontal axis. P: Placebo, S: Sulfide, Pre: pre-I/R, Post: post-I/R. L: Longitudinal axis, H: Horizontal axis. * indicates p<0.05.

Figure 2

(A) Endothelial dependent and (B) Endothelial independent coronary microvascular relaxation was improved in sulfide treated animals. NO: nitric oxide, * indicates p<0.05.

Figure 3

Sulfide treated animals demonstrated significantly smaller infarct sizes relative to placebo treated animals. * indicates p<0.05.

Figure 4

Nitrotyrosine staining intensity was significantly lower in sulfide treated animals. * indicates p<0.05.