Hydrogen sulfide potentiates the protective effects of nitrite against myocardial ischemia-reperfusion injury in type 2 diabetic rats

Abstract

Decreased heart levels of nitric oxide (NO) and hydrogen sulfide (H₂S) in type 2 diabetes (T2D) are associated with a higher risk of mortality following ischemia-reperfusion (IR) injury. This study aimed to determine the effects of co-administration of sodium nitrite and sodium hydrosulfide (NaSH) on IR injury in the isolated heart from rats with T2D. Two-month-old male rats were divided into 5 groups (n = 7/group): Control, T2D, T2D + nitrite, T2D + NaSH, and T2D + nitrite + NaSH. T2D was induced using a high-fat diet and a single low dose streptozotocin (30 mg/kg) in intraperitoneal injection. Nitrite (50 mg/L in drinking water) and NaSH (0.28 mg/kg, daily intraperitoneal injection) were administrated for 9 weeks. At the end of the study, hemodynamic parameters were recorded, and infarct size and mRNA expression of H₂S- and NO-producing enzymes were measured in the isolated hearts. Nitrite administration to rats with T2D improved recovery of left ventricular developed pressure (LVDP) and the peak rates of positive and negative changes in LV pressure (±dp/dt) by 30%, 17%, and 7.9%, respectively, and decreased infarct size by 18.4%. Co-administration of nitrite and NaSH resulted in further improve in recovery of LVDP, +dp/dt, and -dp/dt by 8.3% (P = 0.0478), 8.4% (P = 0.0085), and 9.0% (P = 0.0004), respectively, and also further decrease in infarct size by 24% (P = 0.0473). Nitrite treatment decreased inducible and neuronal NO synthases (iNOS, 0.4-fold; nNOS, 0.4-fold) and cystathionine β-synthase (CBS, 0.1-fold) expression in the isolated heart from rats with T2D. Co-administration of nitrite and NaSH further increased cystathionine γ-lyase (CSE, 2.8-fold) and endothelial NOS (eNOS, 2.0-fold) expression and further decreased iNOS (0.4-fold) expression. In conclusion, NaSH at a low dose potentiates the favorable effects of inorganic nitrite against myocardial IR injury in a rat model of T2D. These anti-ischemic effects, following co-administration of nitrite and NaSH, were associated with higher CSE-derived H₂S and eNOS-derived NO as well as lower iNOS-derived NO in the diabetic hearts.

Keywords: Hydrogen sulfide; Left ventricular developed pressure; Nitric oxide; Nitrite; Peak rates of positive and negative changes in left ventricular pressure; Type 2 diabetes.