Nitric Oxide Resistance, Induced in the Myocardium by Diabetes, Is Circumvented by the Nitric Oxide Redox Sibling, Nitroxyl

Impairment of tissue responsiveness to exogenous and endogenous nitric oxide (NO), known as NO resistance, occurs in many cardiovascular disease states, prominently in diabetes and especially in the presence of marked hyperglycemia. In this study, we sought to determine in moderate and severe diabetes (i) whether NO resistance also occurs in the myocardium, and (ii) whether the NO redox sibling nitroxyl (HNO) circumvents this. The spectrum of acute NO effects (induced by diethylamine-NONOate), including vasodilation, and enhanced myocardial contraction and relaxation were impaired by moderately diabetic rats ([blood glucose] ∼20 m). In contrast, acute HNO effects (induced by isopropylamine-NONOate) were preserved even in more severe diabetes ([blood glucose] >28 m). Intriguingly, the positive inotropic effects of HNO were significantly enhanced in diabetic rat hearts. Further, progressive attenuation of soluble guanylyl cyclase (sGC) contribution to myocardial NO responses occurred with increasing severity of diabetes. Nevertheless, activation of sGC by HNO remained intact in the myocardium. Diabetes is associated with marked attenuation of vascular and myocardial effects of NO and NO donors, and this NO resistance is circumvented by HNO, suggesting potential therapeutic utility for HNO donors in cardiovascular emergencies in diabetics. These results provide the first evidence that NO resistance occurs in diabetic hearts, and that HNO largely circumvents this problem. Further, the positive inotropic and lusitropic effects of HNO are enhanced in a severely diabetic myocardium, a finding that warrants further mechanistic interrogation. The results support a potential role for therapeutic HNO administration in acute treatment of ischemia and/or heart failure in diabetics.