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

Cheng Xue Qin; Jarryd Anthonisz; Chen Huei Leo; Nicola Kahlberg; Anida Velagic; Mandy Li; Edwina Jap; Owen Woodman; Laura Parry; John David Horowitz; Barbara Kathryn Kemp-Harper; Rebecca Helen Ritchie
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 the current study, we sought to determine in moderate and severe diabetes 1) whether NO• resistance also occurs in myocardium, 2) whether 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 mM). In contrast, acute HNO effects (induced by isopropylamine-NONOate) were preserved even in more severe diabetes ([blood glucose]>28 mM). 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.These results provide the first evidence that NO• resistance occurs in diabetic hearts, and HNO largely circumvents this problem. Further, positive inotropic and lusitropic effects of HNO are enhanced in severely diabetic myocardium, a finding which 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.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.
ISSN 1557-7716
Published 02 Nov 2019
DOI 10.1089/ars.2018.7706
Type Journal Article