Cheng Xue Qin1,2,3, Jarryd Anthonisz1,3, Chen Huei Leo4,5, Nicola Kahlberg4, Anida Velagic1,3, Mandy Li1, Edwina Jap1, Owen L Woodman1, Laura J Parry4, John D Horowitz6, Barbara K Kemp-Harper7, Rebecca H Ritchie1,2,3. 1. Heart Failure Pharmacology, Baker Heart & Diabetes Institute, Melbourne, Australia. 2. Department of Pharmacology and Therapeutics, University of Melbourne, Melbourne, Australia. 3. Department of Medicine (Central Clinical School), Monash University, Melbourne, Australia. 4. School of Biosciences, University of Melbourne, Parkville, Australia. 5. Science and Maths Cluster, Singapore University of Technology & Design, Singapore Singapore. 6. Cardiology Unit, The Queen Elizabeth Hospital, Basil Hetzel Institute, The University of Adelaide, Woodville SA, Australia. 7. Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, Australia.
Abstract
Aim: 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. Results: 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. Innovation: 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. Conclusion: 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.
Aim: 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. Results: The spectrum of acute NO• effects (induced by diethylamine-NONOate), including vasodilation, and enhanced myocardial contraction and relaxation were impaired by moderately diabeticrats ([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 diabeticrat 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. Innovation: 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. Conclusion: 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.
Authors: Anida Velagic; Jasmin Chendi Li; Cheng Xue Qin; Mandy Li; Minh Deo; Sarah A Marshall; Dovile Anderson; Owen L Woodman; John D Horowitz; Barbara K Kemp-Harper; Rebecca H Ritchie Journal: Br J Pharmacol Date: 2022-04-26 Impact factor: 9.473