Impaired nitric oxide‐mediated coronary arteriolar dilation in hypertrophic cardiomyopathy: role of angiotensin‐II and oxidative stress

Abstract

Coronary ischemia is commonly observed during exercise in patients with hypertrophic cardiomyopathy (HCM). To determine if alterations in adenosine and nitric oxide− (NO) mediated pathways contribute to the coronary dysfunction observed in HCM, coronary arterioles from HCM transgenic mice (TG) were isolated, cannulated and pressurized for in vitro study. Vasodilation to adenosine (mediated by NO and KATP channels) and A23187 (calcium ionophore; mediated by NO) were reduced in TG, with no change in dilation to pinacidil (KATP channel agonist). The NO synthase inhibitor L-NAME eliminated differences between TG and control in response to adenosine and A23187, suggesting an impairment of NO-mediated dilation in TG. In the presence of the superoxide anion (O2−) scavenger TEMPOL or the NAD(P)H oxidase inhibitor apocynin, impaired vasodilations were restored. Lucigenin-chemiluminescence and dihydroethidium fluorescent signal for O2- was significantly higher in arterioles from TG. Furthermore, ACE protein and mRNA expression and the release of angiotensin-II were increased in arterioles isolated from the TG heart. Given that angiotensin-II is known to increase O2− production via NAD(P)H oxidase, our results suggest that upregulation of vascular renin-angiotensin system in the TG heart increases O2− production and impairs NO-mediated dilation via NAD(P)H-oxidase dependent mechanisms.