Coronary Microvascular Endothelial Stunning after Acute Pressure Overload in the Conscious Dog Is Caused by Oxidant Processes: The Role of Angiotensin II Type I Receptor and NAD(P)H Oxidase

Background-Few studies have examined the effect of acute pressure overload on endothelial function in the coronary microcirculation. Methods and Results-In instrumented conscious dogs with heart rate held constant, veratrine caused a cholinergic nitric oxide (NO)-dependent increase in coronary blood flow by 23±3 mL/min (Bezold-Jarisch reflex). Ten minutes after release of constriction of the ascending aorta to increase left ventricular (LV) systolic pressure to 214±5 mm Hg for 30 minutes, the veratrine-induced increase in coronary blood flow (7±1 mL/min) was reduced by 66% and remained depressed for 2 hours (ie, endothelial stunning [ES]). Nitrite production from isolated coronary microvessels during ES was not different from normal. Ascorbic acid (AA), losartan, or apocynin prevented ES. Myocardial oxygen consumption (MV̇O₂) of LV tissue was measured in vitro in response to bradykinin with preincubation of angiotensin II for 30 minutes. Bradykinin (10^-4 mol/L)-induced reduction in MV̇O₂ was reversed in a concentration-dependent manner by angiotensin II (38±1% versus 19±2% at 10^-8 mol/L) and restored by coincubation of AA (37±2%), tempol (33±2%), losartan (34±2%), or apocynin (36±1%). Exogenous NO-induced reduction in MV̇O₂ was not altered by angiotensin II. Angiotensin II increased lucigenin-detectable superoxide anion in LV tissue in a manner that was inhibited by bradykinin, AA, tempol, losartan, or apocynin. Conclusions-Endothelial stunning is caused by oxidant processes inhibited by ascorbate, and the activation of NAD(P)H oxidase by increased angiotensin II plays an important role in this process.