Modulation of Coronary Autoregulatory Responses by Nitric Oxide: Evidence for Flow-Dependent Resistance Adjustments in Conscious Dogs

The present study tested the hypothesis that nitric oxide production in coronary resistance vessels is an important mechanism affecting the regulation of myocardial perfusion in unanesthetized dogs. We inhibited nitric oxide synthesis with the arginine analogue Nω-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg) and maintained the compressive determinants of myocardial blood flow constant by ventricular pacing. L-NAME did not affect resting coronary blood flow and reduced the receptor-mediated increase in flow to intracoronary acetylcholine (100 μg/min IC) from 143±20% (mean±SEM) under control conditions to 31±10% after L-NAME (P < .001). Coronary autoregulatory relations were determined as steady-state coronary pressure was reduced by inflating a hydraulic occluder. Initial resistance adjustments over the autoregulatory plateau were not affected by L-NAME. Closed-loop autoregulatory gain was 0.84±0.09 under control conditions versus 0.78±0.07 after L-NAME (P=NS). As coronary pressure was reduced further, however, the critical pressure at which myocardial ischemia began (lower autoregulatory break point) increased from 45±3 mm Hg under control conditions to 61±2 mm Hg (P < .001) after L-NAME. In addition, the slope of the coronary pressure-flow relation below the autoregulatory break point was reduced (1.0±0.2 versus 0.58±0.09 mL · min · mm Hg after L-NAME, P < .05), reflecting a reduction in the maximal conductance recruitable during ischemia. In concert with the effects of L-NAME on autoregulatory responses during ischemia, peak reactive hyperemic flow to a 30-second coronary occlusion was also reduced (from 200±22 to 166±24 mL/min after L-NAME, P < .01). In contrast, metabolic flow recruitment to a twofold increase in heart rate was not affected by L-NAME. These results indicate that (1) both initial autoregulatory adjustments to reductions in coronary pressure and metabolic flow recruitment are probably mediated by either myogenic and/or metabolic mechanisms and do not require nitric oxide production, and (2) during ischemia, endothelium-dependent production of nitric oxide is an important mechanism responsible for minimizing coronary vascular resistance. Thus, inhibiting nitric oxide production increases the vulnerability of the myocardium to ischemia at reduced perfusion pressure. In pathophysiological states associated with impaired endothelium-dependent vasodilation, the loss of nitric oxide–dependent resistance adjustments may contribute to the fu