CONTRIBUTION OF NITRIC-OXIDE TO METABOLIC CORONARY VASODILATION IN THE HUMAN HEART

Background The vascular endothelium contributes to smooth muscle relax ation by tonic release of nitric oxide. To investigate the contributio n of nitric oxide to human coronary epicardial and microvascular dilat ion during conditions of increasing myocardial oxygen requirements, we studied the effect of inhibiting nitric oxide synthesis with N-G-mono methyl-L-arginine (L-NMMA) on the coronary vasodilation Juring cardiac pacing in patients with angiographically normal coronary arteries wit h and without multiple risk factors for coronary atherosclerosis. Meth ods and Results In 26 patients with angiographically normal or near-no rmal epicardial coronary arteries, metabolic vasodilation was assessed as a change in coronary vascular resistance and diameter during cardi ac pacing (mean heart rate, 141 beats per minute). Endothelium-depende nt vasodilation was estimated with intracoronary acetylcholine and end othelium-independent dilation with intracoronary sodium nitro-prusside and adenosine. These measurements were repeated after 64 mu mol/min i ntracoronary L-NMMA. At rest, L-NMMA produced a 16+/-25% (mean+/-SD) i ncrease in coronary vascular resistance (P<.05) and an 11% reduction i n distal epicardial coronary artery diameter (P<.01), indicating tonic basal release of nitric oxide from human coronary epicardial vessels and microvessels. Significant inhibition of pacing-induced metabolic c oronary vascular dilation occurred with L-NMMA, coronary vascular resi stance was 38+/-56% higher (P<.03), and epicardial coronary dilation d uring control pacing (9+/-13%) was converted to constriction after L-N MMA and pacing (-6+/-9%, P<.04). L-NMMA specifically inhibited endothe lium-dependent vasodilation with acetylcholine (coronary vascular resi stance was 72% higher [P<.01]) but did not alter endothelium-independe nt dilation with sodium nitroprusside and adenosine. Nine patients had no major risk factors for atherosclerosis, defined as serum cholester ol >240 mg/dL, hypertension, or diabetes. The remaining 17 patients wi th one or more of these risk factors had depressed microvascular vasod ilation during cardiac pacing (coronary vascular resistance decreased by 13% versus 36% in those without risk factors, P<.05). The inhibitor y effect of L-NMMA on pacing-induced coronary epicardial and microvasc ular vasodilation was observed only in patients without risk factors, whereas those with risk factors had an insignificant change, indicatin g that nitric oxide contributes significantly to pacing-induced corona ry vasodilation in patients free of risk factors and without endotheli al dysfunction. Patients with risk factors also had reduced vasodilati on with acetylcholine (40+/-28% versus 68+/-8% decrease in coronary va scular resistance, P<.01), but the responses to sodium nitroprusside w ere similar in both groups. Conclusions During metabolic stimulation o f the human heart, nitric oxide release contributes significantly to m icrovascular vasodilation and is almost entirely responsible for the e picardial vasodilation. This contribution of nitric oxide is reduced i n patients exposed to risk factors for coronary atherosclerosis and le ads to a net reduction in vasodilation during stress. An important imp lication of these findings is that reduced nitric oxide bioavailabilit y during stress in patients with atherosclerosis or risk factors for a therosclerosis may contribute to myocardial ischemia by limiting epica rdial and microvascular coronary vasodilation.