Reduced nitric oxide formation causes coronary vasoconstriction and impaired dilator responses to endogenous agonists and hypoxia in dogs

Abstract

We investigated the relative contribution of basal and agonist stimulated EDRF/NO release to the adjustment of coronary tone and myocardial perfusion in conscious dogs by inhibiting coronary endothelial NO formation with N^G-nitro-l-arginine methyl ester (l-NAME). Chronically instrumented conscious dogs (n = 9) were prepared for measurement of mean arterial blood pressure (MAP), heart rate (HR), coronary blood flow (CF) and diameter of the left circumflex (CD_LC) and left anterior descending (CD_LAD) coronary artery, respectively. Intracoronary infusions of l-NAME (30.3 mM; 0.25 ml × min⁻¹) caused significant increases in MAP and decreases in HR. CD_LC decreased by 3.8% from 3.01 ± 0.04 to 2.90±0.04 mm and CF decreases by 30% from 12.9 ± 0.2 to 9.1 ± 0.2 (aU). Peak reactive hyperemia (CF_max) evoked by 20-s-lasting occlusions of the left circumflex coronary artery decreased from 29.9 ± 0.8 to 25.8 ± 1.0 aU and maximal flow-dependent coronary dilation were reduced from 2.04 ± 0.08 to 0.91±0.12% after inhibition of NO-synthesis. Intracoronary infusions of acetylcholine (ACh), Adenosinc (Ado), bradykinin (Bk), and papaverine (Pap) caused dose-dependent increases in CD_LC and CE Infusion of l-NAME nearly abolished the dilator effect of Ado on CD_LC and reduced those to ACh, Bk and Pap. Increases in CF to ACh, Ado and Bk but not to Pap were reduced by l-NAME. Subsequent intracoronary infusions of l-arginine (303 mM; 0.25 ml × min⁻¹) reduced l-NAME-induced CF-changes partly, but did not reverse coronary constriction. These results suggest that inhibition of the continuous release of nitric oxide markedly reduces myocardial perfusion in vivo. Endogenous dilator mechanisms are likewise impaired. Thus, in the heart, nitric oxide deficiency probably cannot be fully compensated for by counter-regulating mechanisms.