Altered regulation of coronary vascular tone in experimental heart failure, modulation by nitric oxide, nitrovasodilators, and Ã-adrenoceptors

The vasoconstrictor and vasodilator profiles of large (2-4mm in diameter) and small coronary arteries (200-350 gm in diameter) were assessed 'in vitro' from dogs with pacing-induced congestive heart failure. In large endothelium-intact coronary arteries, noradrenaline (mixed Ã-adrenoceptor agonist) and BHT 933 (selective Ã2 -adrenoceptor agonist) elicited concentration-dependent contractions, which were depressed in heart failure compared to control. Addition of the nitric oxide precursor, L-arginine [10-4M], further reduced the contractile response to noradrenaline in heart failure coronary arteries. Nitric oxide synthase inhibition with N[omega]-Nitro-L-Arginine (LNNA, 10-6M, 10-5 M, 10 -4M) restored Ã-adrenoceptor-mediated contractions to noradrenaline and BHT 933 in endothelium-intact heart failure coronary arteries. LNNA alone produced concentration-dependent vasoconstriction in large endothelium-intact coronary arteries, suggesting a role for basal endothelium-derived nitric oxide in the regulation of coronary arterial tone at control and also in heart failure. Interestingly, LNNA elicited a contractile response in endothelium-denuded coronary arteries at heart failure, but not at control, indicative of a nonendothelial source of nitric oxide, possibly from the inducible isoform of nitric oxide synthase. Antagonism of (Ã1-adrenoceptors with prazosin [10 -8M] inhibited maximum contractile response to noradrenaline in endothelium-intact coronary arteries at control and heart failure, whereas in endothelium-denuded arteries, prazosin [10-8M] antagonized only contractions to noradrenaline at heart failure, not at control. Basal cGMP levels in endothelium-intact large coronary arteries were doubled at heart failure compared to control, and were always greater than endothelium-denuded arteries at both control (6.3 ± 2.9 pmol.ml -1 vs. 1.8 ± 1.0 pmol.ml-1, respectively), and heart failure (13.2 ± 4.4 pmol.ml-1 vs. 0.4 ± 0.1 pmol.ml-1, respectively) [p < 0.01]. Acetylcholine [10-5M] augmented cGMP levels to a similar extent at control and heart failure, in endothelium-intact. but not endothelium-denuded, coronary arteries, whereas nitroglycerin [10-5M], an endothelium-independent vasodilator, enhanced cGMP levels in intact and denuded preparations. Levels of cAMP were not significantly altered at heart failure compared to control. Basal cGMP levels (and not basal cAMP levels) were significantly attenuated by LNNA [10-4M] in endothelium-intact arteries at control and in heart failure. In small coronary arteries, noradrenaline-induced contractions and endothelium-dependent relaxations to acetylcholine were preserved in the setting of heart failure. However, relaxations nitroglycerin were significantly enhanced at heart failure compared to control (83 ± 25% vs. 25 ± 6%, respectively). L-arginine potentiated only relaxations to nitroglycerin (from 25 ± 6% to 135 ± 66%) at control, whereas at heart failure, L-arginine attenuated nitroglycerin-mediated relaxations (from 83 ± 25% to 48 ± 15%). LNINA reduced baseline diameter dose-dependently in endothelium-intact coronary microvessels at heart failure, but not at control. These novel data indicate a unique activation and counterbalance of the L-arginine/nitric oxide pathway in the coronary vasculature under basal conditions and in response to both vasoconstrictor and vasodilator stimuli at heart failure. There is a clear heterogeneity between large and small arteries in the coronary circulation. Overall, a definite paradoxical regulation of coronary vascular tone exists as mediated by nitric oxide, and may have important clinical implications with regards to pharmacotherapy in congestive heart failure.