Nitric Oxide–Independent Dilation of Conductance Coronary Arteries to Acetylcholine in Conscious Dogs

Abstract

Abstract NO and prostacyclin formation cannot entirely account for receptor-operated endothelium-dependent dilation of coronary vessels, since vasodilator responses are not completely suppressed by inhibitors of these agents. Therefore, we considered that another factor, such as an endothelium-derived hyperpolarizing factor described in vitro, may participate in NO- and prostacyclin-independent coronary dilator responses. In conscious instrumented dogs, intracoronary acetylcholine (ACh, 30.0 ng · kg −1 · min −1 ) increased the external epicardial coronary diameter (CD) by 0.18±0.03 mm (from 3.44±0.11 mm) when increases in coronary blood flow (CBF) were prevented and increased the CD by 0.20±0.05 when CBF was allowed to increase. After the administration of intracoronary N ω -nitro- l -arginine methyl ester (L-NAME), CBF responses to ACh were abolished, but CD responses (0.23±0.05 from 3.22±0.09 mm) were maintained. Blockade of NO formation was confirmed by reduced CD baselines and blunted flow-dependent CD responses caused by adenosine and transient coronary artery occlusions after L-NAME administration. ACh-induced CD increases resistant to L-NAME and indomethacin were reduced after the administration of intracoronary quinacrine, an inhibitor of phospholipase A 2 , or proadifen, an inhibitor of cytochrome P-450. Quinacrine or proadifen alone (without L-NAME) did not alter CD responses to ACh, but L-NAME given after proadifen blunted ACh-induced increases in CD. The increases in CD caused by arachidonic acid given after L-NAME+indomethacin were antagonized by proadifen but not altered by quinacrine. Thus, a cytochrome P-450 metabolite of arachidonic acid accounts for L-NAME–resistant and indomethacin-resistant dilation of large epicardial coronary arteries to ACh. Conversely, NO formation is the dominant mechanism of ACh-induced dilation after blockade of the cytochrome P-450 pathway.