An indirect influence of phenylephrine on the release of endothelium-derived vasodilators in rat small mesenteric artery

1 The possibility that stimulation of smooth muscle alpha(1)-adrenoceptors modulates contraction via the endothelium was examined in rat small mesente ric arteries. 2 N-omega-nitro-L-arginine methyl ester, (L-NAME, 100 mu M to inhibit NO sy nthase) increased contraction to single concentrations of phenylephrine (1- 3 mu M) by approximately 2 fold (from a control level of 14.2 +/- 3.0 to 34 .1 +/- 4.2% of the maximum contraction of the artery, n = 20). The action o f L-NAME was abolished by disrupting the endothelium. 3 The subsequent addition of apamin (to inhibit small conductance Ca2+-acti vated K+ channels, 50 nM) further augmented phenylephrine contractions, in an endothelium-dependent manner, to more than 3 fold above control (50.4 +/ - 5.3% of the maximum contraction, n = 11). 4 Charybdotoxin (non-selective inhibitor of large conductance Ca2+-activate d K+ channels, BKCa, 50 nM) plus L-NAME augmented the level of phenylephrin e contraction to 4-5-fold above control (64.1 +/- 3.1%, n = 5), but this ef fect was independent of the endothelium. The potentiation of contraction by charybdotoxin could be mimicked with the selective BKCa inhibitor, iberiot oxin,. 5 Apamin together with L-NAME and charybdotoxin further significantly incre ased the phenylephrine contraction by 5-6-fold, to 79.9 +/- 3.5% of the max imum contraction of the artery (n = 13). 6 Phenylephrine failed directly to increase the intracellular Ca2+ concentr ation in endothelial cells freshly isolated from the small mesenteric arter y. 7 Stimulation of smooth muscle alpha(1)-adrenoceptors in the mesenteric art ery induces contraction that is markedly suppressed by the endothelium. The attenuation of contraction appears to reflect both the release of NO from the endothelium and the efflux of K+ from both endothelial and smooth muscl e cells. This suggests that the release of NO and endothelium-derived hyper polarizing factor can be evoked indirectly by agents which act only on the smooth muscle cells.