Analysis of the depressant effect of the endothelium on contractions of rabbit isolated basilar artery to 5-hydroxytryptamine.

Abstract

1. The effects of endothelium removal and of a number of pharmacological agents known to modify endothelial cell function on the contractile response of rabbit isolated basilar arteries to 5-hydroxytryptamine (5-HT) and other vasoconstrictors were studied. 2. Endothelium removal slightly reduced the contractile response to potassium chloride (40 mM) but markedly augmented and potentiated contractions to 5-HT (1 nM-10 microM). 3. L-NG-nitro-arginine (L-NOARG, 1-30 microM), an inhibitor of nitric oxide formation in vascular endothelial cells, evoked endothelium-dependent contraction, and augmented and potentiated contractions to 5-HT in endothelium-intact but not endothelium-denuded tissues. Prior incubation with L-arginine (1 mM), but not D-arginine (1 mM), abolished these effects of L-NOARG (1 microM). L-NOARG (30 microM) also augmented contractions of endothelium-intact tissues to noradrenaline, prostaglandin F2 alpha, and to a lesser degree endothelin-1. 4. Neither glibenclamide (3 microM) nor N-ethylmaleimide (1 microM), putative inhibitors of the effects of endothelium-derived hyperpolarizing factor (EDHF) and of agonist-stimulated endothelium-derived relaxing factor (EDRF) release respectively, had any effect on either resting tension or the contractile response to 5-HT. In some tissues indomethacin (3 microM), a cyclo-oxygenase inhibitor, produced a small contraction and augmented the contractile response to 5-HT, but in most cases indomethacin was without effect. 5. In endothelium-intact tissues precontracted with uridine 5'-triphosphate (UTP; 100 microM), 5-HT did not evoke relaxation but rather caused further contraction. Under the same conditions acetylcholine (0.01-10 microM) evoked endothelium-dependent relaxation.6. These data demonstrate that the endothelium profoundly depresses contractions of rabbit isolated basilar artery to 5-HT, and that this phenomenon can be fully accounted for by the release of an L-NOARG-sensitive relaxing factor. Neither glibenclamide-sensitive EDHF nor cyclo-oxygenase products plays a major role. As we could find no evidence that 5-HT stimulates the production of EDRF per se, and L-NOARG caused endothelium-dependent contraction and augmented contractions to other vasoconstrictor agents, it seems likely that a basal release of EDRF underlies this phenomenon.