ICI-169,369, A 5-HT(2) 5-HT(1C) ANTAGONIST, THAT CAN EVOKE ENDOTHELIUM-DEPENDENT RELAXATION IN RABBIT AORTA

1 The direct effects of ICI 169,369 on vascular reactivity were invest igated in rabbit aortic rings with and without endothelium. 2 ICI 169, 369 evoked an endothelium-dependent relaxation in aortic rings precont racted with PGF2alpha. No direct effects on vascular reactivity were f ound in endothelial denuded rings. 3 The relaxations induced by ICI 16 9,369 were inhibited by haemoglobin, an agent known to interfere with the responses to endothelium-derived nitric oxide (EDRF) but not by th e cyclo-oxygenase inhibitor, indomethacin. Inhibition of the ICI 169,3 69-induced relaxation by the L-arginine analogue, N(G)-monomethyl L-ar ginine (L-NMMA) confirmed that the relaxations evoked by ICI 169,369 w ere mediated by the endothelial L-arginine: nitric oxide pathway. 4 St udies with competitive receptor antagonists showed that in the rabbit aorta, ICI 169,369 evoked relaxations which were not elicited by the a ctivation of any known 5-HT1, 5-HT2, 5-HT3, muscarinic, histamine, ade nosine receptor or adrenoceptors. 5 The diacylglycerol kinase inhibito r, R 59022 also failed to affect these relaxations. It is concluded th at ICI 169,369 has a post-receptor action, possibly by directly affect ing intracellular calcium levels in the endothelial cells.