ICI 169,369, A 5-HT2/5-HT1C antagonist, that can evoke endothelium-dependent relaxation in rabbit aorta

1. The direct effects of ICI 169,369 on vascular reactivity were investigated in rabbit aortic rings with and without endothelium. 2. ICI 169,369 evoked an endothelium-dependent relaxation in aortic rings precontracted with PGF2 alpha. No direct effects on vascular reactivity were found in endothelial denuded rings. 3. The relaxations induced by ICI 169,369 were inhibited by haemoglobin, an agent known to interfere with the responses to endothelium-derived nitric oxide (EDRF) but not by the cyclo-oxygenase inhibitor, indomethacin. Inhibition of the ICI 169,369-induced relaxation by the L-arginine analogue, NG-monomethyl L-arginine (L-NMMA) confirmed that the relaxations evoked by ICI 169,369 were mediated by the endothelial L-arginine: nitric oxide pathway. 4. Studies with competitive receptor antagonists showed that in the rabbit aorta, ICI 169,369 evoked relaxations which were not elicited by the activation of any known 5-HT1, 5-HT2, 5-HT3, muscarinic, histamine, adenosine receptor or adrenoceptors. 5. The diacylglycerol kinase inhibitor, R 59022 also failed to affect these relaxations. It is concluded that ICI 169,369 has a post-receptor action, possibly by directly affecting intracellular calcium levels in the endothelial cells.