Mequitazine, 10-(3-quinuclidinylmethyl) phenothiazine, inhibited contractile responses to KCl, phenylephrine (PE), 5-hydroxytryptamine (5-HT), and Ca2+ in rat aorta. Indomethacin or removal of endothelium did not affect the inhibitory effect of mequitazine on the responses to PE. In Ca(2+)-free medium containing EGTA and nifedipine, mequitazine inhibited both residual response to PE and subsequent response to Ca2+ in the presence of PE. Mequitazine potentiated the relaxation to nitroglycerin (NTG) and isoproterenol. In the presence of forskolin, mequitazine did not cause further potentiation of NTG relaxation. Mequitazine relaxation was slightly inhibited by nifedipine and was potentiated by theophylline. The relaxation was not affected by zaprinast, methylene blue, W-7, propranolol, cimetidine, glyburide, or tetraethylammonium. Tissue level of cyclic AMP in rat aorta was increased by mequitazine. These results suggests that mequitazine may inhibit voltage-operated Ca2+ channels (VOC) and increases the level of cyclic AMP.