Evidence that NAN-190-induced hypotension involves vascular alpha1-adrenoceptor antagonism in the rat

The effect of NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-phthalimido]-butyl] piperazine), described as a mixed 5-HT(1A) receptor agonist/antagonist, on cardiovascular function was studied. The i.v. injection of NAN-190 (1-300 micro/kg) dose-dependently decreased blood pressure (p<0.001), while heart rate was not significantly modified compared to saline-treated, anaesthetized adult rats. WAY 100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide), a highly selective 5-HT(1A) receptor antagonist, increased NAN-190-induced hypotension (p<0.05). In the pithed rat NAN-190 displaced the phenylephrine dose-pressor response curve to the right; ED(50) values were: approximately 14, 20, 40 and 270 microg/kg for saline and NAN-190 (1, 10 and 100 microg/kg, respectively); similar ED(50) values were obtained with prazosin ( approximately 20, 69 and 358 microg/kg for 1, 10 and 100 microg/kg of prazosin, respectively). NAN-190 shifted to the right the concentration-response curves to phenylephrine in rat tail artery (alpha(1A)-adrenoceptors), in rabbit aorta (alpha(1B)-adrenoceptors) and in rat aorta (alpha(1D)-adrenoceptors), with pA(2) values of 9.47, 9.02 and 9.99; while Schild slopes were -0.78, -1.13 and -0.90, respectively (not significantly different from unity). The results show that NAN-190 induced hypotension in the anaesthetized, adult rat and suggest that this effect could be explained by antagonism of vascular alpha(1)-adrenoceptors.