LY53857, a selective and potent serotonergic (5-HT2) receptor antagonist, does not lower blood pressure in the spontaneously hypertensive rat.

LY53857 was a potent antagonist of vascular contraction to serotonin, which is mediated by serotonergic (5-HT2) receptors, with a dissociation constant in vitro of 5.4 X 10(-11) M. Unlike several other serotonin antagonists, LY53857 showed minimal affinity for vascular alpha adrenergic receptors (dissociation constant of 1.4 X 10(-5) M). Thus, LY53857 was a highly potent and selective antagonist at 5-HT2 receptors. In vivo activity paralleled the in vitro observations. In pithed spontaneously hypertensive rats (SHR), LY53857 at 0.1 and 3.0 mg/kg i.p. produced a 22-and 480-fold shift, respectively, in the pressor response to serotonin whereas LY53857 at 10 mg/kg did not alter the pressor response to the alpha receptor agonist, methoxamine. Furthermore, LY53857 administered peripherally also inhibited central serotonin receptors, as evidenced by blockade of the serum corticosterone increase produced by the central actions of the serotonin agonist, quipazine, and by antagonism of tryptamine-induced convulsions in rats. LY53857 in doses that blocked the pressor response to serotonin and that blocked central serotonin receptors did not lower mean arterial blood pressure in the SHR. Thus, the lack of effectiveness of LY53857 to lower blood pressure in the SHR indicates that blockade of both central and vascular serotonin receptors is not a sufficient mechanism to lower blood pressure in this model of hypertension.