Antihypertensive mechanism of action of ketanserin and some ketanserin analogues in the spontaneously hypertensive rat.

Ketanserin is a new antihypertensive agent with affinity to serotonin (5-HT)2 receptors and at higher concentrations also to alpha 1-adrenoceptors. The present study was designed to evaluate the relative functional importance of the antagonism of alpha 1-adrenoceptors and 5-HT2-receptors in the antihypertensive mechanism of action of ketanserin and analogues after acute administration. In the spontaneously hypertensive rat, ketanserin and the two ketanserin analogues, R56413 and R55667 (which have relatively weaker alpha-adrenolytic properties) were studied with regard to their ability to reduce the blood pressure after acute administration in the conscious rat and their ability to shift the dose response curves for 5-HT and phenylephrine in the pithed rat. The agents tested reduced the blood pressure only in a dose range where they blocked alpha 1-adrenoceptors and there was a striking correlation between the degree of hypotension and the degree of inhibition of the phenylephrine induced pressor responses. 5-HT2-receptor blockade alone did not influence basal blood pressure. However, following pretreatment with R55667 in a low dose the blood pressure reduction to prazosin was enhanced. It is concluded that following acute administration in the rat the major portion of the antihypertensive response to ketanserin is due to an alpha 1-adrenoceptor blockade but that the 5-HT2-receptor blockade contributes.