In vivo and in vitro activity of selective 5-hydroxytryptamine2 receptor antagonists

The abilities of ketanserin, ritanserin, R56413 and LY53857 to inhibit 5-hydroxytryptamine (5-HT) and noradrenaline-induced vasoconstrictor responses both in vitro and in vivo and to lower blood pressure in the rat, were compared. In the isolated perfused mesenteric artery preparation of the rat all of the compounds tested were found to be potent inhibitors of 5-HT-induced vasoconstrictor responses. Ritanserin was the most potent compound, producing more than 50% inhibition of a near maximal response to 5-HT at a concentration of 10(-11) M. All four compounds were found to be competitive antagonists of noradrenaline; ketanserin being the most potent with a pA2 value of 7.64 +/- 0.06. 5-HT-induced pressor responses in the pithed rat were inhibited by low doses (0.3-10 micrograms kg-1) of the four compounds. Ketanserin, at doses of 0.1-3.0 mg kg-1, resulted in rightward shifts of the control dose-response curve to noradrenaline in the pithed rat. None of the other compounds had any significant effect on the noradrenaline-induced pressor responses. Ketanserin (0.1-1 mg kg-1) produced a dose-dependent decrease in the mean arterial blood pressure of anaesthetized rats. The maximum decrease in blood pressure observed following a dose of 1 mg kg-1 ketanserin was 73.7 +/- 4.7 mmHg. The other compounds at doses of 1.0-3.0 mg kg-1 produced a decrease in blood pressure of a lesser magnitude than that following ketanserin. In addition, this effect did not appear to be dose-dependent. It is suggested that the acute hypotensive effect of ketanserin results predominantly from alpha 1-adrenoceptor blockade. The involvement ofantagonism of 5-HT2 receptors in the hypotensive effect of the other compounds tested cannot be excluded.