Alpha-adrenergic blockade makes minimal contribution to ketanserin's hypotensive effect.

Ketanserin is a selective (S2) serotonin receptor antagonist currently under investigation as an antihypertensive. It has been suggested that the antihypertensive action of ketanserin might be principally due to alpha-adrenergic receptor antagonism rather than its effect on serotonin receptors. We therefore determined the contribution of alpha-adrenergic blockade to the hypotensive effects of ketanserin in six patients with hypertension and compared that with the alpha-adrenergic blockade produced by prazosin, a known alpha 1-adrenergic antagonist. Each patient received placebo, ketanserin (40 mg every 8 hours), and prazosin (5 mg every 8 hours). Each agent was administered for 4 weeks in random order. Both ketanserin and prazosin lowered blood pressure significantly and to a similar extent. The extent of alpha-adrenergic blockade was determined from the ability to inhibit the hypertensive effect of phenylephrine infusions. The dose of phenylephrine required to raise the blood pressure by 20 mm Hg was significantly higher during both ketanserin (1.41 +/- 0.27 micrograms/kg/min; p less than 0.05) and prazosin (4.99 +/- 0.77 micrograms/kg/min; p less than 0.01) administration compared with placebo (0.85 +/- 0.15 micrograms/kg/min). However, the dose ratio was more than fourfold higher during prazosin treatment (7.38 +/- 1.99; p less than 0.05) than during ketanserin (1.69 +/- 0.21). Thus at equipotent hypotensive doses the extent of alpha-blockade produced by ketanserin was more than fourfold lower than that of prazosin, implying that mechanisms other than alpha-blockade must contribute to the antihypertensive actions of ketanserin.