Evidence that blood pressure reduction by serotonin antagonists is related to alpha receptor blockade in spontaneously hypertensive rats

Abstract

In vitro affinity for vascular 5HT2 and alpha receptors was determined for several compounds (spiperone, ketanserin, mianserin, trazodone, mepiprazole, benzoctamine, m-trifluoromethylphenylpiperazine, m-chlorophenylpiperazine, and l-(l-naphthyl)piperazine) known to interact with serotonin receptors. All compounds competitively inhibited 5HT2 and alpha receptors with differing degrees of selectivity. Based on these observations, ketanserin, benzoctamine, and 1-(1- naphthyl)piperazine were evaluated as antihypertensive agents in spontaneously hypertensive rats (SHR). Of these compounds, l-(l-naphthyl)piperazine was a highly selective 5HT2 receptor antagonist with a ratio of 5HT2 to alpha receptor affinity of greater than 2000. The ratio of 5HT2 to alpha receptor affinity for ketanserin and benzoctamine was 63 and 16, respectively. However, the order of affinity toward 5HT2 receptors was ketanserin > l-(l-naphthyl)piperazine > benzoctamine whereas the order of affinity toward alpha receptors was ketanserin > benzoctamine > l-(l-naphthyl)piperazine. A similar order of potency toward both 5HT2 and alpha receptors was found in pithed SHR based on antagonism of the pressor response to serotonin and methoxamine, respectively. In the SHR, maximum blood pressure reduction at a dose of 10 mg/kg i.p. was approximately 65 and 30 mm Hg for ketanserin and benzoctamine, respectively; l-(l-naphthyl)piperazine did not affect blood pressure. Thus, blood pressure reduction more closely paralleled the in vitro and in vivo potency of these agents toward vascular alpha rather than 5HT2 receptors. These data support the contention that alpha receptor blockade rather than selective 5HT2 receptor blockade is responsible for the antihypertensive activity of "serotonergic antagonists" in the SHR. © 1983 American Heart Association, Inc.