5-HT, alpha-adrenoceptors, and blood pressure. Effects of ketanserin in essential hypertension and autonomic insufficiency.

Abstract

SUMMARY The serotonin (5-hydroxytryptamine, 5-HT) antagonist, ketanserin, has a high affinity for 5-HT 2 -receptors but it also binds to a^adrenoceptors. The compound (10 mg i.v.) lowered mean arterial pressure by 22% ± 2% (mean ± SEM, p < 0.001) in 30 patients with essential hypertension. Measurements of heart rate, cardiac output, cardiac filling pressures, forearm blood flow, renal blood flow, and glomerular filtration rate revealed a hemodynamic pattern compatible with vasodilation of both resistance and capacitance vessels. This was accompanied by moderate reflex cardiostimulation. Ketanserin did not alter the pressor effect of bolus injections of (-)-phenylephrine hydrochloride ( A LTHOUGH 5-hydroxytryptamine (5-HT, serotonin) was among the first vasoactive amines . to be discovered and synthesized, its function in blood pressure regulation is still unclear. Recently, a differentiation between two subtypes of 5-HT-receptors has been made on the basis of radioligand-binding studies using membranes prepared from rat frontal cortex.1 Although specific functions associated with these brain receptors have not been identified, it has been shown that the 5-HT-receptors subserving contraction of vascular smooth muscle cells are of the 5-HT 2 -subtype. for clinical investigation. 4 " 6 Ketanserin, however, is not fully specific for 5-HT 2 -receptors, since it also binds to a,-adrenoceptors. High concentrations of ketanserin have an antagonistic effect on a,-adrenoceptor-mediated contractions of isolated arteries and veins. 4 Experiments in animals 4 and preliminary data in humans 8 9 have shown that ketanserin has antihypertensive properties. This may, at least in part, depend on blockade of a,-adrenoceptors. Indeed, it has been reported that hypotensive doses of ketanserin abolished the pressor response to a,-agonists in the pithed rat, the anesthetized normotensive rat, and the conscious spontaneously hypertensive rat.10 " This paper describes the hemodynamic profile of ketanserin's antihypertensive action in patients with essential hypertension. The possibility that the antihypertensive effect of ketanserin depends on interference with a,-adrenoceptor-mediated vasoconstriction was tested by comparison of the pressor effects of the a,-adrenoceptor agonist, phenylephrine, before and after ketanserin and by assessment of the antihypertensive effect of ketanserin after administration of the a,-adre-

Cardiovascular profile and hypotensive mechanism of ketanserin in the rabbit.

“…The transient tachycardia, which accompanied the initial fall in blood pressure, probably resulted from the hypotension-induced activation of the baroreceptor reflex and the subsequent increase in sympathetic activity and- withdrawal of vagal tone. 7 Indeed, the ketanserin-induced changes in heart rate were not observed after ganglionic blockade. The absence of reflex tachycardia during the prolonged hypotensive action of ketanserin may be related to the reported interference of the drug with the autonomic nervous system activity, 5 l0 where it causes a decrease in sympathetic outflow."…”

“…In hypertensive patients ketanserin can lower the arterial blood pressure without causing any attenuation of the pressor response to phenylephrine. 7 This pharmacological evidence has been used to support the concept that a blockade of 5-HT 2 receptors is responsible for the antihypertensive effect of the drug.…”

“…In hypertensive patients ketanserin can lower the arterial blood pressure without causing any attenuation of the pressor response to phenylephrine. 7 This pharmacological evidence has been used to support the concept that a blockade of 5-HT 2 receptors is responsible for the antihypertensive effect of the drug.7 ' 8 In contrast, studies in spontaneously hypertensive rats provide arguments that ketanserin lowers the blood pressure merely by a competitive blockade of a,-adrenergic receptors. 4 -5 -9 Moreover, a central action has been suggested to contribute to the hypotensive action of ketanserin.…”

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

“…In man, the mechanism ofthe hypotensive effect of ketanserin is also unclear as there are conflicting reports concerning the importance of a,-adrenoceptor blockade (Ball et al, 1983;Reimann & Fr6lich, 1983;Wenting et al, 1984).…”

Ketanserin pharmacokinetics in patients with renal failure.

“…After oral administration, Wenting et al, 1984) and oral administration ketanserin is rapidly and completely absorbed. (Hedner et al, 1983;Trenk et al, 1983).…”