Cardiovascular profile and hypotensive mechanism of ketanserin in the rabbit.

Abstract

SUMMARY Using the radioactive microsphere technique, we studied the systemic and regional hemodynamic effects of ketanserin in conscious renal hypertensive rabbits. To characterize the hypotensive mechanism of the compound, we evaluated its antagonism toward 5-hydroxytryptamine 2 and a,-adrenergic receptors at hypotensive doses and compared the cardiovascular profile of ketanserin with that of the a,-selective adrenergic receptor antagonist prazosin. Ketanserin (0.1, 0.3, and 1.0 mg/kg i.v.) produced a biphasic effect on the arterial blood pressure. A short, pronounced fall in blood pressure accompanied by tachycardia preceded a more moderate and longer lasting doserelated hypotensive effect. The presence of adequate autonomic nervous system activity seems to be required for the prolonged hypotensive action of ketanserin because, in animals pretreated with hexamethonium (30 mg/kg), the blood pressure, after an initial decrease, returned to baseline values within a few minutes after each ketanserin dose. Ketanserin inhibited the pressor responses produced by 5-hydroxytryptamine (10, 30, and 100 /zg/kg i.v.) and phenylephrine (3, 10, and 30 Mg/kg '• v -)> which indicates that, at hypotensive doses, the compound antagonized both 5-hydroxytryptamine 2 receptors and aj-adrenergic receptors. At doses that caused a comparable degree of a,-adrenergic receptor blockade, ketanserin (0.1, 0.3, and 1.0 mg/kg i.v.) as well as prazosin (0.01, 0.03, and 0.10 mg/kg i.v.) decreased the blood pressure as a result of a reduction in total peripheral resistance. While cardiac output increased, especially at the lower doses of ketanserin, a moderate decrease in this variable contributed to the hypotensive effect of the highest dose of prazosin. Both compounds decreased the vascular resistance in the kidneys, gastrointestinal tract, and bones, whereas that in the skin and skeletal muscles was not significantly altered. In contrast to prazosin, ketanserin also caused vasodilatation in the coronary and cerebral vascular beds. The results suggest that, in addition to a direct vasodilator effect of short duration, ketanserin has a prolonged hypotensive action in conscious hypertensive rabbits that is predominantly due to ai-adrenergic receptor blockade. has been shown to reduce the blood pressure in animals 43 and humans 6 -7 by a mechanism that is still a matter of debate. 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. 10-" To provide further information on the hypotensive mechanism of ketan...

LY53857, a 5HT2 Receptor Antagonist, Delays Occlusion and Inhibits Platelet Aggregation in a Rabbit Model of Carotid Artery Occlusion

“…In contrast to the effects of ketanserin which blocks both 5HT 2 and alpha receptors to lower blood pressure in the rabbit, LY53857 (50 to 500 µg/kg IV) exerted only a modest, transient effect on mean arterial pressure with no effect on heart rate in rabbits. Similar data with LY53857 were observed in dogs (3) and are consistent with previous studies in rats demonstrating that LY53857 given intravenously exerts effects on blood pressure only in doses well in excess of those required to block 5HT 2 receptors (44).…”

Serotonin: a review

“…Ketanserin is a 5‐HT 2 antagonist also causes α 1 ‐adrenoreceptor blockade and reliably results in brief resolution of naturally occurring and experimentally induced hypertension. In fact, the hemodynamic effects of ketanserin are remarkably similar to those seen with administration of prazosin, a well known α 1 ‐adrenergic antagonist (Bolt & Saxena, 1985). This likely explains why specific 5‐HT antagonists have no clinical effect on hypertension.…”

Cardiovascular Effects From Stimulation of 5‐hydroxytryptamine Receptors

“…First, a 5-HT2 receptor antagonist, ketanserin, has been found effective in the treatment of hypertension. However, it is far from clear whether the blockade of 5-HTz receptors is responsible for the antihypertensive effect of ketanserin since the drug has other properties (a-adrenoceptor blockade, central sympathoinhibition, direct vasodilatation) and no other selective 5-HT2 receptor antagonist effectively lowers arterial blood pressure (see Bolt and Saxena, 1985 ; Saxena et af., 1987). The second approach is the development of 5-HTlA receptor selective compounds which lower blood pressure by a central nervous system action.…”

“…Since 5-HT has effects on the heart (bradycardia or tachycardia) and blood vessels (relaxation or contraction) as well as the baroreflex, central vasomotor function, and transmitter release from postganglionic sympathetic nerve fibres (see below), the three phases of the blood pressure response are quantitatively different in different species and experimental circumstances. For example, rabbits (Schneider and Yonkman, 1954;Bolt and Saxena, 1985), cats (Schneider and Yonkman, 1954;Saxena et al, 1985a), and pigs (Saxena and Verdouw, 1982) exhibit a poor hypertensive phase which is very prominent in the dog (Schneider and Yonkman, 1954), particularly after ganglion blockade (Cavero et al, 1981). The latter appears to be due to a massive release of catecholamines from the adrenal medulla (Feniuk et al, 1981 ;Kimura and Satoh, 1983).…”