Mechanism of the Hypotensive Effect of Ketanserin

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Abstract
Summary The mechanism of the hypotensive action of ketanserin, a selective 5-HT2 receptor antagonist with appreciable affinity for α1-adrenoceptors, has been investigated. In normotensive Sprague -Dawley rats anesthetized with pentobarbitone, intravenous injections of ketanserin, 0.0625 1.0 mg/kg, produced immediate and sustained, dose-related falls in blood pressure and heart rate. The fall in blood pressure was not a consequence of the fall in heart rate since section of the vagosympathetic trunk reversed the former with no persistent effects on the latter. Blood pressure was also reduced by ketanserin in rats anesthetized with methane and in conscious spontaneously hypertensive rats (SHR). In pithed preparations, the same doses of ketanserin caused sustained inhibition of pressor responses to stimulation of the whole spinal sympathetic outflow and phenylephrine; but responses to noradrenaline and. in particular, angiotensin II were less markedly affected. Blood pressure responses to 5-hydroxytryptamine (5-HT) were strongly inhibited at doses of ketanserin 25− 100 times less than those needed to lower blood pressure. The peripheral, vascular 5-HT antagonist. B.W. 501C67, was 1.5 times more active than ketanserin as an inhibitor of the pressor response to 5-HT in the pithed rat. At a dose (0.2 mg kg) chosen to give substantial 5-HT receptor blockade equivalent to that produced by ketanserin. 0.25 mg/kg, B.W. 501C67 neither lowered blood pressure in the anesthetized rat nor inhibited pressor responses to phenylephrine or to sympathetic stimulation in pithed preparations. Thus, doses of ketanserin that lower blood pressure in anesthetized normotensive rats and in conscious SHR inhibit sympathetic tone to the peripheral vasculature by blocking α1-adrenoceptors. Since selective and substantial blockade of vascular 5-HT receptors by B.W. 501C67 did not result in a fall in blood pressure. α1-adrenoceptor blockade rather than 5-HT receptor blockade would appear to be the major factor contributing to the hypotensive antihypertensive action of ketanserin under the conditions of these experiments.

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