Mechanism of ketanserin-induced sympatho-inhibition

Abstract Experiments were undertaken to determine if sympatho-inhibition produced by ketanserin is due to antagonism of central nervous system α 1 -adrenoceptors rather than central 5-HT 2 receptors and if (like prazosin) it produces sympatho-inhibition indirectly via a central (presynaptic) α 2 -adrenoceptor mechanism. Administration of ketanserin (0.03–3.0 mg/kg i.v.) caused a dose-related depression of sympathetic-cholinergic electrodermal responses evoked by electrical stimulation of the hypothalamus in pentobarbital anesthetized cats. No effect of ketanserin was observed on electrodermal responses evoked by preganglionic sympathetic nerve stimulation nor did the more specific 5-HT 2 receptor antagonist, cinanserin, produce a central sympatholytic effect at dosages up to 3 mg/kg i.v. Pretreatment with α 2 -adrenoceptor blockers yohimbine, idazoxan, or rauwolscine significantly antagonized ketanserin-induced sympatho-inhibition. Depletion of central nervous system (CNS) monoamines totally prevented ketanserin-induced sympatho-inhibition although clonidine (30 μg/kg i.v.) continued to be effective. These results suggest that ketanserin acts in the CNS to reduce sympathetic reactivity by blocking α 1 -adrenoceptors and not 5-HT 2 receptors. In this regard, ketanserin appears to act in a manner similar to other α 1 -adrenoceptor antagonists (e.g. prazosin and indoramin) by an apparent presynaptic facilitation of α 2 -adrenoceptor mediated tonic inhibition descending from the lower brainstem.