Study of the in Vivo and in Vitro Cardiovascular Effects of Four New Analogues of Ketanserin : Implication of 5-HT_<2A> and α_1 Adrenergic Antagonism in Their Hypotensive Effect

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The in vivo and in vitro cardiovascular effects of the novel 5-HT_<2A>/α_1/H_1 antagonist ketanserin analogues QF 0303B, QF 0307B, QF 0311B, QF 0313B were studied in anaesthetized normotensive rats (ANR) and in isolated rubbed rat aorta (IRRA). In ANR, 0.2mg・kg^<-1> i.v. of each compound produced a rapid, remarkable but short-lasting fall in mean arterial blood pressure (MAP) accompanied by bradycardia. All compounds significantly modified the pressor effects induced by 5-hydroxytryptamine (5-HT) and noradrenaline (NA). In IRRA, the compounds inhibited NA- and 5-HT-induced contractions in a competitive fashion. Furthermore, the analogues displayed lower H_1-antagonist activity than ketanserin. Compounds tested showed low 5-HT_<2B> affinity and no activity at muscarinic, nicotinic, or 5-HT_3 receptors, nor any marked ability to produce smooth muscle relaxation via calcium entry blockade. There is a significant correlation between hypotension reached and inhibition of the 5-HT-induced pressor responses (but not for NA). A certain degree of correlation was observed between hypotensive effect endurance vs. α_1-adrenoceptor blockade (but not for serotonin). These results indicate that in this series the brief hypotensive activity in ANR is attributed to a 5-HT_<2A> receptor blockade and the duration of the effect is better attributed to an α_1 adrenoceptor blockade.
公益社団法人日本薬学会の論文
2000-05-01