Study of the in Vivo and in Vitro Cardiovascular Effects of Four New Analogues of Ketanserin : Implication of 5-HT2A and α1 Adrenergic Antagonism in Their Hypotensive Effect

The in vivo and in vitro cardiovascular effects of the novel 5-HT2A/α1/H1 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 H1-antagonist activity than ketanserin. Compounds tested showed low 5-HT2B affinity and no activity at muscarinic, nicotinic, or 5-HT3 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. α1-adrenoceptor blockade (but not for serotonin). These results indicate that in this series the brief hypotensive activity in ANR is attributed to a 5-HT2A receptor blockade and the duration of the effect is better attributed to an α1 adrenoceptor blockade.