Study of the in vivo and in vitro cardiovascular effect of four new analogues of ketanserin: Implication of 5-HT2A and alpha(1) adrenergic antagonismin their hypotensive effect

The in vivo and in vitro cardiovascular effects of the novel 5-HT2A/alpha(1 )/H-1 antagonist ketanserin analogues QF 0303B, QF 0307B, QF 0311B, QF 0313 B were studied in anaesthetized normotensive rats (ANR) and in isolated rub bed rat aorta (IRRA). In ANR, 0.2 mg.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 presser 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-antagon ist activity than ketanserin. Compounds tested showed low 5-HT2B affinity a nd no activity at muscarinic, nicotinic, or 5-HT3 receptors, nor any marked ability to produce smooth muscle relaxation via calcium entry blockade. Th ere is a significant correlation between hypotension reached and inhibition of the 5-HT-induced presser responses (but not for NA). A certain degree o f correlation was observed between hypotensive effect endurance vs. alpha(1 )-adrenoceptor blockade (but not for serotonin). These results indicate tha t 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 alpha(1) adrenoceptor blockade.