RESUMO
The in vivo and in vitro cardiovascular effects of the novel 5-HT2A/alpha1/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, 0.2 mg x 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. alpha1-adrenoceptor blockade (but not for serotonin). These results indicate that in this series the brief hypotensive activity in ANR is attributed to a 5-HT1A receptor blockade and the duration of the effect is better attributed to an alpha1 adrenoceptor blockade.
Assuntos
Anti-Hipertensivos/farmacologia , Ketanserina/farmacologia , Receptores Adrenérgicos alfa 1/metabolismo , Receptores de Serotonina/metabolismo , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Anti-Hipertensivos/química , Aorta , Cobaias , Íleo/efeitos dos fármacos , Íleo/metabolismo , Ketanserina/análogos & derivados , Ketanserina/química , Masculino , Músculos/efeitos dos fármacos , Músculos/metabolismo , Cloreto de Potássio/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2A de Serotonina , Receptor 5-HT2B de Serotonina , Receptores Adrenérgicos alfa 1/efeitos dos fármacos , Receptores Histamínicos H1/efeitos dos fármacos , Receptores Histamínicos H1/metabolismo , Receptores de Serotonina/efeitos dos fármacos , Receptores 5-HT3 de Serotonina , Antagonistas da Serotonina/farmacologia , Vasoconstrição/efeitos dos fármacosRESUMO
In this work, we report for first time that: (1) low doses of ketanserin (0.2 mg/kg) produce a transient hypotensive response in anaesthetized rats, which is basically due to the blockade of 5-hydroxytryptamine (2A) (5-HT)2A receptors, whereas high doses (1 mg/kg) of ketanserin cause a sustained hypotension also mediated by the blockage of alpha1-adrenergic receptors; (2) the in vitro vasorelaxant action of high concentrations of ketanserin (>10 microM) involves Ca2+ antagonism, which may also be responsible, at least in part, for the inhibition of high-K+-induced 45Ca2+ uptake, the inhibition of Ca2+-induced contractions in initially Ca2+-free high-K+ medium, and the negative chronotropic effects on isolated atria. This Ca2+ antagonistic activity does not seem to contribute to the in vivo cardiovascular effects of ketanserin at therapeutic doses.
