Inhibition of R 28935- and R 29814-induced hypotension by prazosin in anaesthetized normotensive rats.

The intravenous administration of erythro 1-(1-[2-(1,4-benzodioxane-2-yl)-2-hydroxyethyl]-4-piperidyl)-2-benzimidazolinone R 28935) and the threo from R 29814 to anaesthetized normotensive rats showed a dose-dependent decrease in mean arterial pressure. Previous (-1 hr) intraperitoneal (0.1 mg/kg) as well as subcutaneous (0.03 mg/kg) treatment with the alpha 1-adrenoceptor blocking drug prazosin antagonized the hypotensive responses to R 28935 and R 29814. The selective antagonist of alpha 2-adrenoceptors yohimbine (0.5 mg/kg) was ineffective. On the other hand, the hypotensive action of clonidine was hardly affected by this prazosin treatment, whereas yohimbine now significantly impaired it. R 28935 and R 29814 showed no direct alpha-adrenoceptor stimulating properties and were moderately active in inhibiting the pressor response to (-)-phenylephrine in pithed normotensive rats when compared with phentolamine and prazosin. The results confirm and extend previous findings in cats. It is concluded that in some way central alpha 1-adrenoceptors are involved in the hypotensive mechanism of R 28935 (R 28914). However, central alpha 1-adrenoceptors are probably not the common sites of interaction, since any alpha 1-adrenoceptor-stimulating potency is lacking for R 28935 (R 29814) and their (moderate) affinity for alpha 1-adrenoceptors bears no relationship to their hypotensive activity.