Cardiovascular effects and interaction with adrenoceptors of urapidil

Urapidil is a novel antihypertensive agent, chemically related to uracil. Its cardiovascular profile was evaluated in a variety of pharmacological models. Urapidil caused a significant decrease of blood pressure in intact rats, both hypertensive (SHR) and normotensive (WKY), as well as in α-glucochloralose-anaesthetized cats. Reflex tachycardia was not observed. An analysis in pithed rats showed that urapidil is an α-adrenoceptor blocking drug with an obvious selectivity for postsynaptic α1- over α2-adrenoceptors. The α1-adrenoceptor blocking potency proved quantitatively less than that of prazosin. Experiments on isolated aorta preparations and radioligand binding studies confirmed the selectivity of urapidil for α1- over α2-adrenoceptors. The involvement of urapidil with presynaptic α2-adrenoceptors proved negligible. Urapidil proved to possess modest but significant β1-adrenoceptor blocking activity, accompanied by a certain degree of intrinsic sympathomimetic activity (TSA) at the level of the cardiac β1-adrenoceptors. No significant interaction with vascular β2-adrenoceptors was observed. High doses of urapidil caused pressor effects of a probably unspecific nature; neither α-adrenoceptors nor 5HT-receptors were involved. When injected into the vertebral artery of the cat, urapidil caused a significant central hypotensive effect which was different from that of clonidine and related drugs, since it could not be blocked by yohimbine (α2-receptor antagonist). Similarly, the modest sedation produced by urapidil in mice remained uninfluenced by yohimbine. The urapidil molecule does not contain any stereoisomers. Accordingly, one and the same molecule possesses the following pharmacodynamic properties: postsynaptic α1-adrenoceptor blockade; weak postsynaptic α2-adrenoceptor blockade; modest but selective β1-adrenoceptor blockade with ISA; central hypotensive activity not mediated by central α2-adrenoceptors