Cardiovascular effects of B-HT 958, an alpha-adrenoceptor agonist with a high pre/postsynaptic activity ratio.

B-HT 958 (2-amino-6-(p-chlorobenzyl)-4H-5,6,7,8-tetrahydrothiazolo[5,4-d]az epine), chemically related to clonidine-like drugs of the azepine type, was described previously as a partial alpha 2-adrenoceptor agonist which acted presynaptically mainly as agonist and postsynaptically as antagonist. Following i.v. infusion in anaesthetized cats, 3 mg/kg of B-HT 958 lowered blood pressure, heart rate, cardiac output and total peripheral vascular resistance. A small central nervous component was indicated, since 100 micrograms/kg injected into the vertebral artery was equipotent to 300 micrograms/kg i.v. in lowering blood pressure and heart rate. The drug (1 mg/kg i.v.) decreased the discharge rate of the preganglionic sympathetic splanchnic nerve, but in contrast to the effect of clonidine this could not be demonstrated in decerebrate cats. As blood pressure and heart rate were decreased by B-HT 958 in decerebrate cats, the main site of action was assumed to be peripheral. Also in contrast to clonidine, B-HT 958 did not induce vagal baroreflex bradycardia in anaesthetized dogs with blocked beta-adrenoceptors following intracisternal (30 micrograms/kg as well as 3 mg/kg) injection. In anaesthetized rats the decrease in blood pressure and heart rate caused by 1 mg/kg B-HT 958 i.v. was antagonized by 0.5 mg/kg piperoxan i.v. It is suggested that the cardiovascular effects of B-HT 958 depend on its high selectivity for alpha 2-adrenoceptors and are due to its agonist action presynaptically on peripheral adrenergic nerve terminals.