VASOMOLOL - AN ULTRA SHORT-ACTING AND VASORELAXANT VANILLOID TYPE BETA(1)-ADRENOCEPTOR ANTAGONIST

The ultra-short-acting and vasorelaxant beta(1)-adrenoceptor blocking activities of vasomolol, a guaiacoxypropanolamine derivative of vanill ic acid ethyl ester, were studied, Vasomolol (0.5, 1.0, 3.0 mg/kg intr avenously, i.v.) produced a dose-dependent bradycardia response and de monstrated particularly a hypotensive action with an ultra-short-actin g property in pentobarbital-anesthetized normotensive rats. Vasomolol' s steady state of beta-blockade was attained less than or equal to 10 min after initial infusion, and a rapid recovery from blockade occurre d after discontinuation of the infusion, although intravenous infusion of vasomolol (300 mu g/kg/min) could not inhibit presser responses in duced by (-)phenylephrine (10 mu g/kg i.v.). In isolated rat thoracic aorta, vasomolol (1-10 mu M) inhibited vascular smooth muscle contract ions induced by both (-)phenylephrine (10(-5) M) and high K+ (75 mM) c oncentration dependently. This inhibitory effect of vasomolol was more sensitive on K+-induced than on (-)phenylephrine-induced contractions , suggesting that the block of Ca2+ influx may involve the major mecha nism of vasorelaxation. In isolated guinea pig tissues, vasomolol (0.0 1-10 mu M) antagonized the (-)isoproterenol (ISO)-induced positive ino tropic and chronotropic effects of the atria and tracheal relaxation r esponses in a concentration-dependent manner. The parallel shift to th e right of the concentration-response curve of (-)ISO suggested that v asomolol was a beta-adrenoceptor competitive antagonist. The effect of vasomolol was more potent on atria than on tracheal tissues, indicati ng that it possesses beta(1)-adrenoceptor selectivity. In addition, va somolol did not show intrinsic sympathomimetic activity (ISA). Moreove r, the binding characteristics of vasomolol were evaluated in [H-3]dih ydroalprenolol ([H-3]DHA) binding to porcine ventricular membranes. Va somolol was an ultrashort-acting and highly selective beta(1)-adrenoce ptor antagonist with vasorelaxant activity and is devoid of ISA.