VANIDILOL - A VANILLOID-TYPE VASORELAXANT AND OCULAR HYPOTENSIVE BETA-ADRENOCEPTOR BLOCKER WITH PARTIAL BETA-2-AGONIST ACTIVITY

Vanidilol, utylamino)propoxy)-3'-methoxyphenyl]-benzaldehyde, newly sy nthesized from vanillin, is a vanilloid-type beta-adrenoceptor blocker . The beta-adrenoceptor-blocking properties of vanidilol were studied both in vivo and in vitro. Intravenous injection of vanidilol (1.0, 3. 0, 5.0 mg/kg) in anesthetized Wistar rats produced a decrease in blood pressure and a dose-dependent bradycardia response. Vanidilol inhibit ed the tachycardia effects induced by (-)isoproterenol, but had no blo cking effect on the arterial presser responses induced by phenylephrin e. In isolated guinea-pig tissues, vanidilol attenuated the (-)isoprot erenol-induced positive chronotropic and inotropic effects of the atri a and trachea relaxation responses in a concentration-dependent manner . The parallel shift to the right of the concentration-response curve of(-)isoproterenol suggested that the agent was a beta-adrenoceptor co mpetitive antagonist. The apparent pA(2) values for vanidilol on the r ight atria,left atria and trachea were 7.67 +/- 0.03, 7.89 +/- 1.02 an d 7.66 +/- 0.15, respectively, denoting that vanidilol was a nonselect ive beta-blocker. The intrinsic sympathomimetic activity of vanidilol and propranolol was determined on isolated atria and trachea from rese rpinized guinea pigs. Propranolol caused significantly negative inotro pic and chronotropic effects at 10(-6) mol/l or above, whereas vanidil ol possessed less cardiodepressant activities than propranolol. In res erpinized tracheal strips, vanidilol produced dose-dependent relaxant responses, but propranolol was ineffective. Preincubating the preparat ions with ICI 118,551 (0.1-10 nmol/l), a beta(2)-adrenoceptor antagoni st, significantly shifted the concentration-relaxation curves of vanid ilol to a region of higher concentrations. In isolated guinea-pig thor acic aorta, vanidilol (0.1-10 mu mol/l) inhibited the phenylephrine (1 0(-5) mol/l)-induced tonic contraction in vascular smooth muscle which was related to the block of calcium influx. In 20% saline-perfused ra bbits, vanidilol showed a marked delay in intraocular pressure recover y, demonstrating an ocular hypotensive action. Binding characteristics of vanidilol and propranolol were evaluated in [H-3]dihydroalprenolol binding to porcine ventricular membranes. Vanidilol was less potent t han propranolol in competing for the beta-adrenoceptor-binding sites. On the other hand, vanidilol had a high hydrophilicity in comparison w ith propranolol. In conclusion, vanidilol exhibited nonselective beta- adrenoceptor blocking, vasorelaxant and ocular hypotensive activities, but was devoid of alpha-adrenoceptor blocking and beta(1)-agonist act ivity. Partial beta(2)-adrenoceptor agonist activity and inhibitory ac tivity on calcium influx may share in the vasorelaxant activity.