Vanidipinedilol: A vanilloid-based beta-adrenoceptor blocker displaying calcium entry blocking and vasorelaxant activities

Calcium channel and beta-adrenoceptor blockade have proved highly useful in antihypertensive therapy. Studies of the mechanisms of action of vanidipin edilol that combine these effects within a single molecule are described he re. Intravenous injection of vanidipinedilol (0.1, 0.25, 0.5, 1.0, and 2.0 mg/kg) produced dose-dependent hypotensive and bradycardic responses, signi ficantly different from nifedipine-induced (0.5 mg/kg, i.v.) hypotensive an d reflex tachycardic effects in pentobarbital-anesthetized Wistar rats, A s ingle oral administration of vanidipinedilol at doses of 10, 25, and 50 mg/ kg dose-dependently reduced blood pressure with a decrease in heart rate in conscious spontaneously hypertensive rats (SHRs). In the isolated Wistar r at atrium, vanidipinedilol (10(-7), 10(-6), and 10(-5) M) competitively ant agonized the (-)isoproterenol-induced positive chronotropic and inotropic e ffects and inhibited the increase in heart rate induced by Ca2+ (3.0-9.0 mM ) in a concentration-dependent manner. The parallel shift to the right of t he concentration-response curve of (-)isoproterenol and CaCl2 suggested tha t vanidipinedilol possessed beta-adrenoceptor-blocking and calcium entry-bl ocking activities. On tracheal strips of reserpinized guinea pig, cumulativ e doses of vanidipinedilol (10(-10) to 3 x 10(-6) M) produced dose-dependen t relaxant responses. Preincubating the preparation with ICI 118,551 (10(-1 0), 10(-9), 10(-8) M), a beta(2)-adrenoceptor antagonist, shifted the vanid ipinedilol concentration-relaxation curve significantly to a region of high er concentrations. These results implied that vanidipinedilol had a partial beta(2)-agonist activity. In the isolated thoracic aorta of rat, vanidipin edilol had a potent effect inhibiting high-K+-induced contractions. KCl-ind uced intracellular calcium changes of blood vessel smooth muscle cell (A7r5 cell Lines) determined by laser cytometry also was decreased after adminis tration of vanidipinedilol (10(-8), 10(-7), 10(-6) M). Furthermore, the bin ding characteristics of vanidipinedilol and various antagonists were evalua ted in [H-3]CGP-12177 binding to ventricle and lung and [H-3]nitrendipine b inding to cerebral cortex membranes in rats. The order of potency of beta(1 )- and beta(2)-adrenoceptor antagonist activity against [H-3]CGP-12177 bind ing was (-)propranolol (pK(i), 8.59 for beta(1) and 8.09 for beta(2)) > van idipinedilol (pK(i), 7.09 for beta(1) and 6.64 for beta(2)) > atenolol (pK( i), 6.58 for beta(1) and 5.12 for beta(2)). The order of potency of calcium channel antagonist activity against [H-3]nitrendipine binding was nifedipi ne (pK(i), 9.36) > vanidipinedilol (pK(i) 8.07). The ratio of beta(1)-adren ergic-blocking/ calcium entry-blocking selectivity is 0.1 and indicated tha t vanidipinedilol revealed more in calcium entry-blocking than in beta-adre nergic-blocking activities. It has been suggested that vanidipinedilol-indu ced smooth muscle relaxation may involve decreased entry of Ca2+ and partia l beta(2)-agonist activities. In conclusion, vanidipinedilol is a nonselect ive beta-adrenoceptor antagonist with calcium channel blocking and partial beta(2)-agonist associated vasorelaxant and tracheal relaxant activities. Particularly, the vasodilator effects of vanidipinedilol are attributed to a synergism of its calcium entry blocking and partial beta(2)-agonist activ ities in the blood vessel. A sustained bradycardic effect results from beta -adrenoceptor blocking and calcium entry blocking, which blunts the sympath etic activation-associated reflex tachycardia in the heart.