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

Calcium channel and β-adrenoceptor blockade have proved highly useful in antihypertensive therapy. Studies of the mechanisms of action of vanidipinedilol that combine these effects within a single molecule are described here. Intravenous injection of vanidipinedilol (0.1, 0.25, 0.5, 1.0, and 2.0 mg/kg) produced dose-dependent hypotensive and bradycardic responses, significantly different from nifedipine-induced (0.5 mg/kg, i.v.) hypotensive and reflex tachycardic effects in pentobarbital-anesthetized Wistar rats. A single 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 rat atrium, vanidipinedilol (10^-7, 10^-16, and 10^-5 M) competitively antagonized the (-)isoproterenol-induced positive chronotropic and inotropic effects 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 the concentration-response curve of (-)isoproterenol and CaCl₂ suggested that vanidipinedilol possessed β-adrenoceptor-blocking and calcium entry-blocking activities. On tracheal strips of reserpinized guinea pig, cumulative doses of vanidipinedilol (10^-10 to 3 x 10^-6 M) produced dose-dependent relaxant responses. Preincubating the preparation with ICI 118,551 (10^-10, 10^-9, 10^-8 M), a β₂-adrenoceptor antagonist, shifted the vanidipinedilol concentration-relaxation curve significantly to a region of higher concentrations. These results implied that vanidipinedilol had a partial β₂-agonist activity. In the isolated thoracic aorta of rat, vanidipinedilol had a potent effect inhibiting high-K⁺-induced contractions. KCl-induced intracellular calcium changes of blood vessel smooth muscle cell (A7r5 cell lines) determined by laser cytometry also was decreased after administration of vanidipinedilol (10^-8, 10^-7, 10^-6 M). Furthermore, the binding characteristics of vanidipinedilol and various antagonists were evaluated in [³H]CGP-12177 binding to ventricle and lung and [³H]nitrendipine binding to cerebral cortex membranes in rats. The order of potency of β₁- and β₂-adrenoceptor antagonist activity against [³H]CGP- 12177 binding was (-)propranolol (pK(i), 8.59 for β₁ and 8.09 for β₂) > vanidipinedilol (pK(i), 7.09 for β₁ and 6.64 for β₂) > atenolol (pK(i), 6.58 for β₁ and 5.12 for β₂). The order of potency of calcium channel antagonist activity against [³H]nitrendipine binding was nifedipine (pK(i), 9.36) > vanidipinedilol (pK(i), 8.07). The ratio of β₁-adrenergic- blocking/calcium entry-blocking selectivity is 0.1 and indicated that vanidipinedilol revealed more in calcium entry-blocking than in β- adrenergic-blocking activities. It has been suggested that vanidipinedilol- induced smooth muscle relaxation may involve decreased entry of Ca²⁺ and partial β₂-agonist activities. In conclusion, vanidipinedilol is a nonselective β-adrenoceptor antagonist with calcium channel blocking and partial β₂-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 β₂- agonist activities in the blood vessel. A sustained bradycardic effect results from β-adrenoceptor blocking and calcium entry blocking, which blunts the sympathetic activation-associated reflex tachycardia in the heart.