Labedipinedilol-A: A vanilloid-based α/β-adrenoceptor blocker with calcium entry blocking and long-acting antihypertensive properties

The combination of β-adrenoceptor blockade and vasodilator action have proved highly useful in antihypertensive therapy. Studies of the mechanisms of action of labedipinedilol-A that combine these effects within a single molecule are described in this report. Intravenous labedipinedilol-A (0.1-1.0 mg/kg) produced dose-dependent hypotensive and bradycardia responses for above 1.0 h, significantly different from nifedipine (0.5 mg/kg, i.v.)- induced hypotensive and reflex tachycardia activities in pentobarbital- anesthetized Wistar rats. Pretreatment with labedipinedilol-A also inhibited phenylephrine (20 μg/kg, i.v.)-induced hypertensive and (-)isoprenaline (0.5 μg/kg, i.v.)-induced tachycardia effects. Oral administration of labedipinedilol-A (5-50 mg/kg) in spontaneously hypertensive rats (SHR) reduced the blood pressure and heart rate for 24 h but did not increase heart rate. Labedipinedilol-A (10^-7 -10^-5 M) competitively antagonized (- )isoprenaline (10^-10-10^-4M)-induced positive chronotropic and inotropic effects of the isolated rat atria and tracheal relaxation responses of the isolated guinea pig tissues. Labedipinedilol-A also prevented the rate- increasing effects of increased extracellular Ca²⁺ (3.0-9.0 mM) in a concentration-dependent manner. In the isolated rat aorta, labedipinedilol-A competitively antagonized CaCl₂ and norepinephrine-induced contractions with pKCa^-1 and pA₂ values of 8.46 ± 0.05 and 8.28 ± 0.03 and had a potent effect of inhibiting high K⁺ -induced vasocontraction. Furthermore, labedipinedilol-A, in an equal antagonist activity, inhibited norepinephrine- induced phasic and tonic contraction. In the cultured blood vessel smooth muscle cell (A7r5 cell line), KCl, norepinephrine, and Bay K 8644-induced intracellular calcium changes were decreased after application of labedipinedilol-A (10^-9-10^-6 M). The binding characteristics of labedipinedilol-A were evaluated in [³H]CGP-12177 binding to ventricle and lung and [³H]nitrendipine and [³H]prazosin binding to brain membranes in rats. The -logIC₅₀ values of labedipinedilol-A for β₁-, β₂-, and α₁- adrenoceptor and calcium channel, were 8.17 x 10^-7 M, 8.20 x 10^-7 M, 2.20 x 10^-8 M, and 2.46 x 10^-8 M, respectively. Labedipinedilol-A-induced sustained depressor effect was mainly attributed to its calcium entry and α- adrenoceptor blocking activities in the blood vessel. Sustained bradycardia effect resulted from β-adrenoceptor and calcium entry blocking, which deleted the sympathetic activation-associated reflex tachycardia in the heart. (C) 2000 Wiley-Liss, Inc.