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

The combination of beta-adrenoceptor blockade and vasodilator action have p roved highly useful in antihypertensive therapy. Studies of the mechanisms of action of labedipinedilol-A that combine these effects within a single m olecule 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.)-indu ced hypotensive and reflex tachycardia activities in pentobarbital-anesthet ized Wistar rats. Pretreatment with labedipinedilol-A also inhibited phenyl ephrine (20 mu g/kg, i.v.)-induced hypertensive and (-)isoprenaline (0.5 mu g/kg, i.v.)-induced tachycardia effects. Oral administration of labedipine ditol-A (5-50 mg/kg) in spontaneously hypertensive rats (SHR) reduced the b lood pressure and heart rate for 24 h but did not increase heart rate. Labe dipinedilol-A (10(-7)-10(-5) M) competitively antagonized (-)isoprenaline ( 10(-10)-10(-4)M)-induced positive chronotropic and inotropic effects of the isolated rat atria and tracheal relaxation responses of the isolated guine a 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 antagoni zed CaCl2 and norepinephrine-induced contractions with pKCa(-1) and pA(2) v alues of 8.46 +/- 0.05 and 8.28 +/- 0.03 and had a potent effect of inhibit ing high K+-induced vasocontraction. Furthermore, labedipinedilol-A, in an equal antagonist activity, inhibited norepinephrine-induced phasic and toni c contraction. In the cultured blood vessel smooth muscle cell (A7r5 cell l ine), KCl, norepinephrine, and Bay K 8644-induced intracellular calcium cha nges were decreased after application of labedipinedilol-A (10(-9)-10(-6) M ). The binding characteristics of labedipinedilol-A, were evaluated in [H-3 ]CGP-12177 binding to ventricle and lung and [H-3]nitrendipine and [H-3]pra zosin binding to brain membranes in rats. The -logIC(50) values of labedipi nedilol-A for beta(1)-, beta(2)-, and alpha 1-adrenoceptor and calcium chan nel, 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. Labedipineditol-A-induced sustained depressor effect w as mainly attributed to its calcium entry and alpha-adrenoceptor blocking a ctivities in the blood vessel. Sustained bradycardia effect resulted from b eta-adrenoceptor and calcium entry blocking, which deleted the sympathetic activation-associated reflex tachycardia in the heart. Drug Dev. Res. 49:94 -108, 2000. (C) 2000 Wiley-Liss, Inc.