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 –4 M)‐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 Ca 2+ (3.0–9.0 mM) in a concentration‐dependent manner. In the isolated rat aorta, labedipinedilol‐A competitively antagonized CaCl 2 and norepinephrine‐induced contractions with pKCa –1 and pA 2 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 [ 3 H]CGP‐12177 binding to ventricle and lung and [ 3 H]nitrendipine and [ 3 H]prazosin binding to brain membranes in rats. The ‐logIC 50 values of labedipinedilol‐A for β 1 ‐, β 2 ‐, and α 1 ‐adrenoceptor and calcium channel, were 8.17 × 10 –7 M, 8.20 × 10 –7 M, 2.20 × 10 –8 M, and 2.46 × 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. Drug Dev. Res. 49:94–108, 2000. © 2000 Wiley‐Liss, Inc.