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

Abstract

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 × 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.

The Vasorelaxing Action of Labedipinedilol-A Involves Endothelial Cell-Derived NO and eNOS Expression Caused by Calcium Influx

“…4 At the beginning of each experiment, aortic rings were stretched to a resting tension of 1 g and then contracted with phenylephrine (PE, 1 mM), and, when the contractions had reached a plateau, the endothelial integrity of the preparations (E + ) or absence of endothelium (E 2 ) was verified by adding acetylcholine (1 mM) to the superfusate. Only the aortic rings with a vasorelaxant response of .70% inhibition of the preconstructed level were considered E + .…”

“…24 Labedipinedilol-A has been reported to relax isolated aortic rings. 4 Our present data confirm that labedipinedilol-A can indeed relax precontracted aortic rings. These results suggest the hypotensive effect of labedipinedilol-A can be explained by the direct relaxing effect of labedipinedilol-A on the vasculature.…”

“…Phenylephrine, methylene blue, EGTA, thrombin, nicardipine HCl, and MTT [3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide] were obtained from Sigma Chemical (St Louis, MO). 1H- [1,2,4]oxadiazolo [4,3-a]quinoxalin-one (ODQ) and N v -nitro-L-arginine methyl ester (L-NAME) were obtained from Research Biochemical International (Natick, MA). F12 nutrient mixture, fetal bovine serum (FBS), penicillin, streptomycin, and all other tissue culture reagents were obtained from GIBCO BRL Life Technologies (Grand Island, NY).…”

“…Labedipinedilol-A has been suggested to possess calcium entry and a/b-adrenoceptor blocking activities in a single molecule, which is different from conventional calcium antagonists such as nifedipine and almodipine. 4 Labedipinedilol-A not only is a vasodilator but also inhibits translocation of ventricle PKCe and various forms of humoral signaling, including endothelin-1, in DOCA-salt-treated rats. 5 In addition, labedipinedilol-A is an inhibitor of vascular smooth muscle cell proliferation induced by a broad group of mitogens, such as serum, platelet-derived growth factor, and norepinephrine, which may have great potential in the prevention of progressive atherosclerosis.…”

Synthesis of a New Series of 4-Aryl-1,4-Dihydropyridines with Calcium Channel Blocking and Vasodilatory Activity

“…The envisaged goal of these new developments was an optimization of vascular selectivity. A new series of 4-aryl-1,4-dihydropyridines possessing vanilloid-based moieties has attracted much attention lately Liang et al, 2000;Liang et al, 2002). These vanilloid-based hybrid molecules, e.g., vanidipinedilol and labedipinedilol ( Fig.…”