Labedipinedilol-A: A vanilloid-based α/β-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.

Protective effect of labedipinedilol-A, a novel dihydropyridine-type calcium channel blocker, on myocardial apoptosis in ischemia–reperfusion injury

“…Animals were infused with a bolus of labedipinedilol-A (0.25 or 0.5 mg/kg) or vehicle (10% polyethylene glycol, 10% Tween 80, 1% 1 N HCl and saline) from a femoral vein 10 min before coronary occlusion. Labedipinedilol-A was prepared according to the method described previously (Liang et al, 2000(Liang et al, , 2002. The coronary artery was occluded for 45 min followed by 2-h reperfusion and animals were randomized in the following groups: (1) sham, (2) operated +vehicle, (3) operated + labedipinedilol-A (0.25 mg/ kg) and (4) operated + labedipinedilol-A (0.5 mg/kg).…”

“…The coronary artery was occluded for 45 min followed by 2-h reperfusion and animals were randomized in the following groups: (1) sham, (2) operated +vehicle, (3) operated + labedipinedilol-A (0.25 mg/ kg) and (4) operated + labedipinedilol-A (0.5 mg/kg). These doses were chosen based on our previous study showing that the administration of labedipinedilol-A at these doses significantly reduces the blood pressure and heart rate (Liang et al, 2000). However, the high dose of calcium antagonists acutely lowers blood pressure and results in a collateral phenomenon (Ehring and Heusch, 1997;Gao et al, 2001).…”

“…Oral administration of labedipinedilol-A in SHR and DOCA-salt hypertensive rats demonstrated a long-acting antihypertensive and slight bradycardia effect. Labedipinedilol-A inhibited the protein kinase C-ε translocation and the formation of angiotensin II, endothelin-1 and atrial natriuretic peptide in DOCA-salt hypertensive rats (Liang et al, 2000;Yeh et al, 2003). 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, and may thus have great potential in the prevention of progressive atherosclerosis (Liou et al, 2004(Liou et al, , 2005.…”

Isoeugenodilol: A vasorelaxant ?/?-adrenoceptor blocker with antioxidant activity

“…Third-generation β-blockers such as eugenodilol, ferulidilol, vanidipinedilol, labedipinedilol-A, and carvedilol that possess ancillary vasorelaxant and antioxidant activities, other than β-blockade, are now emerging [Huang et al, 1999a,b;Yeh et al, 2000;Liang et al, 2000;Michael, 1993]. This resulted in the synthesis of a new compound that possesses potent antioxidant and α/β-adrenoceptor blocking activities in one molecule.…”

“…During the past decade, various vanilloid-based β-blockers have been investigated in our laboratory. They are derived from natural products such as xanthone, capsaicin, vanillin, dehydrozingerone, zingerone, ferulic acid, eugenol, and isoeugenol [Chen et al, 1993[Chen et al, , 1994Wu et al, 1996Wu et al, , 1998Sheu et al, 1997;Lin et al, 1996Lin et al, , 1999Huang et al, 1999a,b;Yeh et al, 2000;Liang et al, 2000].…”