Labedipinedilol-A: A vanilloid-based α/β-adrenoceptor blocker with calcium entry blocking and long-acting antihypertensive properties
✍ Scribed by Jhy-Chong Liang; Jwu-Lai Yeh; Lien-Chai Chiang; Yu-Chiao Yang; Sheng-Hsiung Sheu; Wen-Ter Lai; Ing-Jun Chen
- Publisher
- John Wiley and Sons
- Year
- 2000
- Tongue
- English
- Weight
- 309 KB
- Volume
- 49
- Category
- Article
- ISSN
- 0272-4391
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✦ Synopsis
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.