title: Vanidipinedilol: a vanilloid-based beta-adrenoceptor blocker displaying calcium entry blocking and vasorelaxant activities.
abstract: Calcium channel and beta-adrenoceptor blockade have proved highly useful in antihypertensive therapy. Studies of the mechanisms of action of vanidipinedilol that combine these effects within a single molecule are described here. Intravenous injection of vanidipinedilol (0.1, 0.25, 0.5, 1.0, and 2.0 mg/kg) produced dose-dependent hypotensive and bradycardic responses, significantly different from nifedipine-induced (0.5 mg/kg, i.v.) hypotensive and reflex tachycardic effects in pentobarbital-anesthetized Wistar rats. A single oral administration of vanidipinedilol at doses of 10, 25, and 50 mg/kg dose-dependently reduced blood pressure with a decrease in heart rate in conscious spontaneously hypertensive rats (SHRs). In the isolated Wistar rat atrium, vanidipinedilol (10(-7), 10(-6), and 10(-5) M) competitively antagonized the (-)isoproterenol-induced positive chronotropic and inotropic effects and inhibited the increase in heart rate induced by Ca2+ (3.0-9.0 mM) in a concentration-dependent manner. The parallel shift to the right of the concentration-response curve of (-)isoproterenol and CaCl2 suggested that vanidipinedilol possessed beta-adrenoceptor-blocking and calcium entry-blocking activities. On tracheal strips of reserpinized guinea pig, cumulative doses of vanidipinedilol (10(-10) to 3x10(-6) M) produced dose-dependent relaxant responses. Preincubating the preparation with ICI 118,551 (10(-10), 10(-9), 10(-8) M), a beta2-adrenoceptor antagonist, shifted the vanidipinedilol concentration-relaxation curve significantly to a region of higher concentrations. These results implied that vanidipinedilol had a partial beta2-agonist activity. In the isolated thoracic aorta of rat, vanidipinedilol had a potent effect inhibiting high-K+-induced contractions. KCI-induced intracellular calcium changes of blood vessel smooth muscle cell (A7r5 cell lines) determined by laser cytometry also was decreased after administration of vanidipinedilol (10(-8), 10(-7), 10(-6) M). Furthermore, the binding characteristics of vanidipinedilol and various antagonists were evaluated in [3H]CGP-12177 binding to ventricle and lung and [3H]nitrendipine binding to cerebral cortex membranes in rats. The order of potency of beta1- and beta2-adrenoceptor antagonist activity against [3H]CGP-12177 binding was (-)propranolol (pKi, 8.59 for beta1 and 8.09 for beta2) > vanidipinedilol (pKi, 7.09 for beta1 and 6.64 for beta2) > atenolol (pKi, 6.58 for beta1 and 5.12 for beta2). The order of potency of calcium channel antagonist activity against [3H]nitrendipine binding was nifedipine (pKi, 9.36) > vanidipinedilol (pKi, 8.07). The ratio of beta1-adrenergic-blocking/calcium entry-blocking selectivity is 0.1 and indicated that vanidipinedilol revealed more in calcium entry-blocking than in beta-adrenergic-blocking activities. It has been suggested that vanidipinedilol-induced smooth muscle relaxation may involve decreased entry of Ca2+ and partial beta2-agonist activities. In conclusion, vanidipinedilol is a nonselective beta-adrenoceptor antagonist with calcium channel blocking and partial beta2-agonist associated vasorelaxant and tracheal relaxant activities. Particularly, the vasodilator effects of vanidipinedilol are attributed to a synergism of its calcium entry blocking and partial beta2-agonist activities in the blood vessel. A sustained bradycardic effect results from beta-adrenoceptor blocking and calcium entry blocking, which blunts the sympathetic activation-associated reflex tachycardia in the heart.
authors.affiliation: Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Taiwan, Republic of China.
authors.forename: J L
authors.initials: JL
authors.lastname: Yeh
authors.forename: S F
authors.initials: SF
authors.lastname: Liou
authors.forename: J C
authors.initials: JC
authors.lastname: Liang
authors.forename: Y C
authors.initials: YC
authors.lastname: Huang
authors.forename: L C
authors.initials: LC
authors.lastname: Chiang
authors.forename: J R
authors.initials: JR
authors.lastname: Wu
authors.forename: Y T
authors.initials: YT
authors.lastname: Lin
authors.forename: I J
authors.initials: IJ
authors.lastname: Chen
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000319:Adrenergic beta-Antagonists / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000378:metabolism / Q000494:pharmacology*; D002122:Calcium Chloride / Q000494:pharmacology; D004095:Dihydropyridines / Q000378:metabolism / Q000494:pharmacology*; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D013566:Sympathomimetics / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D011943:Receptors, Adrenergic, beta; D013566:Sympathomimetics; D014665:Vasodilator Agents; C403626:vanidipinedilol; D002122:Calcium Chloride