Vanidipinedilol: A vanilloid-based β-adrenoceptor blocker displaying calcium entry blocking and vasorelaxant activities

Jwu Lai Yeh, Shwu Fen Liou, Jyh Chong Liang, Yeun Chih Huang, Lien Chai Chiang, Jiunn Ren Wu, Young Tso Lin, Ing Jun Chen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)


Calcium channel and β-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, 10-16, 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 β-adrenoceptor-blocking and calcium entry-blocking activities. On tracheal strips of reserpinized guinea pig, cumulative doses of vanidipinedilol (10-10 to 3 x 10-6 M) produced dose-dependent relaxant responses. Preincubating the preparation with ICI 118,551 (10-10, 10-9, 10-8 M), a β2-adrenoceptor antagonist, shifted the vanidipinedilol concentration-relaxation curve significantly to a region of higher concentrations. These results implied that vanidipinedilol had a partial β2-agonist activity. In the isolated thoracic aorta of rat, vanidipinedilol had a potent effect inhibiting high-K+-induced contractions. KCl-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 β1- and β2-adrenoceptor antagonist activity against [3H]CGP- 12177 binding was (-)propranolol (pK(i), 8.59 for β1 and 8.09 for β2) > vanidipinedilol (pK(i), 7.09 for β1 and 6.64 for β2) > atenolol (pK(i), 6.58 for β1 and 5.12 for β2). The order of potency of calcium channel antagonist activity against [3H]nitrendipine binding was nifedipine (pK(i), 9.36) > vanidipinedilol (pK(i), 8.07). The ratio of β1-adrenergic- blocking/calcium entry-blocking selectivity is 0.1 and indicated that vanidipinedilol revealed more in calcium entry-blocking than in β- adrenergic-blocking activities. It has been suggested that vanidipinedilol- induced smooth muscle relaxation may involve decreased entry of Ca2+ and partial β2-agonist activities. In conclusion, vanidipinedilol is a nonselective β-adrenoceptor antagonist with calcium channel blocking and partial β2-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 β2- agonist activities in the blood vessel. A sustained bradycardic effect results from β-adrenoceptor blocking and calcium entry blocking, which blunts the sympathetic activation-associated reflex tachycardia in the heart.

Original languageEnglish
Pages (from-to)51-63
Number of pages13
JournalJournal of Cardiovascular Pharmacology
Issue number1
Publication statusPublished - 2000
Externally publishedYes


  • β-Adrenoceptor blocking
  • 1,4- Dihydropyridine
  • Calcium entry blocking
  • Radioligand-binding assay
  • Vasorelaxant effect

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine


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