title: Vanidilol: a vanilloid-type vasorelaxant and ocular hypotensive beta-adrenoceptor blocker with partial beta-2-agonist activity.
abstract: Vanidilol, [4'-(2-hydroxy-3-(tert-butylamino)propoxy)-3'-methoxyphenyl] -benzaldehyde, newly synthesized from vanillin, is a vanilloid-type beta-adrenoceptor blocker. The beta-adrenoceptor-blocking properties of vanidilol were studied both in vivo and in vitro. Intravenous injection of vanidilol (1.0, 3.0, 5.0 mg/kg) in anesthetized Wistar rats produced a decrease in blood pressure and a dose-dependent bradycardia response. Vanidilol inhibited the tachycardia effects induced by (-)isoproterenol, but had no blocking effect on the arterial pressor responses induced by phenylephrine. In isolated guinea-pig tissues, vanidilol attenuated the (-)isoproterenol-induced positive chronotropic and inotropic effects of the atria and trachea relaxation responses in a concentration-dependent manner. The parallel shift to the right of the concentration-response curve of (-)isoproterenol suggested that the agent was a beta-adrenoceptor competitive antagonist. The apparent pA2 values for vanidilol on the right atria, left atria and trachea were 7.67 +/- 0.03, 7.89 +/- 1.02 and 7.66 +/- 0.15, respectively, denoting that vanidilol was a nonselective beta-blocker. The intrinsic sympathomimetic activity of vanidilol and propranolol was determined on isolated atria and trachea from reserpinized guinea pigs. Propranolol caused significantly negative inotropic and chronotropic effects at 10(-6) mol/l or above, whereas vanidilol possessed less cardiodepressant activities than propranolol. In reserpinized tracheal strips, vanidilol produced dose-dependent relaxant responses, but propranolol was ineffective. Preincubating the preparations with ICI 118,551 (0.1-10 nmol/l), a beta 2-adrenoceptor antagonist, significantly shifted the concentration-relaxation curves of vanidilol to a region of higher concentrations. In isolated guinea-pig thoracic aorta, vanidilol (0.1-10 mumol/l) inhibited the phenylephrine (10(-5) mol/l)-induced tonic contraction in vascular smooth muscle which was related to the block of calcium influx. In 20% saline-perfused rabbits, vanidilol showed a marked delay in intraocular pressure recovery, demonstrating an ocular hypotensive action. Binding characteristics of vanidilol and propranolol were evaluated in [3H]dihydroalprenolol binding to porcine ventricular membranes. Vanidilol was less potent than propranolol in competing for the beta-adrenoceptor-binding sites. On the other hand, vanidilol had a high hydrophilicity in comparison with propranolol. In conclusion, vanidilol exhibited nonselective beta-adrenoceptor blocking, vasorelaxant and ocular hypotensive activities, but was devoid of alpha-adrenoceptor blocking and beta 1-agonist activity. Partial beta 2-adrenoceptor agonist activity and inhibitory activity on calcium influx may share in the vasorelaxant activity.
authors.affiliation: Department of Ophthalmology, Kaohsiung Medical College, Taiwan.
authors.forename: M M
authors.initials: MM
authors.lastname: Sheu
authors.forename: B N
authors.initials: BN
authors.lastname: Wu
authors.forename: W C
authors.initials: WC
authors.lastname: Ho
authors.forename: S J
authors.initials: SJ
authors.lastname: Hong
authors.forename: S J
authors.initials: SJ
authors.lastname: Chen
authors.forename: Y T
authors.initials: YT
authors.lastname: Lin
authors.forename: I J
authors.initials: IJ
authors.lastname: Chen
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001547:Benzaldehydes / Q000138:chemical synthesis / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005260:Female; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007429:Intraocular Pressure / Q000187:drug effects; D008297:Male; D015814:Ocular Hypotension / Q000188:drug therapy; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D014132:Trachea / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D001547:Benzaldehydes; D014665:Vasodilator Agents; C107535:vanidilol