title: Anti-hypertension effect of vanylidilol: a phenylaldehyde alpha/beta-adrenoceptor blocker with endothelium-dependent and K+ channels opening-associated vasorelaxant activities.
abstract: The antihypertensive effect of vanylidilol, a new alpha/beta-adrenoceptor antagonist with endothelium-dependent and K(+)-channel-opening activities, was investigated in normotensive and hypertensive Wistar rats. Vanylidilol competitively antagonized (-)isoproterenol-induced positive chronotropic effects, inotropic effects, and tracheal relaxation effects in isolated rat right atria, left atria, and guinea pig tracheal strips in a concentration-dependent manner. Vanylidilol's apparent pA(2) values were 6.36 +/- 0.08 (right atria), 6.41 +/- 0.07 (left atria), and 6.31 +/- 0.06 (trachea). Vanylidilol also produced a competitive antagonism of phenylephrine-induced contraction in the isolated rat aorta with pA(2) values of 6.79 +/- 0.18. In the radioligand binding assay, vanylidilol inhibited [(3)H]CGP-12177 binding to rat ventricle and lung tissues and [(3)H]prazosin binding to brain membranes with Ki values of 535.17, 2,066.69, and 431.11, respectively. In isolated rat thoracic aorta, vanylidilol's vasorelaxant effects on phenylephrine (10 micromol/l)-induced contractions were attenuated by removing endothelium and by the presence of L-N(G)-nitro arginine methyl ester (L-NAME; 100 micromol/l), methylene blue (10 micromol/l), 1H-[1,2,4]oxadiazolol[4,3,-a] quinoxalin-1-one (ODQ; 10 micromol/l), tetraethylammonium (10 mmol/l), glibenclamide (1 micromol/l), apamin (1 micromol/l), and charybdotoxin (0.1 micromol/l). In addition, vanylidilol, in an equally antagonistic activity, inhibited phenylephrine-induced phasic and tonic contractions. Intravenous vanylidilol further reduced mean blood pressure in pentobarbital-anesthetized normotensive Wistar rats in a dose-dependent manner. The oral administration of vanylidilol to conscious spontaneously hypertensive rats had a long-lasting hypotensive effect on the heart rate and decreased it in a dose-dependent manner. Furthermore, vanylidilol's vasodilator effect can be attributed in part to the release of NO or NO-related substance from vascular endothelium, while the endothelium-independent mechanism involved in vanylidilol's relaxation is probably linked to the activation of the K(+) channels and the alpha-adrenoceptor blocking activity in these vessels.
authors.affiliation: Department of Cardiovascular Surgery, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC.
authors.forename: Chaw-Chi
authors.initials: CC
authors.lastname: Chiu
authors.forename: Jiunn-Ren
authors.initials: JR
authors.lastname: Wu
authors.forename: Chih-Hsiung
authors.initials: CH
authors.lastname: Lee
authors.forename: Shwu-Fen
authors.initials: SF
authors.lastname: Liou
authors.forename: Zen-Kong
authors.initials: ZK
authors.lastname: Dai
authors.forename: Ing-Jun
authors.initials: IJ
authors.lastname: Chen
authors.forename: Jwu-Lai
authors.initials: JL
authors.lastname: Yeh
mesh_terms: D000284:Administration, Oral; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000447:Aldehydes / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001013:Aorta, Thoracic / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D015221:Potassium Channels / Q000187:drug effects / Q000494:pharmacology / Q000502:physiology*; D011869:Radioligand Assay; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000187:drug effects; D014132:Trachea / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D000447:Aldehydes; D000959:Antihypertensive Agents; D010879:Piperazines; D015221:Potassium Channels; D011943:Receptors, Adrenergic, beta; D014665:Vasodilator Agents; C485804:vanylidilol; D019001:Nitric Oxide Synthase; D007545:Isoproterenol; D008751:Methylene Blue; D019331:NG-Nitroarginine Methyl Ester