The semi-synthetic kaurane ent-16 alpha-methoxykauran-19-oic acid induces vascular relaxation and hypotension in rats

Author(s):Show less -

Hipolito, Ulisses V. ^[1] ; Rocha, Juliana T. ; Palazzin, Nathalia B. ; Rodrigues, Gerson J. ^[1] ; Crestani, Carlos C. ^[2] ; Correa, Fernando M. ^[1] ; Bonaventura, Daniella ^[3] ; Ambrosio, Sergio R. ^[4] ; Bendhack, Lusiane M. ^[5] ; Resstel, Leonardo B. ^[1] ; Tirapelli, Carlos R. ^[6]

Affiliation

^[1] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Pharmacol, BR-14040902 Ribeirao Preto, SP - Brazil

^[2] Sao Paulo State Univ, UNESP, Sch Pharmaceut Sci, Dept Nat Act Principles & Toxicol, Araraquara, SP - Brazil

^[3] Univ Fed Minas Gerais, Inst Biol Sci, Dept Pharmacol, Belo Horizonte, MG - Brazil

^[4] Univ Franca, Franca, SP - Brazil

^[5] Univ Sao Paulo, Fac Pharmaceut Sci Ribeirao Preto, Pharmacol Lab, Dept Chem & Phys, BR-14040902 Ribeirao Preto, SP - Brazil

^[6] Univ Sao Paulo, Escola Enfermagem Ribeirao Preto, Coll Nursing Ribeirao Preto, Dept Psychiat Nursing & Human Sci, Lab Pharmacol, BR-14040902 Ribeirao Preto, SP - Brazil

• Document type: Journal article
• Source: European Journal of Pharmacology; v. 660, n. 2-3, p. 402-410, JUN 25 2011.
• Web of Science Citations: 9

Abstract

The present work investigates the mechanisms involved in the vasorelaxant effect of ent-16 alpha-methoxykauran-19-oic acid (KA-OCH(3)), a semi-synthetic derivative obtained from the kaurane-type diterpene ent-kaur-16-en-19-oic acid (kaurenoic acid). Vascular reactivity experiments were performed in aortic rings isolated from male Wistar rats using standard muscle bath procedures. The cytosolic calcium concentration ({[}Ca(2+)]c) was measured by confocal microscopy using the fluorescent probe Fluo-3 AM. Blood pressure measurements were performed in conscious rats. KA-OCH(3) (10,50 and 100 mu mol/l) inhibited phenylephrine-induced contraction in either endothelium-intact or endothelium-denuded rat aortic rings. KA-OCH(3) also reduced CaCl(2)-induced contraction in a Ca(2+)-free solution containing KCl (30 mmol/l) or phenylephrine (0.1 mu mol/l). KA-OCH(3) (0.1-300 mu mol/l) concentration-dependently relaxed endothelium-intact and endothelium-denuded aortas pre-contracted with either phenylephrine or KCl, to a greater extent than kaurenoic acid. Moreover, a Ca(2+) mobilisation study showed that KA-OCH(3) (100 mu mol/l) inhibited the increase in Ca(2+) concentration in smooth muscle and endothelial cells induced by phenylephrine or KCl. Pre-incubation of intact or denuded aortic rings with N(G)-nitro-L-arginine methyl ester (L-NAME, 100 mu mol/l), 7-nitroindazole (100 mu mol/l), wortmannin (0.5 mu mol/l) and 1H-{[}1,2,4]Oxadiazolo{[}4,3-a]quinoxalin-1-one (ODQ 1 mu mol/l) produced a rightward displacement of the KA-OCH(3) concentration-response curve. Intravenous administration of KA-OCH(3) (1-10 mg/kg) reduced mean arterial blood pressure in normotensive rats. Collectively, our results show that KA-OCH(3) induces vascular relaxation and hypotension. The mechanisms underlying the cardiovascular actions of KA-OCH(3) involve blockade of Ca(2+) influx and activation of the NO-cGMP pathway. (C) 2011 Elsevier B.V. All rights reserved. (AU)