Mechanisms underlying the vasorelaxant action of the pimarane ent-8(14),15-pimaradien-3 beta-ol in the isolated rat aorta

Author(s)

Hipolito, Ulisses V. ^{[1, 2]} ; Rodrigues, Gerson J. ^{[3, 1]} ; Lunardi, Claure N. ^{[3, 4]} ; Bonaventura, Daniella ^[3] ; Ambrosio, Sergio R. ^[5] ; de Oliveira, Ana M. ^[3] ; Bendhack, Lusiane M. ^[3] ; da Costa, Fernando B. ^[6] ; Tirapelli, Carlos R. ^[2]

Affiliation

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

^[2] Univ Sao Paulo, Dept Psychiat Nursing & Human Sci, Pharmacol Lab, Coll Nursing Ribeirao Preto, BR-14040902 Ribeirao Preto, SP - Brazil

^[3] Univ Sao Paulo, Dept Chem & Phys, Pharmacol Lab, Fac Pharmaceut Sci, BR-14040902 Ribeirao Preto, SP - Brazil

^[4] UnB, Fac Ceilandia, Brasilia, DF - Brazil

^[5] Univ Franca, Franca, SP - Brazil

^[6] Univ Sao Paulo, Dept Pharmaceut Sci, Pharmacol Lab, Fac Pharmaceut Sci, BR-14040902 Ribeirao Preto, SP - Brazil

• Document type: Journal article
• Source: European Journal of Pharmacology; v. 616, n. 1-3, p. 183-191, AUG 15 2009.
• Web of Science Citations: 15

Abstract

Pimarane-type diterpenes were described to exert antispasmodic and relaxant activities. Based on this observation we hypothesized that the diterpene ent-8(14),15-pimaradien-3 beta-ol (PA-3 beta-ol) induced vascular relaxation. With this purpose, the present work investigates the mechanisms involved in the vasorelaxant effect of the pimarane-type diterpene PA-3 beta-ol. Vascular reactivity experiments, using standard muscle bath procedures, were performed in isolated aortic rings from male Wistar rats. Cytosolic calcium concentration ({[}Ca(2+)]c) was measured by confocal microscopy using the fluorescent probe Fluo-3AM. PA-3 beta-ol (10, 50 and 100 mu mol/l) inhibited phenylephrine and KCl-induced contraction in either endothelium-intact or denuded rat aortic rings. PA-3 beta-ol also reduced CaCl(2)-induced contraction in Ca(2+)-free solution containing KCl (30 mmol/l) or phenylephrine (0.1 mu mol/l). PA-3 beta-ol (1-300 mu mol/l) concentration dependently relaxed phenylephrine-pre-contracted rings with intact or denuded endothelium. The diterpene also relaxed KCl-pre-contracted rings with intact or denuded endothelium. Moreover, Ca(2+) mobilization study showed that PA-3 beta-ol (100 mu mol/l) and verapamil (1 mu mol/l) inhibited the increase in Ca(2+)-concentration in smooth muscle and endothelial cells induced by phenylephrine (10 mu mol/l) or KCl (60 mmol/l). Pre-incubation of intact or denuded aortic rings with N(G)-nitro-L-arginine methyl ester (L-NAME, 100 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 PA-3 beta-ol concentration-response curves. On the other hand, 7-nitroindazole (100 mu mol/l), 1400 W (1 mu mol/l), indomethacin (10 mu mol/l) and tetraethylammonium (1 mmol/l) did not affect PA-3 beta-ol-induced relaxation. Collectively, our results provide evidence that the effects elicited by PA-3 beta-ol involve extracellular Ca(2+) influx blockade. Its effects are also partly mediated by the activation of NO-cGMP pathway. (C) 2009 Elsevier B.V. All rights reserved. (AU)