IngentaConnect Pimaradienoic acid inhibits vascular contraction and induces hypo...

Authors: Tirapelli, Carlos R.¹; dos Anjos Neto Filho, Mario²; Bonaventura, Daniella²; Melo, Mirian C.C.²; Ambrosio, Sergio R.³; de Oliveira, Ana M.²; Bendhack, Lusiane M.²; da Costa, Fernando B.⁴

Source: Journal of Pharmacy and Pharmacology, Volume 60, Number 4, April 2008 , pp. 453-459(7)

Publisher: Pharmaceutical Press

Abstract:

The present investigation was designed to investigate the effect of the diterpene ent-pimara-8(14),15-dien-19-oic acid (pimaradienoic acid, PA) on smooth muscle extracellular Ca²⁺ influx. To this end, the effect of PA on phenylephrine- and KCl-induced increases in cytosolic calcium concentration ([Ca²⁺]_c), measured by the variation in the ratio of fluorescence intensities (R340/380 nm) of Fura-2, was analysed. Whether bolus injection of PA could induce hypotensive responses in conscious normotensive rats was also evaluated. PA inhibited the contraction induced by phenylephrine (0.03 or 10 μmol L⁻¹) and KCl (30 or 90 mmol L⁻¹) in endothelium-denuded rat aortic rings in a concentration dependent manner. Pre-treatment with PA (10, 100, 200 μmol L⁻¹) attenuated the contraction induced by CaCl₂ (0.5 nmol L⁻¹ or 2.5 mmol L⁻¹) in denuded rat aorta exposed to Ca²⁺-free medium containing phenylephrine (0.1 μ mol L⁻¹) or KCl (30 mmol L⁻¹). Interestingly, the inhibitory effect displayed by PA on CaCl₂-induced contraction was more pronounced when KCl was used as the stimulant. Phenylephrine- and KCl-induced increases in [Ca²⁺]_c were inhibited by PA. Similarly, verapamil, a Ca²⁺-channel blocker, also inhibited the increase in [Ca²⁺]_c induced by either phenylephrine or KCl. Finally, bolus injection of PA (1-15 mg kg⁻¹) produced a dose-dependent decrease in mean arterial pressure in conscious normotensive rats. The results provide the first direct evidence that PA reduces vascular contractility by reducing extracellular Ca²⁺ influx through smooth muscle cellular membrane, a mechanism that could mediate the hypotensive response induced by this diterpene in normotensive rats.

Document Type: Research article

DOI: 10.1211/jpp.60.4.0007

Affiliations: 1: Department of Psychiatry Nursing and Human Sciences, Laboratory of Pharmacology, College of Nursing of Ribeirão Preto, University de São Paulo (USP), Ribeirão Preto, SP, Brazil 2: Department of Physics and Chemistry, Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, USP, Ribeirão Preto, SP, Brazil 3: Nucleus of Research in Sciences and Technology, University of Franca, Unifran, Franca, SP, Brazil 4: Department of Pharmaceutical Sciences, Laboratory of Pharmacognosy, Faculty of Pharmaceutical Sciences, USP, Ribeirão Preto, SP, Brazil

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Pimaradienoic acid inhibits vascular contraction and induces hypotension in normotensive rats