Pimaradienoic acid inhibits vascular contraction and induces hypotension in normotensive rats.

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. [ABSTRACT FROM AUTHOR]