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

The present investigation was designed to investigate the effect of the diterpene entpimara-8(14),15-dien-19-oic acid (pimaradienoic acid, PA) on smooth muscle extracellular ca 2+ influx. To this end, the effect of PA on phenylephrine- and KCl-induced increases in cytosolic calcium concentration ([Ca 2+ ] 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 KCI (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 cacl 2 (0.5 nmol L -1 or 2.5 mmol L -1 ) in denuded rat aorta exposed to ca 2+ -free medium containing phenylephrine (0.1 μmol L -1 ) or KCI (30 mmol L -1 ). Interestingly, the inhibitory effect displayed by PA on cacl 2 -induced contraction was more pronounced when KCI was used as the stimulant. Phenylephrine- and KCl-induced increases in [ca 2+ ] c were inhibited by PA. Similarly, verapamil, a Ca 2+ -channel blocker, also inhibited the increase in [Ca 2+ ] c induced by either phenylephrine or KCI. 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 Ca 2+ influx through smooth muscle cellular membrane, a mechanism that could mediate the hypotensive response induced by this diterpene in normotensive rats.