Pimaradienoic acid inhibits vascular contraction and induces hypotension in normotensive rats |
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Authors: | Tirapelli Carlos R dos Anjos Neto Filho Mario Bonaventura Daniella Melo Mirian C C Ambrosio Sergio R de Oliveira Ana M Bendhack Lusiane M da Costa Fernando B |
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Institution: | 1. Department of Psychiatry Nursing and Human Sciences, Laboratory of Pharmacology, College of Nursing of Ribeir?o Preto, University de S?o Paulo (USP), Ribeir?o Preto, SP, Brazil;2. Department of Physics and Chemistry, Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, USP, Ribeir?o 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, Ribeir?o Preto, SP, Brazil |
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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 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 micromol 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 micromol 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 micro mol L(-1)) or KCl (30 mmol L(-1)). Interestingly, the inhibitory effect displayed by PA on CaCl(2)-induced contraction was more pronounced when KCl 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 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 Ca(2+) influx through smooth muscle cellular membrane, a mechanism that could mediate the hypotensive response induced by this diterpene in normotensive rats. |
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