title: Pimaradienoic acid inhibits vascular contraction and induces hypotension in normotensive rats.
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.
authors.affiliation: Department of Psychiatry Nursing and Human Sciences, Laboratory of Pharmacology, College of Nursing of Ribeirão Preto, University de São Paulo, Ribeirão Preto, SP, Brazil. crtirapelli@eerp.usp.br
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Tirapelli
authors.forename: Mario
authors.initials: M
authors.lastname: dos Anjos Neto Filho
authors.forename: Daniella
authors.initials: D
authors.lastname: Bonaventura
authors.forename: Mirian C C
authors.initials: MC
authors.lastname: Melo
authors.forename: Sergio R
authors.initials: SR
authors.lastname: Ambrosio
authors.forename: Ana M
authors.initials: AM
authors.lastname: de Oliveira
authors.forename: Lusiane M
authors.initials: LM
authors.lastname: Bendhack
authors.forename: Fernando B
authors.initials: FB
authors.lastname: da Costa
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002122:Calcium Chloride / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D004224:Diterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology
chemical_list: D004224:Diterpenes; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D010656:Phenylephrine; C008911:pimaric acid; D014700:Verapamil; D002122:Calcium Chloride; D002118:Calcium