Evidence for the mechanisms underlying the effects of pimaradienoic acid isolated from the roots of Viguiera arenaria on rat aorta.
The present study examines the effects of the diterpene ENT-pimara-8(14),15-dien-19-oic acid (PA) on rat thoracic aorta. PA (10(-5), 3 x 10(-5) and 10(-4) mol/l) caused concentration-dependent inhibition of phenylephrine (Phe)-induced contraction in either endothelium-intact or endothelium-denuded aortic rings. PA attenuated the contraction induced by CaCl(2) in Ca(2+)-free solution containing Phe (10(-7) mol/l) or KCl (30 mmol/l). This diterpene did not interfere with Ca(2+) release from intracellular stores mediated by either Phe (10(-6) mol/l) or caffeine (30 mmol/l). PA (10(-6) to 3 x 10(-4) mol/l) concentration dependently relaxed Phe-pre-contracted rings with intact (92.64 +/- 7.60%) or denuded endothelium (98.82 +/- 1.56%). Pre-incubation of denuded aortic rings with N(G)-nitro-L-arginine methyl ester (10(-4) mol/l), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (10(-6) mol/l) or indomethacin (10(-5) mol/l) reduced PA-induced relaxation (percentage of relaxation: 77.50 +/- 3.95, 78.56 +/- 2.81, 77.11 +/- 6.22, respectively). However, the relaxant responses induced by PA on Phe-pre-contracted rings were unaffected by tetraethylammonium (1 and 5 mmol/l). PA also relaxed KCl-pre-contracted rings with intact (97.44 +/- 3.66%) or denuded endothelium (95.95 +/- 3.72%). Collectively, these results support the notion that the effects elicited by PA on vascular smooth muscle are endothelium-independent and involve extracellular Ca(2+) influx blocked. In addition, PA effects are partly dependent on the release of nitric oxide from the vascular smooth muscle through an activation of guanylyl cyclase-dependent mechanism and are related to the release of metabolites derived from the arachidonic acid pathway. Finally, our results demonstrated that the PA relaxant action is not related with the opening of potassium (K(+)) channels.
Tirapelli
Carlos R
CR
Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Brazil.
Ambrosio
Sergio R
SR
da Costa
Fernando B
FB
de Oliveira
Ana M
AM
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000293:injuries; D019659:Asteraceae; D001938:Brazil; D004224:Diterpenes / Q000008:administration & dosage / Q000302:isolation & purification* / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000293:injuries; D000431:Ethanol; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010656:Phenylephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010936:Plant Extracts / Q000008:administration & dosage / Q000302:isolation & purification / Q000493:pharmacokinetics; D018517:Plant Roots / Q000737:chemistry*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D019789:Tetraethylammonium / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004224:Diterpenes; D010069:Oxadiazoles; D010936:Plant Extracts; D011810:Quinoxalines; D010656:Phenylephrine; D000431:Ethanol; D019789:Tetraethylammonium; C008911:pimaric acid; D009543:Nifedipine; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin