Pharmacological comparison of the vasorelaxant action displayed by kaurenoic acid and pimaradienoic acid.
The vascular effects of two natural occurring diterpenes from the kaurane and pimarane classes were compared. The diterpenes ent-kaur-16-en-19-oic acid (kaurenoic acid; KA) and ent-pimara-8(14), 15-dien-19-oic acid (pimaradienoic acid; PA) were tested for their antispasmodic activity on isolated rat aorta. Vascular reactivity experiments, using standard muscle bath procedures, showed that KA and PA (both at 50 and 100 microM) inhibited phenylephrine and KCl-induced contraction in both endothelium-intact and endothelium-denuded rat aortic rings, with PA being more effective than KA. These compounds also reduced CaCl(2)-induced contraction in Ca(2+)-free solution containing KCl (30 mm). Again, PA produced a greater reduction in CaCl(2)-induced contraction than KA. PA (1-300 microM) and KA (1-450 microM) concentration dependently relaxed endothelium-denuded aortic rings pre-contracted with KCl (maximum relaxation 102.31+/-6.94% and 82.71+/-1.40%, respectively). Similarly, the relaxation induced by KA on aortic rings pre-contracted with phenylephrine (73.06+/-3.68%) was less pronounced than that found for PA (102.21+/-3.64%). Incubation of endothelium-denuded rings for different periods showed that at 50 microM, KA and PA achieved maximum inhibitory activity on KCl-induced contraction after incubation for 60 (53.48+/-5.83%) and 30 min (83.89+/-2.12%), respectively. At 100 microM, KA and PA inhibited KCl-induced contraction, with a maximum after incubation for 30 min (73.58+/-5.30% and 92.07+/-1.20%, respectively). The maximum inhibition induced by PA at both concentrations tested was greater than that induced by KA. The results provide evidence that structural differences between diterpenes, independent of the C-19 carboxylic acid site, influence selectivity for voltage-operated Ca2+ channels and rate of equilibrium with the target site for their vasorelaxant action in rat aortic rings.
Tirapelli
Carlos R
CR
Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, Brazil.
Ambrosio
Sergio R
SR
Coutinho
Silvia T
ST
de Oliveira
Dionéia C R
DC
da Costa
Fernando B
FB
de Oliveira
Ana M
AM
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects*; D019659:Asteraceae / Q000737:chemistry; D004224:Diterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D010276:Parasympatholytics / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D010656:Phenylephrine; D051381:Rats; D013329:Structure-Activity Relationship; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects*
D004224:Diterpenes; D010276:Parasympatholytics; D010656:Phenylephrine; C051436:kaurenoic acid; C008911:pimaric acid