Role of the carboxylic group in the antispasmodic and vasorelaxant action displayed by kaurenoic acid

Abstract

The present work describes the investigation of the role of the carboxylic group in the structure-activity relationship of the diterpene ent-kaur-16-en-19-oic acid (kaurenoic acid, KA) in inhibiting rat aorta contraction. For this purpose the methylation of the C-19 carboxyl group of KA was carried out. The effects of the obtained ent-methyl-kaur-16-en-19-oate (KAMe) were compared with those induced by KA. Vascular reactivity experiments showed that KA (50 and 100 microM) concentration-dependently inhibited KCl-induced contraction in both endothelium-intact and denuded rat aortic rings. On the other hand, KAMe attenuated KCl-induced contraction at 100 microM, but not at 50 microM. KA also reduced CaCl(2)-induced contraction in Ca(2+)-free solution containing KCl (30 mM). Again, KAMe produced a less accentuated reduction in CaCl(2)-induced contraction than that induced by the acid KA. KAMe (1-450 microM) concentration-dependently relaxed KCl-pre-contracted rings (percentages of relaxation 82.57 +/- 1.65 and 70.55 +/- 4.71, respectively) with denuded endothelium. Similarly, the relaxation induced by KA on phenylephrine (Phe)-pre-contracted rings (73.06 +/- 3.68%) was more pronounced than that found for KAMe (53.68 +/- 4.75%). Pre-incubation of denuded rings for different periods with KA and KAMe showed that the equilibrium periods required by each compound to achieve its maximal inhibitory response on KCl-induced contraction are different. Collectively, our results provide functional evidence that methylation of the C-19 carboxyl group of KA reduces but does not abolish the antispasmodic activity displayed by KA. Additionally, we showed that the equilibrium period is a critical step for the inhibitory effect displayed by kaurane-type diterpenes.

Vasorelaxant properties of acid and neutral fractions of Dimerocostus strobilaceus Kuntze used by Kuna Indians of Panama

“…These insaturations produce a conformational restriction and seem to account for the activity showed by these fractions. The carboxylic group present in these compounds seems to play an important role in inhibiting rat aorta contraction which is in agreement with the results shown by several kaurane (Ambrosio et al, 2004) and labdane-type diterpenoids (Lahlou et al, 2006).…”

Assessment of the in vitro and in vivo genotoxic and antigenotoxic effects of pimaradienoic acid in mammalian cells

“…About 30 g of a crude dichloromethane extract of the roots of Viguiera arenaria, which was previously prepared in our laboratory, was suspended in a solution of CH3OH/H2O (9:1, v/v) and partitioned with n-hexane and dichloromethane according to Ambrosio et al [3]. The n-hexane fraction (6.75 g) was re-fractioned using vacuum liquid chromatography [12] and yielded seven new fractions (Fr1-Fr7).…”

“…Increased attention has been paid in recent years to the study of the biological effects of diterpenes, a recognized class of natural compounds with a broad spectrum of biological activities such as antiparasitic [1], anti-inflammatory [2], and antispasmodic properties [3]. Among these metabolites, the pimarane-type diterpene, ent-pimara-8 (14),15-dien-19-oic acid (pimaradienoic acid, PA; Fig.…”

“…Among these metabolites, the pimarane-type diterpene, ent-pimara-8 (14),15-dien-19-oic acid (pimaradienoic acid, PA; Fig. 1), is found in high amounts in the roots of a Brazilian species of Viguiera [3]. PA exerts anti-inflammatory activity, inhibiting cyclooxygenase-2 [4,5], and has been shown to inhibit contraction induced by potassium chloride (KCl) and phenylephrine in rat thoracic aorta [6].…”

Diterpenes: A Therapeutic Promise for Cardiovascular Diseases

“…More recently, a chemical blockade of the carboxylic group at the C-19 of kaurenoic acid was carried out and the effects of the methyl ester derivative obtained were compared with those induced by kaurenoic acid [44]. Vascular reactivity experiments, using standard muscle bath procedures, showed that kaurenoic acid was more effective at inhibiting CaCl 2 and KCl-induced contraction than its methyl ester derivative.…”