Dehydroabietic Acid Isolated from Commiphora opobalsamum Causes Endothelium-Dependent Relaxation of Pulmonary Artery via PI3K/Akt-eNOS Signaling Pathway

Commiphora opobalsamum is a Traditional Chinese Medicine used to treat traumatic injury, mainly by relaxing blood vessels. In this study, two diterpenes, dehydroabietic acid (DA) and sandaracopimaric acid (SA) were obtained from it by a bioassay-guided approach using isolated rat pulmonary artery rings. The structures of the two compounds were elucidated by spectroscopic methods (IR, 1H- and 13C-NMR, HR-ESI-MS). Both DA and SA reduced the contraction of phenylephrine-induced pulmonary arteries in a concentration-dependent manner, and endothelium contributed greatly to the vasodilatory effect of DA. This effect of DA was attenuated by NG-Nitro-L-arginine methyl ester (L-NAME, an eNOS inhibitor). Meanwhile, DA increased nitric oxide (NO) production, along with the increase of phosphorylation level of eNOS and Akt in endothelial cells. LY294002 (a PI3K inhibitor) could reverse this effect, which suggested the endothelial PI3K/Akt pathway involved in the mechanism underlying DA-induced relaxation of pulmonary artery. This work provided evidence of vasorelaxant substances in Commiphora opobalsamum and validated that PI3K/Akt-eNOS pathway was associated with DA-induced pulmonary artery vasodilation.

[1]  M. Humbert,et al.  Pulmonary arterial hypertension , 2013, Orphanet Journal of Rare Diseases.

[2]  Daling Zhu,et al.  Osthole relaxes pulmonary arteries through endothelial phosphatidylinositol 3-kinase/Akt-eNOS-NO signaling pathway in rats. , 2013, European journal of pharmacology.

[3]  Minggang Chen,et al.  Hydroxysafflor Yellow A (HSYA) from Flowers of Carthamus tinctorius L. and Its Vasodilatation Effects on Pulmonary Artery , 2012, Molecules.

[4]  J. Medina-Franco,et al.  Vasorelaxant activity of some structurally related triterpenic acids from Phoradendron reichenbachianum (Viscaceae) mainly by NO production: ex vivo and in silico studies. , 2012, Fitoterapia.

[5]  D. Kang,et al.  Vasodilatory effects of ethanol extract of Radix Paeoniae Rubra and its mechanism of action in the rat aorta. , 2012, Journal of ethnopharmacology.

[6]  C. Auger,et al.  Natural Product Extract of Dicksonia sellowiana Induces Endothelium-Dependent Relaxations by a Redox-Sensitive Src- and Akt-Dependent Activation of eNOS in Porcine Coronary Arteries , 2012, Journal of Vascular Research.

[7]  H. Aisa,et al.  Bioassay-guided isolation of vasorelaxant compounds from Ziziphora clinopodioides Lam. (Lamiaceae). , 2012, Fitoterapia.

[8]  Christopher S Coffey,et al.  Predicting Survival in Pulmonary Arterial Hypertension: Insights From the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) , 2010, Circulation.

[9]  A. M. de Oliveira,et al.  Mechanisms underlying the vasorelaxant action of the pimarane ent-8(14),15-pimaradien-3beta-ol in the isolated rat aorta. , 2009, European journal of pharmacology.

[10]  S. Su,et al.  Isolation and biological activities of neomyrrhaol and other terpenes from the resin of Commiphora myrrha. , 2009, Planta medica.

[11]  Xiaobo Tang,et al.  20-Hydroxyeicosatetraenoic acid inhibits the apoptotic responses in pulmonary artery smooth muscle cells. , 2008, European journal of pharmacology.

[12]  C. R. Tirapelli,et al.  Pimaradienoic acid inhibits vascular contraction and induces hypotension in normotensive rats , 2008, The Journal of pharmacy and pharmacology.

[13]  Huiqing Yuan,et al.  Secondary metabolites from Commiphora opobalsamum and their antiproliferative effect on human prostate cancer cells. , 2007, Phytochemistry.

[14]  Myung-Hwa Kang,et al.  Endothelium-dependent vasodilatory and hypotensive effects of Crotalaria sessiliflora L. in rats. , 2007, Biological & pharmaceutical bulletin.

[15]  U. Lendeckel,et al.  Effect of L-arginine on asymmetric dimethylarginine (ADMA) or homocysteine-accelerated endothelial cell aging. , 2006, Biochemical and biophysical research communications.

[16]  K. Hisamoto,et al.  Vascular cell signaling by membrane estrogen receptors , 2005, Steroids.

[17]  M. Al-Said,et al.  Effect of Commiphora opobalsamum (L.) Engl. (Balessan) on experimental gastric ulcers and secretion in rats. , 2005, Journal of ethnopharmacology.

[18]  V. Schini-Kerth,et al.  Red wine polyphenols‐induced, endothelium‐dependent NO‐mediated relaxation is due to the redox‐sensitive PI3‐kinase/Akt‐dependent phosphorylation of endothelial NO‐synthase in the isolated porcine coronary artery , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[19]  S. Sim,et al.  Vascular effects of Siberian ginseng (Eleutherococcus senticosus): endothelium-dependent NO- and EDHF-mediated relaxation depending on vessel size , 2004, Naunyn-Schmiedeberg's Archives of Pharmacology.

[20]  M. Al-Said,et al.  Hepatoprotective properties of Commiphora opobalsamum ("Balessan"), a traditional medicinal plant of Saudi Arabia. , 2004, Drugs under experimental and clinical research.

[21]  K. Muraki,et al.  Dehydroabietic acid derivatives as a novel scaffold for large-conductance calcium-activated K+ channel openers. , 2003, Bioorganic & medicinal chemistry letters.

[22]  A. M. de Oliveira,et al.  Pimarane diterpene from Viguiera arenaria (Asteraceae) inhibit rat carotid contraction. , 2002, Fitoterapia.

[23]  R. D. Rudic,et al.  Acute modulation of endothelial Akt/PKB activity alters nitric oxide-dependent vasomotor activity in vivo. , 2000, The Journal of clinical investigation.

[24]  M. Rand,et al.  Mechanisms of nitric oxide‐independent relaxations induced by carbachol and acetylcholine in rat isolated renal arteries , 2000, British journal of pharmacology.

[25]  Kojima,et al.  Fluorescent Indicators for Imaging Nitric Oxide Production. , 1999, Angewandte Chemie.

[26]  I. A. de Medeiros,et al.  Muscarinic agonist properties of the hydrobutanol extract from aerial parts of Waltheria viscosissima St. Hil. (Sterculiaceae) in Rats † , 1999, Phytotherapy research : PTR.

[27]  A. Abdul-Ghani,et al.  Effect of aqueous extract of Commiphora opobalsamum on blood pressure and heart rate in rats. , 1997, Journal of ethnopharmacology.

[28]  H. Cheung.  Further acidic constituents and neutral components of pinus massoniana Resin , 1993 .

[29]  Jim-Min Fang,et al.  Serratene triterpenes from Pinus armandii bark , 1991 .