Mechanisms underlying the vascular and hypotensive actions of the labdane ent-3-acetoxy-labda-8(17),13-dien-15-oic acid

Author(s)

Ap Simplicio, Janaina ^[1] ; Pernomian, Larissa ^[2] ; Simao, Marilia R. ^[3] ; Carnio, Evelin C. ^[4] ; Batalhao, Marcelo E. ^[4] ; Ambrosio, Sergio R. ^[3] ; Tirapelli, Carlos R. ^[4]

Affiliation

^[1] Univ Sao Paulo, Fac Med Ribeirao Preto, Programa Posgrad Farmacol, BR-14040902 Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Dept Fis & Quim, BR-14040902 Ribeirao Preto, SP - Brazil

^[3] Univ Franca, Nucleo Pesquisa Ciencias & Tecnol, Franca, SP - Brazil

^[4] Univ Sao Paulo, Escola Enfermagem Ribeirao Preto, Dept Enfermagem Psiquiatr & Ciencias Humanas, Lab Farmacol, BR-14040902 Ribeirao Preto, SP - Brazil

• Document type: Journal article
• Source: European Journal of Pharmacology; v. 726, p. 66-76, MAR 5 2014.
• Web of Science Citations: 12

Abstract

We investigated the mechanisms underlying the vasorelaxant and hypotensive actions of the labdane-type diterpene ent-3-acetoxy-labda-8(17),13-dien-15-oic acid (labda-15-oic acid). Vascular reactivity experiments were performed in aortic rings isolated from male Wistar rats, cAMP and cGMP were measured by enzyme immunoassay (EIA) whereas nitrate measurement was performed by chemiluminescence. Nitric oxide (NO) concentration ({[}NO]c) was measured in endothelial cells by flow cytometry. The cylosolic calcium concentration ({[}Ca2+]c) in vascular smooth muscle cells (VSMC) was measured by confocal microscopy. Blood pressure measurements were performed in conscious rats. Labda-15-oic add inhibited the contraction induced by phenylephrine and serotonin in either endothelium-intact or endothelium-denuded rat aortic rings. The labdane significantly reduced CaCl2-induced contraction in a Ca2+-free solution containing KCl or phenylephrine. Labda-15-oic acid (0.1-300 mu mol/l) concentration dependently relaxed endothelium-intact and endothelium-denuded aortas pre-contracted with either phenylephrine or (Cl. In endothelium-intact rings, the relaxation induced by labda-15-oic acid was affected by L-NAME, 7-nitroindazole, ODQ, hemoglobin, Rp-8-Br-Pet-cGMPS and thapsigargin. Blockade of K+ channels with 4-aminopyridine, apamin, charybdotoxin and glibenclamide affected the relaxation induced by labda-15-oic acid. The labdane increased cGMP and nitrate levels but did not affect cAMP levels in endothelium-intact aortas. Labda-15-oic acid increased {[}NO]c in endothelial cells and decreased {[}Ca2+]c in VSMC. The hypotension induced by intravenous administration of labda-15-oic acid (0.3-3 mg/kg) was partially reduced by L-NAME. In conclusion, the mechanisms underlying the cardiovascular actions of the labdane involve the activation of the endothelial NO-cGMP pathway, the opening of K+ channels and the alteration on Ca2+ mobilization. (C) 2014 Elsevier B.V. All rights reserved. (AU)

• FAPESP's process: 11/13630-7 - Chemical and pharmacological validation of extracts and active compounds of Copaifera species
• Grantee: Jairo Kenupp Bastos
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 10/01009-3 - Evaluation of the cardiovascular effects elicited by the labdan acid ent-3-acetoxi-labda-8(17),13-dieno-15-oic
• Grantee: Carlos Renato Tirapelli
• Support Opportunities: Regular Research Grants