title: The semi-synthetic kaurane ent-16α-methoxykauran-19-oic acid induces vascular relaxation and hypotension in rats.
abstract: The present work investigates the mechanisms involved in the vasorelaxant effect of ent-16α-methoxykauran-19-oic acid (KA-OCH3), a semi-synthetic derivative obtained from the kaurane-type diterpene ent-kaur-16-en-19-oic acid (kaurenoic acid). Vascular reactivity experiments were performed in aortic rings isolated from male Wistar rats using standard muscle bath procedures. The cytosolic calcium concentration ([Ca2+]c) was measured by confocal microscopy using the fluorescent probe Fluo-3 AM. Blood pressure measurements were performed in conscious rats. KA-OCH3 (10, 50 and 100 μmol/l) inhibited phenylephrine-induced contraction in either endothelium-intact or endothelium-denuded rat aortic rings. KA-OCH3 also reduced CaCl2-induced contraction in a Ca2+-free solution containing KCl (30 mmol/l) or phenylephrine (0.1 μmol/l). KA-OCH3 (0.1-300 μmol/l) concentration-dependently relaxed endothelium-intact and endothelium-denuded aortas pre-contracted with either phenylephrine or KCl, to a greater extent than kaurenoic acid. Moreover, a Ca2+ mobilisation study showed that KA-OCH3 (100 μmol/l) inhibited the increase in Ca2+ concentration in smooth muscle and endothelial cells induced by phenylephrine or KCl. Pre-incubation of intact or denuded aortic rings with NG-nitro-L-arginine methyl ester (L-NAME, 100 μmol/l), 7-nitroindazole (100 μmol/l), wortmannin (0.5 μmol/l) and 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 1 μmol/l) produced a rightward displacement of the KA-OCH3 concentration-response curve. Intravenous administration of KA-OCH3 (1-10 mg/kg) reduced mean arterial blood pressure in normotensive rats. Collectively, our results show that KA-OCH3 induces vascular relaxation and hypotension. The mechanisms underlying the cardiovascular actions of KA-OCH3 involve blockade of Ca2+ influx and activation of the NO-cGMP pathway.
authors.affiliation: Department of Psychiatric Nursing and Human Sciences, Laboratory of Pharmacology, College of Nursing of Ribeirão Preto, University de São Paulo (USP), Ribeirão Preto, SP, Brazil. vilelahipolito@yahoo.com.br
authors.forename: Ulisses V
authors.initials: UV
authors.lastname: Hipólito
authors.forename: Juliana T
authors.initials: JT
authors.lastname: Rocha
authors.forename: Nathalia B
authors.initials: NB
authors.lastname: Palazzin
authors.forename: Gerson J
authors.initials: GJ
authors.lastname: Rodrigues
authors.forename: Carlos C
authors.initials: CC
authors.lastname: Crestani
authors.forename: Fernando M
authors.initials: FM
authors.lastname: Corrêa
authors.forename: Daniella
authors.initials: D
authors.lastname: Bonaventura
authors.forename: Sergio R
authors.initials: SR
authors.lastname: Ambrosio
authors.forename: Lusiane M
authors.initials: LM
authors.lastname: Bendhack
authors.forename: Leonardo B
authors.initials: LB
authors.lastname: Resstel
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Tirapelli
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000502:physiology / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002122:Calcium Chloride / Q000494:pharmacology; D045786:Diterpenes, Kaurane / Q000138:chemical synthesis / Q000494:pharmacology*; D007022:Hypotension / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D066298:In Vitro Techniques; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010656:Phenylephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D045786:Diterpenes, Kaurane; C560736:ent-16alpha-methoxykauran-19-oic acid; D010656:Phenylephrine; D011189:Potassium Chloride; D002122:Calcium Chloride; D002118:Calcium