title: Blocking the L-type Ca2+ channel (Cav 1.2) is the key mechanism for the vascular relaxing effect of Pterodon spp. and its isolated diterpene methyl-6α-acetoxy-7β-hydroxyvouacapan-17β-oate.
abstract: Pterodon spp. Vogel (Fabaceae), popularly known as "sucupira", has ethnopharmacological application which is described as having antispasmodic and relaxant effects. Hence, it was hypothesized that sucupira oil-resin (SOR) could induce smooth muscle relaxation. So, this study investigated the mechanisms involved in the vasorelaxant effect of SOR and its isolated diterpene (methyl-6α-acetoxy-7β-hydroxyvouacapan-17β-oate). Vascular reactivity experiments were performed using rat aortic rings (n=5-8) with (E+) or without endothelium (E-) in an isolated bath organ. The SOR (0-56 μg/mL) relaxed phenylephrine (E+: 86.7±7.1%; E-: 92.3±4.7%) and KCl contracted rings (E-: 97.1±2.8%). In the same way, diterpene (0-48 μg/mL) also relaxed phenylephrine (E+: 94.5±3.6%; E-: 92.2±3.4%) and KCl contracted rings (E-: 99.7±0.2%). The pre-incubation of arterial rings with cyclopiazonic acid (reticular Ca2+-ATPase inhibitor), tetraethylammonium (K+ channels blocker) or MDL-12,330A (adenylyl cyclesinhibitor) did not modify either SOR- or diterpeneinduced vasorelaxation. However, ODQ (guanylyl cyclase inhibitor) impaired only diterpene-induced vasorelaxation. SOR and diterpene significantly reduced CaCl2-induced contraction stimulated by Bay K8644 (1 μM), phenylephrine (0.1 μM) or KCl solution (40 mM). Computational molecular docking studies demonstrated that the vasodilator effect of diterpene relies on blocking the Cav 1.2 channel, and patch clamp results showed that diterpene substantially decreased the ionic current through Cav 1.2 in freshly dissociated vascular smooth muscle cells. These findings suggest that SOR and its isolated diterpene induce endothelium-independent vascular relaxation by blocking the L-type Ca2+ channel (Cav 1.2).
authors: Laboratory of Cardiovascular Pharmacology, Faculty of Pharmacy, Federal University of Goias, Goiânia, GO, Brazil.
authors: Carolina
authors: C
authors: de Fátima Reis
authors: Laboratory of Cardiovascular Pharmacology, Faculty of Pharmacy, Federal University of Goias, Goiânia, GO, Brazil.
authors: Daniela Medeiros Lobo
authors: DM
authors: de Andrade
authors: Laboratory for Molecular Modeling and Drug design, Faculty of Pharmacy, Federal University of Goias, Goiânia, GO, Brazil.
authors: Bruno
authors: B
authors: Junior Neves
authors: Laboratory of Natural Products Research, Faculty of Pharmacy, Federal University of Goias, Goiânia, GO, Brazil.
authors: Leandra
authors: L
authors: de Almeida Ribeiro Oliveira
authors: Laboratory of Excitable Membranes and Cardiovascular Biology, Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, UFMG, Brazil.
authors: José Felippe
authors: JF
authors: Pinho
authors: Laboratory of Excitable Membranes and Cardiovascular Biology, Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, UFMG, Brazil.
authors: Leidiane Pinha
authors: LP
authors: da Silva
authors: Laboratory of Excitable Membranes and Cardiovascular Biology, Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, UFMG, Brazil.
authors: Jader
authors: J
authors: Dos Santos Cruz
authors: Laboratory of Natural Products Research, Faculty of Pharmacy, Federal University of Goias, Goiânia, GO, Brazil.
authors: Maria Teresa Freitas
authors: MT
authors: Bara
authors: Laboratory for Molecular Modeling and Drug design, Faculty of Pharmacy, Federal University of Goias, Goiânia, GO, Brazil.
authors: Carolina Horta
authors: CH
authors: Andrade
authors: Laboratory of Cardiovascular Pharmacology, Faculty of Pharmacy, Federal University of Goias, Goiânia, GO, Brazil. Electronic address: matheusroch@yahoo.com.br.
authors: Matheus Lavorenti
authors: ML
authors: Rocha
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D004224:Diterpenes / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D007887:Fabaceae / Q000737:chemistry*; D006162:Guanylate Cyclase / Q000378:metabolism; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D010936:Plant Extracts / Q000494:pharmacology*; D015221:Potassium Channels / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D020746:Calcium Channels, L-Type; D004224:Diterpenes; D010936:Plant Extracts; D015221:Potassium Channels; D014665:Vasodilator Agents; D010656:Phenylephrine; D006162:Guanylate Cyclase; D002118:Calcium
keywords: Acetylcholine chloride (PubChem CID: 6060); Bay K8644 (PubChem CID: 2303); Ca(2+) channel; Ca(2+) channel blocker; Cyclopiazonic acid (PubChem CID: 54682463); Diterpene; ODQ ([1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) (PubChem CID: 1456); Phenylephrine hydrochloride (PubChem CID: 5284443); Pterodon spp.; Tetraethylammonium chloride (PubChem CID: 5946); Vasodilation; Verapamil hydrochloride (PubChem CID: 62969)