title: Antihypertensive and vasorelaxant effects of dihydrospinochalcone-A isolated from Lonchocarpus xuul Lundell by NO production: computational and ex vivo approaches.
abstract: Current work was conducted to evaluate the vasorelaxant effect of dihydrospinochalcone-A (1) and isocordoin (2), compounds type chalcone isolated from Lonchocarpus xuul, an endemic tree of the Yucatan Peninsula, Mexico. Compounds 1 and 2 were found to induce significant relaxant effect in a concentration-dependent manner on aortic rat rings pre-contracted with noradrenaline (NA, 0.1 μM). Compound 1 was the most active and its effect was endothelium-dependent (Emax=79.67% and EC50=21.46 μM with endothelium and Emax=23.58% and EC50=91.8 μM without endothelium, respectively). The functional mechanism of action for 1 was elucidated. Pre-incubation with L-NAME (unspecific nitric oxide synthase inhibitor), indomethacin (unspecific COX inhibitor), ODQ (soluble guanylyl cyclase inhibitor), atropine (cholinergic receptor antagonist), TEA (unspecific potassium channel blocker) reduced relaxations induced by 1. Oral administration of 50 mg/kg of compound 1 exhibited significant decrease in diastolic and systolic blood pressure in SHR rats. The heart rate was not modified. Compound 1 was docked with a crystal structure of eNOS. Dihydrospinochalcone-A showed calculated affinity with eNOS in the C1 binding pockets, near the catalytic site; Trp449, Trp447 and His373 through aromatic and π-π interactions, also His463 and Arg367 are the residues that make hydrogen bonds with the carbonyl and hydroxyl groups. In conclusion, dihydrospinochalcone-A induces a significant antihypertensive effect due to its direct vasorelaxant action on rat aorta rings, through NO/sCG/PKG pathway and potassium channel opening.
authors.affiliation: Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Avenida Universidad 1001, Colonia Chamilpa, 62209 Cuernavaca, Morelos, Mexico.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Avila-Villarreal
authors.forename: Oswaldo
authors.initials: O
authors.lastname: Hernández-Abreu
authors.forename: Sergio
authors.initials: S
authors.lastname: Hidalgo-Figueroa
authors.forename: Gabriel
authors.initials: G
authors.lastname: Navarrete-Vázquez
authors.forename: Fabiola
authors.initials: F
authors.lastname: Escalante-Erosa
authors.forename: Luis M
authors.initials: LM
authors.lastname: Peña-Rodríguez
authors.forename: Rafael
authors.initials: R
authors.lastname: Villalobos-Molina
authors.forename: Samuel
authors.initials: S
authors.lastname: Estrada-Soto
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000302:isolation & purification / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects; D001285:Atropine / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D002396:Catechols / Q000302:isolation & purification / Q000494:pharmacology*; D047188:Chalcones / Q000302:isolation & purification / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects; D007887:Fabaceae / Q000737:chemistry*; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006339:Heart Rate / Q000187:drug effects; D007213:Indomethacin / Q000494:pharmacology; D008800:Mexico; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009638:Norepinephrine; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors; D000071756:Soluble Guanylyl Cyclase; D014661:Vasoconstriction / Q000187:drug effects; D014665:Vasodilator Agents / Q000302:isolation & purification / Q000494:pharmacology*
chemical_list: D000959:Antihypertensive Agents; D002396:Catechols; D047188:Chalcones; D010936:Plant Extracts; D026902:Potassium Channel Blockers; D018160:Receptors, Cytoplasmic and Nuclear; D014665:Vasodilator Agents; C578744:dihydrospinochalcone-a; C438026:isocordoin; D009569:Nitric Oxide; D001285:Atropine; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D019331:NG-Nitroarginine Methyl Ester; D009638:Norepinephrine; D007213:Indomethacin
keywords: Antihypertensive; Dihydrospinochalcone-A; Docking; Isocordoin; Lonchocarpus xuul; Nitric oxide; Vasorelaxant