title: Insights on the vasorelaxant mode of action of malbrancheamide.
abstract: OBJECTIVE
  This study was conducted to evaluate the vasorelaxant effect of the fungal alkaloids malbrancheamides on pre-contracted rat aorta rings. Also, we explored the probable mode of action using experimental and theoretical docking studies.
  
  
  METHODS
  The vasorelaxant effect was assessed on rat aorta rings pre-contracted with noradrenaline (0.1 μm). The mechanism of action was evaluated using different inhibitors of the pathways involved in the vasorelaxation process, such as l-NAME, indomethacin, tetraethylammonium and atropine. The docking analyses were carried out with AutoDock 4.2 software using the crystallized structure of the cyclooxygenase domain of eNOS.
  
  
  RESULTS
  Malbrancheamides (1-3) induced a significant vasorelaxant activity in a concentration- and endothelium-intact model in rat aorta rings, and a lesser effect in an endothelium-denuded model. Malbrancheamide-induced vasorelaxation was significantly weakened by pretreatment of endothelium-intact aortic rings with L-NAME (10 μm), indicating a nitrergic relaxant mechanism. Docking analysis predicted that 1-3 could activate eNOS throughout an allosteric fashion at C1 and C2 pockets.
  
  
  CONCLUSIONS
  Experimental evidence revealed that malbrancheamides induced both endothelium-independent and endothelium-dependent relaxant effects. According to theoretical studies, it is feasible that the endothelium-independent relaxation exerted by malbrancheamide could be mediated by its calmodulin inhibitory properties throughout an interference with myosin light chain phosphorylation and a positive modulation of eNOS.
authors: Facultad de Química, Universidad Nacional Autónoma de México, México, México.
authors: Abraham
authors: A
authors: Madariaga-Mazón
authors: Oswaldo
authors: O
authors: Hernández-Abreu
authors: Samuel
authors: S
authors: Estrada-Soto
authors: Rachel
authors: R
authors: Mata
mesh_terms: D000818:Animals; D001011:Aorta; D001688:Biological Products / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects*; D005658:Fungi / Q000737:chemistry*; D026121:Indole Alkaloids / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D051381:Rats; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D001688:Biological Products; D026121:Indole Alkaloids; C529354:malbrancheamide; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D019331:NG-Nitroarginine Methyl Ester
keywords: calmodulin; endothelial nitric oxide synthase; malbrancheamides; vasorelaxation