期刊
JOURNAL OF PHARMACY AND PHARMACOLOGY
卷 67, 期 4, 页码 551-558出版社
WILEY-BLACKWELL
DOI: 10.1111/jphp.12346
关键词
calmodulin; endothelial nitric oxide synthase; malbrancheamides; vasorelaxation
资金
- CONACyT [99395]
ObjectivesThis 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. MethodsThe vasorelaxant effect was assessed on rat aorta rings pre-contracted with noradrenaline (0.1m). 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. Key findingsMalbrancheamides (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 (10m), indicating a nitrergic relaxant mechanism. Docking analysis predicted that 1-3 could activate eNOS throughout an allosteric fashion at C1 and C2 pockets. ConclusionsExperimental 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.
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