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  • Title: Nitric oxide mediated endothelium-dependent relaxation induced by glibenclamide in rat isolated aorta.
    Author: Chan W, Yao X, Ko W, Huang Y.
    Journal: Cardiovasc Res; 2000 Apr; 46(1):180-7. PubMed ID: 10727666.
    Abstract:
    OBJECTIVES: Glibenclamide was found to act as both a selective ATP-sensitive K(+) channel blocker and a vasorelaxant. The exact mechanisms underlying the relaxant effect of glibenclamide are unknown. The present study was designed to examine the role of endothelium/nitric oxide in glibenclamide-induced relaxation in rat isolated aortic rings. METHODS: A combination of experimental approaches including isometric force measurement, cell culture, Ca(2+) fluorescence measurement and radioimmunoassay were used to examine the vascular effect of glibenclamide. RESULTS: Glibenclamide induced a concentration-dependent relaxation more effectively in rings with endothelium (IC(50) of 32+/-4 microM) than those without endothelium (IC(50) of 365+/-29 microM). Incubation with N(G)-nitro-L-arginine methyl ester (L-NAME) or methylene blue significantly reduced and L-arginine (3 mM) potentiated the glibenclamide-induced relaxation. L-Arginine (3 mM) partially antagonized the effect of L-NAME. Glibenclamide (100 microM) increased the cyclic GMP content of endothelium-intact tissues. Pretreatment with N(G)-nitro-L-arginine (100 microM) or removal of endothelium significantly suppressed the effect of glibenclamide on cyclic GMP production. Glibenclamide elevated the intracellular Ca(2+) levels in cultured rat aortic endothelial cells. Glibenclamide also inhibited the endothelium-independent contractile response to 60 mM K(+) (IC(50) of 137+/-21 microM) and caused a rightward shift in the concentration-contraction curve for CaCl(2). Besides, glibenclamide inhibited phorbol-12,13-diacetate (1 microM)-induced contraction in Ca(2+)-free Krebs solution. CONCLUSION: These results indicate that glibenclamide-induced endothelium-dependent relaxation involves nitric oxide release and this effect may be related to its stimulatory effect on endothelial Ca(2+) levels. However, the glibenclamide-induced endothelium-independent relaxation may be associated with its inhibitory effect on Ca(2+) influx through Ca(2+) channels and on the protein kinase C-mediated contractile mechanism.
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