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• W2083624373 abstract "This study investigated the role of endothelium- and smooth muscle-dependent mechanisms in the interaction of cyclosporine (CyA), an immunosuppressant drug, with β-adrenoceptor (isoprenaline)-mediated relaxations in isolated rat aortas precontracted with phenylephrine. CyA effects were assessed in the absence and presence of NG-nitro-l-arginine methyl ester (l-NAME, nitric oxide synthase inhibitor), methylene blue (guanylate cyclase inhibitor), or propranolol (β-adrenoceptor antagonist). In aortas with intact endothelium (E+), pretreatment with l-NAME or methylene blue significantly reduced isoprenaline (1 × 10−9 to 1 × 10−7 M) relaxations in contrast to no effect for tetraethylammonium (K+ channel blocker), or diclophenac (cyclooxygenase inhibitor), suggesting a major role for the nitric oxide-guanylate cyclase (NO-GC) pathway, but not endothelial hyperpolarizing factor or vasodilator prostanoids, in isoprenaline responses. Isoprenaline relaxations were still evident, though significantly attenuated, in endothelium-denuded aortas (E−) and were resistant to l-NAME or methylene blue. Acute exposure to CyA (2 μM) caused propranolol-sensitive reductions in isoprenaline responses in E+ and E− aortas. The CyA-induced attenuation of isoprenaline responses in E+ aortas largely disappeared in l-NAME-treated aortas and after supplementation with l-arginine, the substrate of nitric oxide. CyA also reduced the endothelium-independent, GC-dependent aortic relaxations evoked by sodium nitroprusside, an effect that was virtually abolished by methylene blue. We conclude that: (i) endothelial and smooth muscle mechanisms contribute to aortic β-adrenoceptor relaxations and both components are negatively influenced by CyA, and (ii) NO-GC signaling plays an integral role in the vascular CyA-β-adrenoceptor interaction. The clinical relevance of the present study is warranted given the established role of impaired vascular function in CyA toxicity." @default.
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• W2083624373 date "2007-02-01" @default.
• W2083624373 modified "2023-09-27" @default.
• W2083624373 title "Inhibition of nitric oxide-guanylate cyclase-dependent and -independent signaling contributes to impairment of β-adrenergic vasorelaxations by cyclosporine" @default.
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• W2083624373 doi "https://doi.org/10.1016/j.bcp.2006.10.015" @default.
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