Abstract:
:This study investigated the role of endothelium- and smooth muscle-dependent mechanisms in the interaction of cyclosporine (CyA), an immunosuppressant drug, with beta-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 (beta-adrenoceptor antagonist). In aortas with intact endothelium (E+), pretreatment with L-NAME or methylene blue significantly reduced isoprenaline (1 x 10(-9) to 1 x 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 microM) 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 beta-adrenoceptor relaxations and both components are negatively influenced by CyA, and (ii) NO-GC signaling plays an integral role in the vascular CyA-beta-adrenoceptor interaction. The clinical relevance of the present study is warranted given the established role of impaired vascular function in CyA toxicity.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
El-Mas MM,Sharabi FM,El-Gowilly SM,El-Din MMdoi
10.1016/j.bcp.2006.10.015subject
Has Abstractpub_date
2007-02-01 00:00:00pages
359-67issue
3eissn
0006-2952issn
1873-2968pii
S0006-2952(06)00666-6journal_volume
73pub_type
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