Inhibition of nitric oxide-guanylate cyclase-dependent and -independent signaling contributes to impairment of beta-adrenergic vasorelaxations by cyclosporine.
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.
El-Mas
Mahmoud M
MM
Department of Pharmacology, Faculty of Pharmacy, University of Alexandria, Alexandria, Egypt. mahelm@hotmail.com
Sharabi
Fouad M
FM
El-Gowilly
Sahar M
SM
El-Din
Mahmoud M Mohy
MM
D000818:Animals; D003524:Cyclosporins / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000502:physiology*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000502:physiology*; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects*
D003524:Cyclosporins; D011943:Receptors, Adrenergic, beta; D009599:Nitroprusside; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D007545:Isoproterenol