Regional and Endothelial Differences in Cyclosporine Attenuation of Adenosine Receptor-Mediated Vasorelaxations


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Abstract

The present study investigated the acute effects of the immunosuppressant drug cyclosporine A on vasorelaxations evoked via activation of adenosine receptors in the phenylephrine-preconstricted rat perfused kidney and isolated aorta. The roles of endothelial relaxing factors in this interaction were also evaluated. The adenosine analogue 5′-N-ethylcarboxamidoadenosine (NECA; kidney, 6 × 10−9−1 × 10−7 mol; aorta, 1 × 10−9−1 × 10−5 M) elicited dose-dependent vasorelaxations. In the perfused kidney, NECA responses were similarly and significantly attenuated by NG-nitro-L-arginine methyl ester (L-NAME, nitric oxide synthase inhibitor) or tetraethylammonium (K+ channel blocker) versus no effect for diclophenac (cyclooxygenase inhibitor). NECA relaxations in the aorta were reduced by the three inhibitors; the reduction in the response evoked by the highest dose of NECA (1 × 10−5 M) amounted to 37.7 ± 2.0% (L-NAME), 19.8 ± 1.7% (tetraethylammonium), and 29.4 ± 1.1% (diclophenac). A combination of the three inhibitors almost abolished NECA relaxations in the two preparations. Cyclosporine (2 μM) reduced NECA relaxations in the two preparations. In the aorta, cyclosporine attenuation of NECA responses was significantly reduced after exposure to L-NAME or diclophenac but not tetraethyl-ammonium, suggesting selective involvement of nitric oxide and vasodilator prostanoids in the interaction. In contrast, the cyclosporine attenuation of NECA responses in the kidney was reduced by L-NAME or tetraethylammonium. L-arginine, a nitric oxide substrate, partially restored NECA relaxations in cyclosporine-treated preparations. These findings demonstrate that cyclosporine attenuates endothelium-dependent vasorelaxations elicited via activation of adenosine receptors and highlight the interesting possibility that the relative contribution of the endothelial relaxing factors to cyclosporine-NECA interaction is largely region dependent.

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