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Regulation of Adenosine Receptor Function by Theophylline in Rat Aorta

The effect of chronic theophylline treatment on adenosine receptor function was investigated in rat aorta. Male Wistar rats were fed theophylline (1 g/L) in drinking water for 30 days. The relaxation-response curves to various adenosine receptor agonists, nonselective 5'-N-ethylcarboxamidoadenosine (NECA), A2-selective 2-phenylaminoadenosine (CV-1808), and A1-selective N6-(2-endo-norbornyl) adenosine (S-ENBA) were generated in aortic rings from control and treated rats. The relaxation curves to both NECA and CV-1808 (10(-9)-10(-4) M) were significantly attenuated in treated rings (endothelium intact) as compared with control. S-ENBA showed a contraction at a lower concentration (10(-10)-10(-6) M) in treated rings as compared with control. Because S-ENBA is highly A1 selective, it produced relaxation only at 10(-4) M. Similar to that of adenosine analogues, the isoproterenol (ISO 10(-9)-10(-5) M) concentration-relaxation curve was shifted to the right in treated rats. Endothelium removal of the vascular rings decreased the magnitude of relaxation to these agonists and eliminated the difference in relaxation between control and treated groups. The relaxation to acetylcholine (ACh), an endothelium-dependent relaxing agent, was also attenuated in the theophylline-treated group. The relaxation responses to forskolin (10(-11)-10(-8) M) and sodium nitroprusside (SNP 10(-10)-10(-7) M) were unaltered in treated rats. These data suggest an endothelium-dependent downregulation of adenosine receptor function together with beta-adrenoceptor after chronic theophylline treatment.