METABOLISM OF EXOGENOUS CYCLIC-AMP TO ADENOSINE IN THE RAT-KIDNEY

Although adenosine contributes importantly to the regulation of renin release, renal vascular resistance and renal tubular reabsorption, the metabolic pathways that control the intrarenal production rate of ade nosine remain ill defined. The objective of this study was to determin e whether extracellular metabolism of cyclic AMP to AMP by extracellul ar phosphodiesterase and hence to adenosine by ecto-5'-nucleotidase ca n occur in the intact kidney. To test this hypothesis, five experiment al series were conducted in kidneys from male Sprague-Dawley rats perf used in a nonrecirculating system (5 ml/min) in vitro with oxygenated Tyrode's solution at 37 degrees C. In each experimental series, cyclic AMP was added to the Tyrode's solution and the renal secretion rates (i.e., the renal venous concentration of purine x the perfusion flow r ate) of AMP, adenosine and inosine were determined using high-performa nce liquid chromatography. In the first experimental series, only cycl ic AMP was added to the perfusate. In the second, third, fourth and fi fth experimental series, kidneys were perfused with Tyrode's solution containing both cyclic AMP and either 3-isobutyl-1-methylxanthine (a p hosphodiesterase inhibitor), alpha,beta-methyleneadenosine-5'-diphosph ate (an ecto-5'-nucleotidase inhibitor), dilazep (an adenosine transpo rt inhibitor) or 1,3-dipropyl-8-p-sulfophenylxanthine (a xanthine that is restricted to the extracellular compartment). In the first experim ental series (n = 8), addition of cyclic AMP to the perfusate resulted in significant concentration-related increases in the renal secretion rates of AMP, adenosine and inosine, with the increase in AMP secreti on being significantly greater than the increases in adenosine or inos ine secretions (Delta adenosine secretion/Delta AMP secretion = 0.38 /- 0.10). 3-lsobutyl-1-methylxanthine (n = 5) completely blocked the i ncreases in AMP, adenosine and inosine secretion rates caused by exoge nous cyclic AMP. When cyclic AMP was coadministered with alpha,beta-me thyleneadenosine-5'-diphosphate (n = 5), the secretion rates of AMP an d inosine were still increased; however, the increase in adenosine sec retion was blocked. In the presence of dilazep (n = 6), exogenous cycl ic AMP increased renal secretion rates of AMP, adenosine and inosine b ut the relative increase in adenosine compared with AMP was greater (i .e., Delta adenosine secretion/Delta AMP secretion = 1.26 +/- 0.36, P = .0282 compared with control group). In the fifth study (n = 5), 1,3- dipropyl-8-p-sulfophenylxanthine inhibited the conversion of exogenous cyclic AMP to AMP and adenosine. These results suggest that, in the i ntact kidney, extracellular conversion of cyclic AMP to AMP and hence to adenosine is a viable metabolic pathway.