Mechanism of inhibition of organic acid transport in rabbit renal cortex by cyclic AMP.

The mechanism by which isoproterenol and cyclic AMP inhibit organic acid transport was examined. Accumulation of 131I-Hippuran (S/M) was used as an index of organic acid transport. Propranolol, an antagonist of isoproterenol's beta-adrenergic response, not only inhibited accumulation of Hippuran but, when combined with isoproterenol, caused further inhibition. PTH elicited larger increases than isoproterenol in cortical-slice cyclic AMP content but did not inhibit accumulation of Hippuran. This lack of correlation between a positive effect on the adenylate-cyclase-cyclic AMP system and inhibition of transport was also seen when other agents were tested. Cyclic GMP, which has been postulated to work in opposition to cyclic AMP, was as potent as cyclic AMP in decreasing S/M. The decreasing of S/M by adenine and uric acid could not be related to any known effect of these agents on tissue cyclic AMP content. Similarly, although 0.1 mM theophylline significantly decreased S/M, cortical cyclic-AMP content was not increased until a 100-fold greater concentration of theophylline was employed. The data suggest that the inhibitory effect of these agents was attributable to their molecular configurations, which interact directly with the organic acid transport system rather than indirectly via the adenylate-cyclase-cyclic AMP system.