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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

cAMP-Adenosine Pathway in the Proximal Tubule

Center for Clinical Pharmacology (E.K.J., L.C.Z., M.Z., D.G.G., C.Z., R.K.D.) and Departments of Medicine (E.K.J., L.C.Z., M.Z., D.G.G., C.Z., R.K.D.) and Pharmacology (E.K.J.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Clinic for Endocrinology, Department of Obstetrics and Gynecology, University Hospital Zurich, Zurich, Switzerland (R.K.D.)

The "extracellular cAMP-adenosine pathway" refers to the conversion of cAMP to AMP by ecto-phosphodiesterase, followed by metabolism of AMP to adenosine by ecto-5'-nucleotidase, with all the steps occurring in the extracellular compartment. This study investigated whether the extracellular cAMP-adenosine pathway exists in proximal tubules. Freshly isolated proximal tubules rapidly converted basolaterally administered cAMP to AMP and adenosine. Proximal tubular cells in culture (first passage) rapidly converted apically administered cAMP to AMP and adenosine. In both freshly isolated proximal tubules and cultured proximal tubular cells, conversion of cAMP to AMP and adenosine was affected by a broad-spectrum phosphodiesterase inhibitor (3-isobutyl-1-methylxanthine), an ecto-phosphodiesterase inhibitor (1,3-dipropyl-8-p-sulfophenylxanthine), and a blocker of ecto-5'-nucleotidase (,-methyleneadenosine-5'-diphosphate) in a manner consistent with exogenous cAMP being processed by the extracellular cAMP-adenosine pathway. In cultured proximal tubular cells, but not freshly isolated proximal tubules, stimulation of adenylyl cyclase increased extracellular concentrations of cAMP, AMP, and adenosine plus inosine, and these changes were also modulated by the inhibitors in a manner consistent with the extracellular cAMP-adenosine pathway. Conversion of renal interstitial (basolateral) cAMP and AMP to adenosine in vivo was shown by microdialysis coupled with ion trap mass spectrometry. Western blot analysis showed A₁, A_2A, and A₃ receptors on both apical and basolateral proximal tubular membranes, with A₁ and A_2A receptors more highly expressed on basolateral compared with apical membranes. We conclude that cAMP that reaches either the apical or basolateral membranes of proximal tubular cells is converted in part to adenosine that has ready access to adenosine receptors.

Address correspondence to: Edwin K. Jackson, Center for Clinical Pharmacology, University of Pittsburgh School of Medicine, 100 Technology Drive, Suite 450, Pittsburgh, PA 15219. E-mail: edj{at}pitt.edu

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