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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Characterization of Renal Ecto-Phosphodiesterase

Center for Clinical Pharmacology, Departments of Pharmacology (E.K.J.) and Medicine (E.K.J., J.R., L.C.Z., Z.M.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

In kidneys, stimulation of adenylyl cyclase causes egress of cAMP, conversion of cAMP to AMP by ecto-phosphodiesterase, and metabolism of AMP to adenosine by ecto-5'-nucleotidase. Although much is known about ecto-5'-nucleotidase, the renal ecto-phosphodiesterase remains uncharacterized. We administered cAMP (10 µM in the perfusate) to 12 different groups of perfused kidneys. AMP was measured in perfusate using ion trap mass spectrometry. In control kidneys (n = 19), basal renal secretion rate of AMP was 0.49 ± 0.08 and increased to 3.0 ± 0.2 nmol AMP/g kidney weight/min during administration of cAMP. A broad-spectrum phosphodiesterase (PDE) inhibitor (1,3-isobutyl-1-methylxanthine, 300 µM, n = 6) and an ecto-phosphodiesterase inhibitor (1,3-dipropyl-8-p-sulfophenylxanthine, 1 mM, n = 6) significantly attenuated cAMP-induced AMP secretion by 60 and 74%, respectively. Blockade of PDE1 (8-methoxymethyl-3-isobutyl-1-methylxanthine, 100 µM), PDE2 [erythro-9-(2-hydroxy-3-nonyl)adenine, 30 µM], PDE3 (milrinone, 10 µM; cGMP, 10 µM), PDE4 (Ro 20-1724 [4-(3-butoxy-4-methoxybenzyl)imidazolidin-2-one], 100 µM), PDE5 and PDE6 (zaprinast, 30 µM), and PDE7 [BRL-50481 (5-nitro-2,N,N-trimethylbenzenesulfonamide), 10 µM] did not alter renal ecto-phosphodiesterase activity. Administration of a concentration (100 µM) of dipyridamole that blocks PDE8 inhibited ecto-phosphodiesterase activity (by 44%). However, a lower concentration of dipyridamole (3 µM) that blocks PDE9, PDE10, and PDE11, but not PDE8, did not inhibit ecto-phosphodiesterase activity. These data support the conclusion that renal ecto-phosphodiesterase activity is not mediated by PDE1, PDE2, PDE3, PDE4, PDE5, PDE6, PDE7, PDE9, PDE10, or PDE11 and is inhibited by high concentrations of dipyridamole. Ecto-phosphodiesterase has some pharmacological characteristics similar to PDE8.

Address correspondence to: Dr. 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

This article has been cited by other articles:

				E. K. Jackson and Z. Mi Regulation of Renal Ectophosphodiesterase by Protein Kinase C and Sodium Diet J. Pharmacol. Exp. Ther., April 1, 2008; 325(1): 210 - 216. [Abstract] [Full Text] [PDF]