PMID: 6169824Nov 1, 1981Paper

Inhibition of bradykinin stimulation of renal medullary prostaglandin E2 synthesis by phosphodiesterase inhibitors

The Journal of Pharmacology and Experimental Therapeutics
N S RappB B Davis

Abstract

Effects of phosphodiesterase inhibitors DL-4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro-20) and 1-methyl-3-isobutylxanthine (MIX) on prostaglandin E2 (PGE2) synthesis were examined using rabbit renal inner medullary slices incubated in Krebs' buffer with or without 1 mM RO-20 or 2 mM MIX. Basal and bradykinin-mediated PGE2 synthesis were inhibited in a dose-dependent, reversible manner by both RO-20 and MIX. Arachidonic acid-mediated increases in PGE2 synthesis were not inhibited. By contrast, 1 mM aspirin completely inhibited PGE2 synthesis. Phosphodiesterase inhibitors increased slice cyclic AMP content more than 6-fold. However, this elevation in tissue cyclic AMP content did not appear to be the cause of decreased PGE2 synthesis. Exogenous 3 mM cyclic AMP and 3 mM dibutyryl cyclic AMP did not alter PGE2 synthesis. 2',5'-Dideoxyadenosine, an inhibitor of adenylate cyclase, prevented RO-20 and MIX-mediated increases in cyclic AMP but had no effect on PGE2 synthesis. Exogenous 3 mM cyclic GMP and dibutyryl cyclic GMP did not alter PGE2 synthesis. Neither RO-20 nor MIX had a direct effect on PG endoperoxide synthetase. These results indicate MIX and RO-20 inhibit renal medullary PGE2 production by limiting the availabilit...Continue Reading

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