Inhibition of bradykinin stimulation of renal medullary prostaglandin E2 synthesis by phosphodiesterase inhibitors.
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 availability of arachidonic acid. These effects of MIX and RO-20 on PGE2 synthesis are not secondary to their effects on cyclic nucleotide phosphodiesterase.
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000037:antagonists & inhibitors*; D000242:Cyclic AMP / Q000378:metabolism; D015232:Dinoprostone; D005200:FANFT / Q000378:metabolism; D066298:In Vitro Techniques; D007679:Kidney Medulla / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008861:Microsomes / Q000378:metabolism; D009712:Nucleotides, Cyclic / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011458:Prostaglandins E / Q000096:biosynthesis*; D011817:Rabbits; D012669:Seminal Vesicles / Q000378:metabolism; D012756:Sheep
D009712:Nucleotides, Cyclic; D010726:Phosphodiesterase Inhibitors; D011458:Prostaglandins E; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; D005200:FANFT; D000242:Cyclic AMP; D015232:Dinoprostone; D001920:Bradykinin; D015056:1-Methyl-3-isobutylxanthine