Inhibitory modulation by cAMP of isoproterenol-induced prostacyclin synthesis in rabbit heart.
beta-Adrenergic receptor activation in heart is associated with enhanced production of adenosine 3',5'-cyclic monophosphate (cAMP) and prostaglandins (PG). The purpose of the present study was to test the hypothesis that cAMP mediates or modulates PG synthesis elicited by activation of beta-adrenergic receptors in the isolated, perfused rabbit heart. Infusion of 8-(4-chlorophenylthio) (cpt)-cAMP (100 microM), an analogue of cAMP, or stimulation of endogenous cAMP generation with forskolin (2 microM) resulted in a reduction of perfusion pressure and an increase in heart rate and contractility but had no effect on 6-keto-PGF1 alpha output. 6-Keto-PGF1 alpha production elicited by a bolus injection of isoproterenol (Isop) (475 pmol), however, was reduced by greater than 50% in the presence of these agents, cpt-cAMP was also found to inhibit 6-keto-PGF1 alpha output elicited by the calcium ionophore A23187 but not that in response to exogenous arachidonic acid. Perfusion with the adenosine analogue adenylate cyclase inhibitor PIA (1 microM) enhanced by twofold Isop-stimulated output of 6-keto-PGF1 alpha, whereas cAMP accumulation was prevented. Isop-stimulated production of 6-keto-PGF1 alpha was inhibited by 50% in the presence of the phosphodiesterase inhibitors 1-methyl-3-isobutylxanthine (50 microM), Ro 20-1724 (300 microM), or cilostamide (5 microM), whereas both basal and Isop-stimulated cAMP accumulations were enhanced by these agents. These data suggest that cAMP acts as an inhibitory modulator of PG synthesis in response to beta-adrenergic receptor activation in rabbit heart.
Williams
J L
JL
Department of Pharmacology, School of Medicine, University of Tennessee, Memphis 38163.
Malik
K U
KU
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis*; D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000494:pharmacology / Q000502:physiology* / Q000031:analogs & derivatives; D011464:Epoprostenol / Q000096:biosynthesis*; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010660:Phenylisopropyladenosine / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D011817:Rabbits; D013873:Thionucleotides / Q000494:pharmacology*
D000067956:Adenylyl Cyclase Inhibitors; D010975:Platelet Aggregation Inhibitors; D015363:Quinolones; D013873:Thionucleotides; D005576:Colforsin; D010660:Phenylisopropyladenosine; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; C021294:cilostamide; D015121:6-Ketoprostaglandin F1 alpha; D011464:Epoprostenol; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D007545:Isoproterenol; D015056:1-Methyl-3-isobutylxanthine