title: Activation of cyclic AMP-dependent protein kinase during canine lower esophageal sphincter relaxation.
abstract: In isolated strips of opossum lower esophageal sphincter (LES) smooth muscle, elevation of cyclic AMP (cAMP) content is associated with relaxation. Because the activation state of cyclic nucleotide-dependent protein kinases may be a more sensitive measure of functionally important changes in cyclic nucleotide levels, we examined the ability of several pharmacological agents and electrical stimulation of the enteric neurons to activate cAMP dependent-protein kinase (cA-PK) and to relax isolated strips of LES smooth muscle. Addition of either isoproterenol or SK&F 94120, a selective inhibitor of the low Km cAMP phosphodiesterase to isolated strips of canine LES produced concentration-dependent increases in the activity ratio of cA-PK and concentration-dependent relaxations of canine LES. In contrast, although both zaprinast (M&B 22948), a selective inhibitor of the cyclic GMP selective phosphodiesterase, and sodium nitroprusside relaxed canine LES neither drug significantly increased the activity ratio of cA-PK. Furthermore, electrical stimulation of the enteric neurons produced a frequency-dependent relaxation but did not significantly activate cA-PK. To eliminate the possibility that the rapid metabolism of cAMP prevented us from observing a significant activation of cA-PK during electrical field stimulation, the ability of electrical field stimulation (1.0 Hz) to activate cA-PK was examined in the presence of 0.1 mM 3-isobutyl-1-methylxanthine. At at concentration of 0.1 mM, 3-isobutyl-1-methylxanthine, by itself, significantly increased the activity ratio of cA-PK; however, there was no additional activation produced by electrical field stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pharmacology, Smith Kline Beecham p.l.c., King of Prussia, Pennsylvania.
authors.forename: M S
authors.initials: MS
authors.lastname: Barnette
authors.forename: M
authors.initials: M
authors.lastname: Grous
authors.forename: T J
authors.initials: TJ
authors.lastname: Torphy
authors.forename: H S
authors.initials: HS
authors.lastname: Ormsbee
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D004285:Dogs; D004558:Electric Stimulation; D004789:Enzyme Activation / Q000187:drug effects; D004943:Esophagogastric Junction / Q000187:drug effects / Q000201:enzymology*; D005260:Female; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009126:Muscle Relaxation / Q000187:drug effects*; D011494:Protein Kinases / Q000378:metabolism*; D011688:Purinones / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology
chemical_list: D002316:Cardiotonic Agents; D011688:Purinones; D011719:Pyrazines; C048350:5-(4-acetamidophenyl)pyrazin-2(1H)-one; D011494:Protein Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C011145:zaprinast; D007545:Isoproterenol