Effects of Cyclic Adenosine Monophosphate-Dependent Protein Kinase and Calcium-Dependent Protein Kinase Modulators on Stimulated Gastric Acid Secretion in the Perfused Rat Stomach

The effects of cyclic adenosine monophosphate-dependent protein kinase (PKA) and calcium-dependent protein kinase (PKC) modulators on secretagogue-stimulated gastric acid secretion were studied in the continuously perfused stomach of the anesthetized rat. Intravenous histamine (0.25 mg/kg/h) and pentagastrin (2 µg/kg/h) increased secretion above baseline by three- and fourfold, respectively. Parenteral administration of a PKC activator, 12-o-tetradecanoylphorbol-13-acetate (TPA; 0.1 nmol/h), decreased histamine- and pentagastrin-stimulated secretion by 64 and 40%, respectively. Administration of PKC inhibitors, calphostin C and 1-(5-isoquinolinyl sulfonyl)-2 methylpiperazine (H-7; 10 nmol/h, each), increased histamine- and pentagastrin-stimulated secretion by 115 and 74% and 42 and 79%, respectively, while equimolar concentrations (10 nmol/h) of three other isoquinoline sulfonamides (HA-1004, H-8, and H-89) had no effect, except for H-89 (100 nmol/h) which inhibited the histamine- and pentagastrin-stimulated acid secretion by 44%. Basal secretion was not significantly altered by the aforementioned drugs. The TPA-induced inhibition of pentagastrin-stimulated secretion was partially reversed by treatment with H-7. These findings support a role of PKA and PKC in the modulation of stimulated gastric acid secretion in vivo.