Inhibition by the protein kinase inhibitors, isoquinolinesulfonamides, of fluid accumulation induced by Escherichia coli heat-stable enterotoxin, 8-bromo-cGMP and 8-bromo-cAMP in suckling mice.
The effects of isoquinolinesulfonamides, which inhibit protein kinase, on fluid accumulations induced by heat-stable enterotoxin of enterotoxigenic Escherichia coli (STh), 8-bromo-cGMP and 8-bromo-cAMP in suckling mice were studied. Both N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide (H-8) and N-(2-aminoethyl)-5-isoquinolinesulfonamide (H-9) inhibited the fluid accumulation induced by STh. Fluid accumulation induced by four mouse units of STh (four-fold the minimum effective dose, 10 ng) was completely inhibited by 0.4 mumol of H-8 or H-9. H-8 and H-9 also inhibited fluid accumulation induced by 8-bromo-cGMP. On the other hand, H-8 and H-9 only partially inhibited fluid accumulation in suckling mice induced by 8-bromo-cAMP, probably because their affinities to cAMP-dependent protein kinase were lower than their affinities to cGMP-dependent protein kinase. From these results, it is concluded that the activation of cGMP-dependent protein kinase by increase in cGMP by ST or by 8-bromo-cGMP, and very probably the activation of cAMP-dependent protein kinase by increase in cAMP by cholera enterotoxin and heat-labile enterotoxin of enterotoxigenic E. coli and by 8-bromo-cAMP are necessary steps in signal transduction following increases in concentrations of cGMP and cAMP in intestinal brush border cells.
Hirayama
T
T
Department of Bacterial Infection, University of Tokyo, Japan.
Ito
H
H
Takeda
Y
Y
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology*; D000818:Animals; D000833:Animals, Suckling; D001427:Bacterial Toxins / Q000494:pharmacology*; D002352:Carrier Proteins / Q000494:pharmacology*; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D004768:Enterotoxins / Q000494:pharmacology*; D029968:Escherichia coli Proteins; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007546:Isoquinolines / Q000494:pharmacology*; D051379:Mice; D013449:Sulfonamides / Q000494:pharmacology*; D014882:Water-Electrolyte Balance / Q000187:drug effects*
D001427:Bacterial Toxins; D002352:Carrier Proteins; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007546:Isoquinolines; D013449:Sulfonamides; C034151:heat stable toxin (E coli); C015482:protein kinase modulator; D015124:8-Bromo Cyclic Adenosine Monophosphate; C016276:8-bromocyclic GMP; D006152:Cyclic GMP