Implication of protein kinase A for a hepato-protective mechanism of milrinone pretreatment.
BACKGROUND
We have previously reported that an increase of adenosine 3',5'-cyclic monophosphate (cAMP) in liver tissue after an administration of milrinone, a phosphodiesterase-3 inhibitor attenuates hepatic warm ischemia-reperfusion injury. The aim of this study was to determine whether cAMP-dependent protein kinase (protein kinase A) activation was involved in the milrinone-induced hepatoprotective effect on an ischemia-reperfusion injury in an in vivo model.


METHODS
Male Lewis rats were allocated into 3 groups. In Group M, milrinone was administrated before ischemia; in Group I, a protein kinase A inhibitor, adenosine 3',5'-cyclic monophosphorothioate, 8-bromo-, Rp-isomer, sodium salt (Rp-8-Br-cAMPS), was injected prior to the administration of milrinone; and in Group C, the control group, there was no pretreatment. After pretreatment, all rats were exposed to a 45-min total hepatic inflow occlusion.


RESULTS
After milrinone administration, liver cAMP concentrations and protein kinase A activity ratios were elevated. They protected the liver from ischemia-reperfusion injury. Rp-8-Br-cAMPS suppressed protein kinase A activation without affecting cAMP elevating responses to milrinone. Compared with Group C, hepatocellular necrosis, neutrophil infiltration, and congestion were ameliorated, and serum tumor necrosis factor-alpha, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase levels were significantly suppressed in Group M. Rp-8-Br-cAMPS canceled this effect, showing histological damages in Group I as severe as in Group C. The levels of tumor necrosis factor-alpha, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase were the same in Groups C and I.


CONCLUSIONS
Activation of protein kinase A might play an important role in the mechanism of milrinone-induced ischemic tolerance in the liver.
Satoh
Kohei
K
Department of Gastroenterological Surgery, Akita University School of Medicine, Akita, Japan.
Kume
Makoto
M
Abe
Yuki
Y
Uchinami
Hiroshi
H
Yakubouski
Siarhei V
SV
Takahashi
Tomokazu
T
Sato
Tsutomu
T
Yamamoto
Yuzo
Y
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001794:Blood Pressure; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006339:Heart Rate; D045022:Lactate Dehydrogenases / Q000097:blood; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D020105:Milrinone / Q000494:pharmacology* / Q000627:therapeutic use; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011674:Pulse; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D000242:Cyclic AMP; D045022:Lactate Dehydrogenases; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D017868:Cyclic AMP-Dependent Protein Kinases; D020105:Milrinone