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Implication of protein kinase A for a hepato-protective mechanism of milrinone pretreatment.

Author(s): Satoh K, Kume M, Abe Y, Uchinami H, Yakubouski SV, Takahashi T, Sato T, Yamamoto Y

Affiliation(s): Department of Gastroenterological Surgery, Akita University School of Medicine, Akita, Japan.

Publication date & source: 2009-07, J Surg Res., 155(1):32-9. Epub 2008 Aug 15.

Publication type: Research Support, Non-U.S. Gov't

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. MATERIALS AND 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.

Page last updated: 2009-10-20

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