Implication of Protein Kinase A for a Hepato-Protective Mechanism of Milrinone Pretreatment

Satoh, Kohei; Kume, Makoto; Abe, Yuki; Uchinami, Hiroshi; Yakubouski, Siarhei V.; Takahashi, Tomokazu; Sato, Tsutomu; Yamamoto, Yuzo

doi:10.1016/j.jss.2008.07.004

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Volume 155, Issue 1 , Pages 32-39, July 2009

Implication of Protein Kinase A for a Hepato-Protective Mechanism of Milrinone Pretreatment

Kohei Satoh, M.D.
- Department of Gastroenterological Surgery, Akita University School of Medicine, Akita, Japan
Makoto Kume, M.D.
- Department of Gastroenterological Surgery, Akita University School of Medicine, Akita, Japan
- To whom correspondence and reprint requests should be addressed at Department of Gastroenterological Surgery, Akita University School of Medicine, 1-1-1 Hondo, Akita 010-5843, Japan.
Yuki Abe, M.D.
- Department of Gastroenterological Surgery, Akita University School of Medicine, Akita, Japan
Hiroshi Uchinami, M.D.
- Department of Gastroenterological Surgery, Akita University School of Medicine, Akita, Japan
Siarhei V. Yakubouski, M.D.
- Department of Gastroenterological Surgery, Akita University School of Medicine, Akita, Japan
- Department of Surgical Disease No. 1, Belarussian State Medical University, Minsk, Republic of Belarus
Tomokazu Takahashi, M.D.
- Department of Gastroenterological Surgery, Akita University School of Medicine, Akita, Japan
Tsutomu Sato, M.D.
- Department of Gastroenterological Surgery, Akita University School of Medicine, Akita, Japan
Yuzo Yamamoto, M.D.
- Department of Gastroenterological Surgery, Akita University School of Medicine, Akita, Japan

Received 8 March 2008 published online 19 August 2008.

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.