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

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

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

J Surg Res. 2009 Jul;155(1):32-9.

PMID: 19111324

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42417844	Adenosine 3ʹ,5ʹ-cyclic Monophosphorothioate, 8-Bromo-, Rp-Isomer, Sodium Salt			Price

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