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

Milrinone-induced postconditioning reduces hepatic ischemia-reperfusion injury in rats: the roles of phosphatidylinositol 3-kinase and nitric oxide

“…Recent studies have demonstrated that some agents, such as adenosine A2A receptor agonist [8], rhEPO [9], and sevoflurane [10], can be used as pharmacological inducers of PostC as well as PreC. Milrinone has been shown to have PreC properties using an orthotopic liver transplantation model and warm IR injury model in rats [14,15]. The present study is, to our knowledge, the first to demonstrate that milrinone also has PostC properties against hepatic warm IR injury.…”

“…Previous studies showed that milrinone administration stimulated immediate accumulation of cAMP and elevation of PKA in the liver tissue, and pretreatment with a PKA inhibitor prevented milrinone-induced PreC [14,15]. In heart, milrinone-induced PostC also increased myocardial PKA activity and Akt phosphorylation, and reduced myocardial infarct size and myocyte apoptosis [16].…”

“…Second, we did not measure systemic hemodynamics such as blood pressure and heart rate in this study. It has been shown that milrinone treatment (50 µg/kg) before liver ischemia [15], or after myocardial ischemia [16] did not affect systemic hemodynamics. In another study, wortmannin or L-NAME administered 5 min before reperfusion also did not affect systemic hemodynamics in myocardial infarction models [29].…”

“…Milrinone has been clinically used for the treatment of acute heart failure or low-output syndrome to facilitate functional recovery from myocardial dysfunction and to preserve the perfusion of major organs [12,13]. It has been reported that milrinone has PreC properties against hepatic IR injury via cAMP/PKA activation [14,15]. Milrinone-induced heart PostC is associated with the activation of PKA/Akt-dependent anti-apoptotic signaling [16].…”

Effect of milrinone on the inflammatory response and NF-kB activation in renal ischemia-reperfusion injury in mice

“…Kume et al [11] reported that the pre-treatment of milrinone protected the liver from warm I/R injury, and this pre-treatment mimics the physiological phenomena of ischemic pre-conditioning. Satoh et al [12] demonstrated that milrinone treatment alleviated warm ischemia-reperfusion induced liver injury, and the activation of cAMP-dependent protein kinase A played a key role in this protection against I/R injury. Furthermore, it is reported that milrinone reduced the inflammatory response and improved microcirculation during inflammation [7,13], which suggest that milrinone can reduce I/R injury effectively.…”