Dynamic Changes of Post-Ischemic Hepatic Microcirculation Improved by a Pre-Treatment of Phosphodiesterase-3 Inhibitor, Milrinone

Pharmacological preconditioning by milrinone: Memory preserving and neuroprotective effect in ischemia-reperfusion injury in mice

“…Phosphodiesterase mediates metabolism of the second messenger, cyclic-adenosine-monophosphate (cAMP), and several isoforms exist (Conti, 2000;Lugnier, 2006). Phosphodiesterase type III inhibitors like milrinone and amrinone are used in heart failure as inodialators, and have preconditioning-like effects in the heart (Saltman et al, 2000) and liver (Kume et al, 2006). Milrinone also has beneficial effects in the treatment of cerebral vasospasm (Fraticelli et al, 2008), but its PP activity is unclear.…”

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

“…Pretreatment of rat livers with the phosphodiesterase 3 (PDE3) inhibitor, milrinone, attenuates hepatic warm ischemia-reperfusion injury [1]. A major pharmacologic action of PDE3 inhibitors is their positive inotropic and vasodilating properties.…”

“…In fact, milrinone demonstrates a selective PDE3 inhibitory action in these tissues [3][4][5]. In milrinone-treated rat livers, adenosine 3',5'-cyclic monophosphate (cAMP) concentrations were increased and the acquired ischemic tolerance seemed to be attributable to the increase of cAMP [1]. But it is not clear how cAMP-related signals act in liver injury resulting from warm ischemia reperfusion.…”

cAMP-GEF cytoprotection by Src tyrosine kinase activation of phosphoinositide-3-kinase p110 β/α in rat hepatocytes

“…Increases in cAMP, such as occur during times of metabolic stress when circulating glucagon levels are high, protect cultured hepatocytes from apoptosis due to several stimuli including bile acids, Fas, and TNF-␣ (12,21,36,61). In vivo, oral administration of phosphodiesterase inhibitors (18,32) or ␤ 2 -adrenergic agonists (1), agents that increase hepatic cAMP levels, or parenteral administration of glucagon (24) or cell-permeable cAMP analogs (28,57) protect against toxic and ischemic hepatic injury in laboratory animals. Furthermore, it is known that the diseased liver develops dysregulations in cAMP signaling that contribute to increased hepatobiliary damage (15,19,20,27,35).…”