Dynamic changes of post-ischemic hepatic microcirculation improved by a pre-treatment of phosphodiesterase-3 inhibitor, milrinone.
BACKGROUND
Phosphodiesterase-3 inhibition has been shown to attenuate hepatic warm ischemia-reperfusion injury. The aim of this study was to investigate the effect of milrinone, phosphodiesterase-3 inhibitor, on post-ischemic microcirculation of rat livers by intravital microscopy.


METHODS
Male Wistar rats were randomly assigned to three groups; group A, milrinone pre-treatment; group B, ischemic pre-conditioning; and group C, no pre-treatment. All animals underwent a 60-min warm ischemia of the left lateral liver lobe. Microvascular perfusion and leukocyte-endothelial interaction were observed by intravital videomicroscopy. Hepatocellular viability and cellular damage were quantified by adenosine triphosphate tissue concentration as well as alanine aminotransferase and lactate dehydrogenase blood levels, respectively.


RESULTS
In groups A and B, cyclic AMP hepatic tissue concentration was elevated significantly. After reperfusion, microvascular perfusion in hepatic sinusoids was significantly better maintained, and the number of adherent leukocytes was reduced in sinusoids and in post-sinusoidal venules in these rats. Serum transaminase blood levels were suppressed significantly in these groups compared with controls.


CONCLUSIONS
The demonstrated improvement of hepatic microcirculation is certainly derived from milrinone induced cell protection in ischemia reperfusion of the liver. This effect is outlined by improved energy status and reduced liver enzyme liberation and mimics the effect of ischemic pre-conditioning.
Kume
Makoto
M
Department of General Surgery, University of Heidelberg, Heidelberg, Germany. kumacmd-gi@umin.ac.jp
Banafsche
Ramin
R
Yamamoto
Yuzo
Y
Yamaoka
Yoshio
Y
Nobiling
Rainer
R
Gebhard
Martha-Maria
MM
Klar
Ernst
E
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D001794:Blood Pressure; D002450:Cell Communication / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D042783:Endothelial Cells / Q000166:cytology; D006339:Heart Rate; D006400:Hematocrit; D019194:Ischemic Preconditioning / Q000379:methods*; D007962:Leukocytes / Q000166:cytology; D008099:Liver / Q000098:blood supply / Q000166:cytology / Q000378:metabolism; D008102:Liver Circulation / Q000187:drug effects; D016031:Liver Transplantation; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D018715:Microscopy, Video; D020105:Milrinone / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy / Q000517:prevention & control*; D014699:Venules / Q000187:drug effects
D010726:Phosphodiesterase Inhibitors; D009569:Nitric Oxide; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D006152:Cyclic GMP; D020105:Milrinone