Olprinone attenuates excessive shear stress through up-regulation of endothelial nitric oxide synthase in a rat excessive hepatectomy model.
After extended hepatectomy, excessive shear stress in the remnant liver causes postoperative liver failure. Olprinone (OLP), a selective phosphodiesterase inhibitor, has been reported to improve microcirculation and attenuate inflammation. The aim of this study was to investigate the effects of OLP on shear stress in rats with an excessive hepatectomy (EHx) model. In this study, EHx comprised 90% hepatectomy with ligation of the left and right Glisson's sheaths in Lewis rats. OLP or saline was intraperitoneally administered with an osmotic pump 48 hours before EHx. To evaluate the shear stress, we measured the portal vein (PV) pressure. We also assessed sinusoidal endothelial cell injury by immunohistochemistry and electron microscopy. Furthermore, we assessed apoptosis in the liver with the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling method. Treatment with OLP up-regulated hepatic endothelial nitric oxide synthase (eNOS) expression. The increase in the PV pressure due to Glisson's sheath ligation was attenuated in OLP-treated rats during a 30-minute period after ligation. Treatment with OLP preserved sinusoidal endothelial cells and reduced apoptosis in the remnant liver. The probability of survival in the OLP-treated rats was significantly better than that in the controls (33.3% versus 13.3%). Furthermore, the postoperative eNOS activity in the OLP-treated rats was higher than that in the controls. The administration of Nω-nitro-l-arginine methyl ester to OLP-treated rats eliminated the effects of OLP on PV pressure and survival after EHx. Therefore, we concluded that OLP attenuates excessive shear stress through the up-regulation of eNOS and improves the survival rate after EHx.
Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Kenya
K
Yamanaka
Etsuro
E
Hatano
Masato
M
Narita
Koji
K
Kitamura
Atsuko
A
Yanagida
Hiroyuki
H
Asechi
Hiromitsu
H
Nagata
Kojiro
K
Taura
Takashi
T
Nitta
Shinji
S
Uemoto
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006498:Hepatectomy; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007263:Infusions, Parenteral; D008099:Liver / Q000098:blood supply / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000601:surgery*; D008102:Liver Circulation / Q000187:drug effects*; D017093:Liver Failure / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism*; D058987:Phosphodiesterase 3 Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D017082:Portal Pressure / Q000187:drug effects; D011728:Pyridones / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D013314:Stress, Mechanical; D013997:Time Factors; D015854:Up-Regulation
D004791:Enzyme Inhibitors; D007093:Imidazoles; D058987:Phosphodiesterase 3 Inhibitors; D011728:Pyridones; C059498:olprinone; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D019331:NG-Nitroarginine Methyl Ester