Hepatoprotective effect by pretreatment with olprinone in a swine partial hepatectomy model.
Excessive portal flow to a small remnant liver or small-for-size graft is a primary factor of small-for-size syndrome. We demonstrated that olprinone (OLP), a phosphodiesterase III inhibitor, had a hepatoprotective effect in a rat extended hepatectomy model and a small-for-size liver transplantation model through a modification of the portal venous pressure (PVP). To identify the appropriate dose and duration of treatment for clinical applications, we conducted experiments with a swine partial hepatectomy model. Twenty microminipigs were divided into 4 groups that received the following treatments: (A) saline (control group), (B) OLP at 0.3 μg/kg/minute (preoperative and postoperative administration), (C) OLP at 0.1 μg/kg/minute (preoperative administration), and (D) OLP at 0.3 μg/kg/minute (preoperative administration). The pigs underwent 70% partial hepatectomy. Hemodynamic changes, including changes in PVP, were examined. Liver biopsy was performed 1 and 3 hours after hepatectomy. Blood samples were collected until postoperative day 7 (POD7). In comparison with group A, PVP elevations, periportal edema, and sinusoidal hemorrhaging were attenuated after left Glisson's ligation in groups C and D. Pretreatment with OLP in groups C and D preserved the microstructure of sinusoids and improved the prothrombin activity 1 and 3 hours after hepatectomy. These animals showed better recovery of the remnant liver volume and the plasma disappearance rate of indocyanine green on POD7. In contrast, group B showed exacerbation of liver damage. Measurements of the serum OLP concentration showed that 10 ng/mL OLP was appropriate for a hepatoprotective effect. In conclusion, pretreatment with OLP shows hepatoprotective effects in a swine partial hepatectomy model. OLP may have the potential to ameliorate patients' outcomes after hepatectomy or liver transplantation.
Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Kohta
K
Iguchi
Etsuro
E
Hatano
Kenya
K
Yamanaka
Motohiko
M
Sato
Gen
G
Yamamoto
Yosuke
Y
Kasai
Tatsuya
T
Okamoto
Masayuki
M
Okuno
Kojiro
K
Taura
Kyoko
K
Fukumoto
Kazuyuki
K
Ueno
Shinji
S
Uemoto
D000818:Animals; D001663:Bilirubin / Q000097:blood; D001706:Biopsy; D004487:Edema; D042783:Endothelial Cells / Q000166:cytology; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D006439:Hemodynamics; D006498:Hepatectomy / Q000009:adverse effects / Q000379:methods*; D007093:Imidazoles / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007813:Laparotomy; D008099:Liver / Q000473:pathology; D016031:Liver Transplantation / Q000009:adverse effects*; D008854:Microscopy, Electron; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D058987:Phosphodiesterase 3 Inhibitors / Q000627:therapeutic use; D017082:Portal Pressure; D011184:Postoperative Period; D011516:Prothrombin / Q000378:metabolism; D011728:Pyridones / Q000627:therapeutic use*; D013552:Swine; D013556:Swine, Miniature; D057170:Translational Research, Biomedical; D016896:Treatment Outcome
D004791:Enzyme Inhibitors; D007093:Imidazoles; D058987:Phosphodiesterase 3 Inhibitors; D011728:Pyridones; C059498:olprinone; D011516:Prothrombin; D052250:Nitric Oxide Synthase Type III; D001663:Bilirubin