Ann Surg Treat Res.  2018 Mar;94(3):118-128. 10.4174/astr.2018.94.3.118.

Effects of splanchnic vasoconstrictors on liver regeneration and survival after 90% rat hepatectomy

• Kim DS
• Ji WB
• Han JH
• Choi YY
• Park HJ
• Yu YD
• Kim JY

• KMID: 2405323
• DOI: http://doi.org/10.4174/astr.2018.94.3.118

Abstract

PURPOSE
Posthepatectomy liver failure is a serious complication and considered to be caused by increased portal pressure and flow. Splanchnic vasoactive agents and propranolol are known to decrease portal pressure. The aim of this study was to identify optimal candidates with potential for clinical use among somatostatin, terlipressin, and propranolol using rats with 90% hepatectomy.
METHODS
Rats were divided into 5 groups: sham operation (n = 6), control (n = 20), propranolol (n = 20), somatostatin (n = 20), and terlipressin group (n = 20). Seven-day survival rates and portal pressure change were measured, and biochemical, histologic, and molecular analyses were performed.
RESULTS
Portal pressure was significantly decreased in all 3 treatment groups compared to control. All treatment groups showed a tendency of decreased liver injury markers, and somatostatin showed the most prominent effect at 24 hours postoperatively. Histologic liver injury at 24 hours was significantly decreased in propranolol and terlipressin groups (P = 0.016, respectively) and somatostatin group showed borderline significance (P = 0.056). Hepatocyte proliferation was significantly increased after 24 hours in all treatment groups. Median survival was significantly increased in terlipressin group compared to control group (P < 0.01).
CONCLUSION
Terlipressin is considered as the best candidate, while somatostatin has good potential for clinical use, considering their effects on portal pressure and subsequent decrease in liver injury and increase in liver regeneration.

Keyword

Hepatectomy; Liver failure; Liver regeneration; Somatostatin; Terlipressin

MeSH Terms

Animals
Hepatectomy*
Hepatocytes
Liver Failure
Liver Regeneration*
Liver*
Portal Pressure
Propranolol
Rats*
Somatostatin
Survival Rate
Vasoconstrictor Agents*
Propranolol
Somatostatin
Vasoconstrictor Agents

Figure

• 

  Fig. 1 Schematic drawing of experimental flow. S represents a subgroup for survival analysis. Ten rats were used for control, propranolol, somatostatin, and terlipressin group, respectively. Animals were followed up for 7 days after surgery. M6 and M24 represent subgroups for measurement of portal pressure, sampling of blood and liver tissue at 6 and 24 hours after surgery, respectively. Each subgroup was comprised of sham (n = 3), control (n = 5), propranolol (n = 5), somatostatin (n = 5), and terlipressin group (n = 5).

• 

  Fig. 2 Portal pressure was measured at 10, 30, 60 minutes, and 24 hours after completion of 90% hepatectomy. Dots indicate the mean and whiskers the standard error of the mean. aP < 0.05 vs. control in the same time point.

• 

  Fig. 3 Postoperative evolutions of AST (A), ALT (B), and total bilirubin (C) among sham, control, and each treatment group. Data are expressed as the median, with the 25%–75% percentiles in boxes and the 5%–95% percentiles as whiskers. aP < 0.05 vs. control group in the same time point.

• 

  Fig. 4 Level of mRNA expression of endothelin-1 (ET-1) (A), endothelial nitric oxide synthase (eNOS) (B), and hepatocyte growth factor (HGF) (C) was measured from liver tissue obtained at 6 and 24 hours after 90% hepatectomy using real-time quantitative polymerase chain reaction. Data are expressed as the median, with the 25%–75% percentiles in boxes and the 5%–95% percentiles as whiskers. aP < 0.05 vs. sham group; bP = 0.068 control vs. somatostatin; cP = 0.058 control vs. somatostatin. GAPDH, glyceraldehyde 3-phosphate dehydrogenase.

• 

  Fig. 5 (A) Representative images of microscopic findings after 90% partial hepatectomy (H&E, ×1,000). White arrow in each image indicates small vacuolar transformation of the hepatocyte cytoplasm (i), activated Kupffer cell (ii), confluent necrosis (iii), small cell necrosis (iv), sinusoidal dilatation (v), and eosinophilic globuli (vi) in the hepatocyte cytoplasm. (B) Results of histologic scoring at 6 and 24 hours after partial hepatectomy. (C) Representative images of Ki-67 immunohistochemical staining positive hepatocytes in each group. M6 and M24 represent tissues obtained at 6 and 24 hours after hepatectomy, respectively. (D) Count of Ki-67 immunohistochemical stain (×1,000) positive hepatocytes for evaluation of cellular proliferation. Number of Ki-67 positive hepatocyte was increased in all treatment groups at 24 hours postoperatively. Somatostatin group showed the most pronounced increase, which was significantly higher than propranolol group. Data are expressed as the median, with the 25%–75% percentiles in boxes and the 5%–95% percentiles as whiskers. aP < 0.05 vs. control group in the same time point, bP < 0.05 propranolol vs. somatostatin group.

• 

  Fig. 6 Kaplan-Meier survival analysis after 90% hepatectomy in rats. Terlipressin group showed a significantly increased 7-day survival rate (P < 0.001 vs. control, P = 0.007 vs. somatostatin group). Propranolol and somatostatin groups did not show significant survival improvement compared to control group.

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