Background and aim: We have reported that gut ischemia/reperfusion (I/R) causes hepatic microvascular dysfunction. Nitric oxide (NO) has been found to be a modulator of the adhesive interactions between leukocytes, platelets, and endothelial cells. Sho-saiko-to (TJ-9), a Japanese herbal medicine, is reported to have protective effects against liver injury and to regulate NO production. The objective of this study was to determine whether TJ-9 affects hepatic microvascular dysfunction elicited by gut I/R, and to investigate the role of NO.
Methods: Male Wistar rats were exposed to 30 min of gut ischemia followed by 60 min of reperfusion. Intravital microscopy was used to monitor leukocyte recruitment and the number of non-perfused sinusoids (NPS). Plasma tumor necrosis factor (TNF)-alpha and alanine aminotransferase (ALT) activities were measured. In another set of experiments, TJ-9 (1 g/kg per day intragastrically) was administered to rats for 7 days. In some experiments, dexamethasone (ST) (2 mg/kg per day intravenously) was administered.
Results: In control rats, gut I/R elicited increases in the number of stationary leukocytes, NPS, and plasma TNF-alpha and ALT activities, and these changes were mitigated by the pretreatment with TJ-9. Pretreatment with an NO synthase inhibitor diminished the protective effects of TJ-9 on the increase in leukostasis in the pericentral region, NPS, and plasma TNF-alpha levels, but not its effect on the increase in leukostasis in the midzonal region, total number of stationary leukocytes, or plasma ALT activities. Pretreatment with TJ-9 increased plasma nitrite/nitrate levels. The responses caused by gut I/R were attenuated by the pretreatment with ST. Pretreatment with an NO synthase inhibitor did not affect the effect of ST.
Conclusions: These results suggest that TJ-9 attenuates the gut I/R-induced hepatic microvascular dysfunction and inflammatory responses such as TNF-alpha production in the early phase via enhancement of NO production, and sequential hepatocellular damage via its anti-inflammatory effect like corticosteroid effect.