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.
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.
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.
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.