Summary
We previously reported that antithrombin (AT) reduced ischemia/ reperfusion (I/R)-induced
liver injury in rats by increasing endothelial production of prostacyclin (PGI2). However, the mechanism(s) underlying this phenomenon remains to be fully elucidated.
We also demonstrated that activation of capsaicinsensitive sensory neurons increased
endothelial production of PGI2 by releasing calcitonin gene-related peptide (CGRP) in rats subjected to hepatic
I/R. In the present study, we investigated whether AT increases endothelial production
of PGI2 through activation of the sensory neurons in rats subjected to hepatic I/R. AT significantly
enhanced the I/R-induced increases in hepatic tissue levels of CGRP in rats. Increases
in hepatic tissue levels of 6-keto-PGF1α, a stable metabolite of PGI2 , the increase in hepatic-tissue blood flow, and attenuation of both hepatic local
inflammatory responses and liver injury in rats administered AT were completely reversed
by administration of capsazepine, an inhibitor of sensory neuron activation and CGRP(8–37),
a CGRP antagonist.AT did not show any protective effect on liver injury in animals
undergoing functional denervation by administration of a large amount of capsaicin.AT
significantly increased CGRP release from cultured dorsal root ganglion neurons isolated
from rats in the presence of capsaicin.Taken together,these observations strongly
suggested that AT might increase hepatic tissue levels of PGI2 via enhancement of hepatic I/R-induced activation of capsaicin-sensitive sensory
neurons,thereby reducing liver injury in rats. In this process, CGRP-induced activation
of both endothelial nitric oxide synthase and cyclooxygenase-1 might be critically
involved.
Keywords
Antithrombin - ischemia/reperfusion - capsaicin-sensitive sensory neurons - calcitonin
gene-related peptide - prostacyclin