Rho-kinase signaling regulates important features of inflammatory reactions. Herein, we investigated the effect and mechanisms of action of the Rho-kinase inhibitor fasudil in endotoxemic liver injury. C57/BL/6 mice were challenged with lipopolysaccharide (LPS) and D-galactosamine, with or without pretreatment with the Rho-kinase inhibitor fasudil. Six hours after endotoxin challenge, leukocyte-endothelium interactions in the hepatic microvasculature were studied by use of intravital fluorescence microscopy and tumor necrosis factor alpha (TNF-alpha); CXC chemokines as well as liver enzymes and apoptosis were determined. Administration of fasudil reduced LPS-induced leukocyte adhesion in postsinusoidal venules and sequestration in sinusoids. Moreover, we found that fasudil abolished extravascular infiltration of leukocytes as well as production of TNF-alpha and CXC chemokines in the liver of endotoxemic mice. Liver enzymes and hepatocellular apoptosis were markedly reduced, and sinusoidal perfusion was improved significantly in endotoxemic mice pretreated with fasudil. Our novel data document that fasudil is a potent inhibitor of endotoxin-induced expression of TNF-alpha and CXC chemokines as well as leukocyte infiltration and hepatocellular apoptosis in the liver. Based on the present findings, it is suggested that inhibition of the Rho-kinase signaling pathway may be a useful target in the treatment of septic liver injury.

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Sevoflurane depresses sympathetic neuromuscular transmission in human omental vessels by reducing neuronal NE release and NE sensitivity in arteries and by reducing NE release in veins. This could contribute to the hypotension seen during sevoflurane anaesthesia, at least at concentrations above 1 MAC.

Anesthesia with sevoflurane is accompanied by vasodilatation. This could be due to the effects of sevoflurane on endothelium-dependent relaxation. We measured muscle tension of isolated human omental arteries and veins in response to substance P or glyceryl trinitrate in the presence of sevoflurane (0%, 1%, 2%, or 4%). Vascular levels of guanosine 3', 5'-cyclic monophosphate were measured with enzyme-linked immunosorbent assay. Substance P induced an endothelium- and concentration-dependent relaxation in omental vessels that was not affected by sevoflurane. In the presence of L-N(G)-nitroarginine methyl ester (nitric oxide synthase inhibitor), KCl (prevention of hyperpolarization), or both, sevoflurane at 4% enhanced the relaxation in the arteries (P < 0.05). In the vein segments, the relaxation was enhanced by sevoflurane at 4% in the presence of KCl and 2% and 4% in the presence of both L-N(G)-nitroarginine methyl ester and KCl (P < 0.05). The glyceryl trinitrate-induced endothelium-independent relaxation was enhanced by sevoflurane at 4% in both artery and vein segments (P < 0.05). Substance P increased the levels of guanosine 3', 5'-cyclic monophosphate similarly in the presence and absence of sevoflurane. These results show that sevoflurane, in contrast to its effect in animal models, promotes endothelium-dependent relaxation in human omental arteries and veins via an enhancement of the smooth muscle response to relaxing second messengers.

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