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Am J Physiol Gastrointest Liver Physiol 292: G556-G564, 2007. First published September 28, 2006; doi:10.1152/ajpgi.00196.2006
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LIVER AND BILIARY TRACT

Both Ca²⁺-dependent and -independent pathways are involved in rat hepatic stellate cell contraction and intrahepatic hyperresponsiveness to methoxamine

Departments of ¹Hepatology, ²Gastroenterology, and ³Histopathology, University Hospital Gasthuisberg, Leuven, Belgium

Submitted 8 May 2006 ; accepted in final form 22 September 2006

In chronic liver injury, hepatic stellate cells (HSCs) have been implicated as regulators of sinusoidal vascular tone. We studied the relative role of Ca²⁺-dependent and Ca²⁺-independent contraction pathways in rat HSCs and correlated these findings to in situ perfused cirrhotic rat livers. Contraction of primary rat HSCs was studied by a stress-relaxed collagen lattice model. Dose-response curves to the Ca²⁺ ionophore A-23187 and to the calmodulin/myosin light chain kinase inhibitor W-7 served to study Ca²⁺-dependent pathways. Y-27632, staurosporin, and calyculin (inhibitors of Rho kinase, protein kinase C, and myosin light chain phosphatase, respectively) were used to investigate Ca²⁺-independent pathways. The actomyosin interaction, the common end target, was inhibited by 2,3-butanedione monoxime. Additionally, the effects of W-7, Y-27632, and staurosporin on intrahepatic vascular resistance were evaluated by in situ perfusion of normal and thioacetamide-treated cirrhotic rat livers stimulated with methoxamine (n = 25 each). In vitro, HSC contraction was shown to be actomyosin based with a regulating role for both Ca²⁺-dependent and -independent pathways. Although the former seem important, an important auxiliary role for the latter was illustrated through their involvement in the phenomenon of "Ca²⁺ sensitization." In vivo, preincubation of cirrhotic livers with Y-27632 (10^–4 M) and staurosporin (25 nM), more than with W-7 (10^–4 M), significantly reduced the hyperresponsiveness to methoxamine (10^–4 M) by –66.8 ± 1.3%, –52.4 ± 2.7%, and –28.7 ± 2.8%, respectively, whereas in normal livers this was significantly less: –43.1 ± 4.2%, –40.2 ± 4.2%, and –3.8 ± 6.3%, respectively. Taken together, these results suggest that HSC contraction is based on both Ca²⁺-dependent and -independent pathways, which were shown to be upregulated in the perfused cirrhotic liver, with a predominance of Ca²⁺-independent pathways.

portal hypertension; RhoA; protein kinase C; calcium-calmodulin; stress-relaxed matrix contraction; intrahepatic vascular resistance

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