Vol. 303, Issue 1, 58-65, October 2002

Effect of Cyclosporine A on Hepatic Compensatory Growth: Role of Calcium Status

Sébastien J. Provencher and Marielle Gascon-Barré

Centre de Recherche, Centre Hospitalier de l'Université de Montréal, Hôpital Saint-Luc, and Départements de Pharmacologie, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada

Cyclosporine A (CsA) has been reported to positively influence hepatic compensatory growth (HCG) in normal animals. The role of calcium in the CsA-mediated influence on HCG was studied in normal and in chronically hypocalcemic rats, a model in which HCG is perturbed. CsA (3.33 mg/kg/day for 10 days) was administered before 2/3 partial hepatectomy (PHx). CsA did not influence serum Ca²⁺ but significantly increased concentrations of the vitamin D hormone calcitriol. After PHx in normal animals, CsA accelerated DNA synthesis without influencing liver weight restitution, suggesting that its main effect was to mediate an accelerated progression through the cell cycle G₀ to G₁/S phase(s). In hypocalcemic rats, CsA did not influence DNA synthesis, but normalization of circulating calcium alone accelerated DNA synthesis but abrogated the stimulatory effect of CsA, indicating that CsA could not superimpose its stimulatory effect on the calcium effect. In vitro investigation on the CsA mechanisms of action revealed a dose-dependent increase in hepatocyte basal resting cytoplasmic Ca²⁺ and an increase in inositol-1,4,5-trisphosphate-sensitive Ca²⁺ pool, which was dependent on the presence of normal extracellular Ca²⁺ during CsA exposure. CsA also mediated a significant increase in cellular Ca²⁺ mobilization by phenylephrine, vasopressin, and epidermal growth factor (EGF) in the presence of extracellular Ca²⁺ concentration. Our data, therefore, demonstrate that CsA accelerates HCG after PHx by, in part, increasing the cellular Ca²⁺ pools and the response to EGF and Ca²⁺-mobilizing hormones known to be comitogens for hepatocytes.