Abstract
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.
Footnotes
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These studies were supported by the Canadian Institutes of Health Research. S.P. was the recipient of a Studentship award from the Canadian Liver Foundation.
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DOI: 10.1124/jpet.102.035980
- Abbreviations:
- CsA
- cyclosporine A
- PHx
- 2/3 partial hepatectomy
- IP3
- inositol-1,4,5-trisphosphate
- 25(OH)D3
- 25-hydroxyvitamin D3
- [Ca2+]i
- intracellular calcium
- [Ca2+]e
- extracellular calcium
- EGF
- epidermal growth factor
- N.S.
- not significant
- Received March 26, 2002.
- Accepted June 4, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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