[Effects of calcitriol and alfacalcidol on an osteoporosis model in rats with hepatic failure].

To predict the potential utility of calcitriol in human osteoporosis with hepatic dysfunction, we examined the effects of calcitriol and alfacalcidol in ovariectomized (OVX) aged-rats with CCl4-induced hepatic failure. In OVX+CCl4 rats, GOT, GTP, alkaline phosphatase and total bilirubin increased and hepatic enzyme activity (cytochrome b5 and P450) decreased. Repeated oral doses of calcitriol (0.1 and 0.2 microgram/kg) for 51 days inhibited a decrease in serum calcium concentration. This effect was more potent than that of alfacalcidol at the same dose. Both drugs tended to inhibit a decrease in femoral calcium contents. Calcitriol (0.2 microgram/kg) prevented a decrease in femoral bone density (dry and ash weight per volume), unlike alfacalcidol. Soft X-ray imaging analysis revealed that both drugs tended to inhibit the decrease in femoral bone density. There were no differences in the femoral bone strength between OVX+CCl4 and sham-operated rats. The serum calcitriol concentrations increased after the last doses of calcitriol, while they did not increase after the last dose of alfacalcidol. All these effects of calcitriol were related to the serum calcitriol levels. These results suggest that calcitriol, unlike alfacalcidol, may have a clinical therapeutic effect in osteoporosis with hepatic dysfunction.

Sequential changes in the localization of the type IV collagen alpha chain in the infarct zone: immunohistochemical study of experimental myocardial infarction in the rat.

Collagen, as a component of the extracellular matrix, have a role in the healing process after myocardial infarction (MI). For type IV collagen, a major structural protein present in the basal membrane of myocytes, six alpha chains [alpha 1 (IV)-alpha 6(IV)] have been identified. We examined the sequential changes in the appearance and localization of the alpha 1 (IV)-alpha 5(IV) after experimental MI in rats. Hearts were excised from 1 day to 8 weeks after permanent left coronary artery ligation. Immunohistochemical staining with monoclonal antibodies was performed. On day 3, staining for both alpha 1(IV) and alpha 2(IV) first appeared, forming a wavy pattern in the infarct peripheral zone, and the staining was not restricted to the cell membrane. The staining intensity and distribution for both alpha 1(IV) and alpha 2(IV) in the peripheral zone then gradually increased, reaching a maximum around day 7. The distribution progressed from the peripheral to the central zone of the infarct for 1-2 days, reaching the center point after 2 weeks. The staining distribution gradually decreased after reaching the maximum, but the staining had not completely disappeared at 8 weeks. In contrast, no positive staining for alpha 3(IV), alpha 4(IV) or alpha 5(IV) was observed at any time during the 8-week observation period. Thus, the present results demonstrated that in rats, type IV collagen consisting of alpha 1 and alpha 2 chains appears in the infarct zone at a relatively early phase after MI, indicating that type IV collagen composed of alpha 1 and alpha 2 chains contributes to infarct healing.

Localization of type IV collagen alpha chain in the myocardium of dilated and hypertrophic cardiomyopathy.

A total of 6 alpha chains [alpha 1 (IV) to alpha 6 (IV)] have been identified in type IV collagen. We examined the localization of these chains in the myocardium of patients with dilated (DCM) and hypertrophic (HCM) cardiomyopathy. The localization of alpha 1 (IV)-alpha 6 (IV) in biopsy specimens of 5 patients with DCM and 4 with HCM was examined using immunohistochemistry with monoclonal antibodies. Both alpha 1 (IV) and alpha 2 (IV) immunostaining formed thin homogeneous outlines around myocytes in control hearts. In the DCM specimens, alpha 1 (IV) and alpha 2 (IV) immunostaining formed thick and irregular patterns around myocytes. Staining for alpha 1(IV) and alpha 2 (IV) was also observed in some enlarged intercellular spaces. In 3 DCM hearts, moderate staining for alpha 1 (IV) and alpha 2 (IV) was observed in small replacement fibrotic lesions. In large replacement fibrotic lesions, no alpha 1 (IV) or alpha 2 (IV) staining was observed. In the HCM specimens, alpha 1 (IV) and alpha 2 (IV) staining formed thick homogeneous patterns around myocytes. In the enlarged intercellular spaces, no alpha 1 (IV) or alpha 2 (IV) staining was observed. No labeling for alpha 3 (IV)-alpha 6 (IV) was observed in any heart examined. In conclusion, the present results demonstrate that type IV collagen consisting of alpha 1 and alpha 2 chains appears in the fibrotic lesions of DCM, indicating its contribution to the development of fibrotic changes in the myocardium of DCM patients. In contrast, type IV collagen was restricted to the myocyte membrane in the HCM hearts. Fibrotic processes in the intercellular spaces may differ between DCM and HCM hearts.

Tenascin expression in endomyocardial biopsy specimens in patients with dilated cardiomyopathy: distribution along margin of fibrotic lesions.

OBJECTIVE: To examine the hypothesis that tenascin, an extracellular matrix glycoprotein, contributes to fibrotic changes in dilated cardiomyopathy. METHODS: The localisation of tenascin in biopsy specimens of the hearts obtained from eight patients with dilated cardiomyopathy was examined using staining by the avidin-biotin-peroxidase complex method. RESULTS: (1) Perimysium and endomysium. Although positive staining for tenascin was observed in the enlarged perimysium and endomysium in all patients, moderately intense staining was characteristically observed near the replacement fibrotic lesions. In the narrow perimysium and endomysium of the myocardium not containing replacement fibrotic lesions, tenascin was not present, as in the control specimens. (2) Replacement fibrotic lesions. Non-homogeneous positive staining for tenascin was detected in all replacement fibrotic lesions examined. Intense tenascin deposition was observed in the peripheral portion of the replacement fibrotic lesions. The tenascin staining observed in the small replacement fibrotic lesions was more intense than that in the large lesions. CONCLUSIONS: Tenascin contributes to the development of the fibrotic changes seen in the dilated cardiomyopathic heart. Its characteristic location, specifically the distribution along the margin of the fibrosis, suggests that fibrotic change is a continuous process in hearts with dilated cardiomyopathy.