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  • Title: Selective downregulation of rat cardiac beta 1-adrenoceptors by cyclosporine A: prevention by diltiazem or angiotensin-converting enzyme inhibitors.
    Author: Brodde OE, Adamczyk M, Busch F, Bossaller C, Duske E, Fleck E, Götze S, Auch-Schwelk W.
    Journal: J Am Coll Cardiol; 1995 Mar 01; 25(3):761-7. PubMed ID: 7860926.
    Abstract:
    OBJECTIVES: This study attempted to determine whether long-term treatment with cyclosporine A in rats affects cardiac beta 1-adrenoceptors and whether this can be prevented by angiotensin-converting enzyme inhibitors or calcium-entry blocking agents. BACKGROUND: In the transplanted human heart the density of beta 1-adrenoceptors decreases with time after transplantation, whereas that of beta 2-adrenoceptors does not. Because heart transplant recipients are treated with cyclosporine A, we studied whether administration of cyclosporine A in rats might cause this beta 1-adrenoceptor downregulation. METHODS: We performed two studies. First, we treated groups of 10 male normotensive Wistar rats orally with 30 mg/kg body weight per day of cyclosporine A, 10 mg/kg per day of enalapril and 60 mg/kg per day of diltiazem, alone or in combination, for 6 weeks each. Second, we treated groups of 15 male normotensive Wistar rats orally with 15 mg/kg per day of cyclosporine A and 10 mg/kg per day of lisinopril, alone or in combination, for 6 weeks each. At the end of each treatment regimen, cardiac beta-adrenoceptor density and subtype distribution were assessed by (-)-[125I]iodocyanopindolol binding. RESULTS: Both doses of cyclosporine A caused a significant decrease in cardiac beta 1-adrenoceptor density without affecting beta 2-adrenoceptor density. Although diltiazem and the angiotensin-converting enzyme inhibitors alone did not affect cardiac beta-adrenoceptors, they prevented the cyclosporine A-induced downregulation of beta 1-adrenoceptors. CONCLUSIONS: In normotensive Wistar rats, cyclosporine A causes a significant decrease in cardiac beta 1-adrenoceptors without affecting beta 2-adrenoceptors. This can be prevented by diltiazem or angiotensin-converting enzyme inhibitors. In heart transplant recipients, who undergo long-term treatment with cyclosporine A, there is a very similar beta 1-adrenoceptor down-regulation with time after transplantation. Thus, administration of cyclosporine A may cause these beta-adrenoceptor subtype alterations.
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