SELECTIVE DOWN-REGULATION OF RAT CARDIAC BETA(1)-ADRENOCEPTORS BY CYCLOSPORINE-A - PREVENTION BY DILTIAZEM OR ANGIOTENSIN-CONVERTING ENZYME-INHIBITORS

Objectives. This study attempted to determine whether longterm 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 (-)-[I-125]iodocyanopindolol binding. Results. Both doses of cyclosporine A caused a significant decrease in cardiac beta(1)-adrenoceptor density without affecting beta(1)-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.