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 treatme nt with cyclosporine A in rats affects cardiac beta(1)-adrenoceptors a nd whether this can be prevented by angiotensin-converting enzyme inhi bitors or calcium-entry blocking agents. Background. In the transplant ed human heart the density of beta(1)-adrenoceptors decreases with tim e after transplantation, whereas that of beta(2)-adrenoceptors does no t. Because heart transplant recipients are treated with cyclosporine A , we studied whether administration of cyclosporine A in rats might ca use this beta(1)-adrenoceptor downregulation. Methods. We performed tw o studies, First, we treated groups of 10 male normotensive Wistar rat s 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 c ombination, for 6 weeks each. Second, we treated groups of 15 male nor motensive Wistar rats orally with 15 mg/kg per day of cyclosporine A a nd 10 mg/kg per day of lisinopril, alone or in combination, for 6 week s each, At the end of each treatment regimen, cardiac beta-adrenocepto r density and subtype distribution were assessed by (-)-[I-125]iodocya nopindolol binding. Results. Both doses of cyclosporine A caused a sig nificant decrease in cardiac beta(1)-adrenoceptor density without affe cting beta(1)-adrenoceptor density. Although diltiazem and the angiote nsin-converting enzyme inhibitors alone did not affect cardiac beta-ad renoceptors, they prevented the cyclosporine A-induced downregulation of beta(1)-adrenoceptors. Conclusions. In normotensive Wistar rats, cy closporine A causes a significant decrease in cardiac beta(1)-adrenoce ptors without affecting beta(2)-adrenoceptors. This can be prevented b y diltiazem or angiotensin-converting enzyme inhibitors, In heart tran splant recipients, who undergo long-term treatment with cyclosporine A , there is a very similar beta(1)-adrenoceptor down-regulation with ti me after transplantation. Thus, administration of cyclosporine A may c ause these beta adrenoceptor subtype alterations.