Selective downregulation of rat cardiac beta1-adrenoceptors by cyclosporine a: Prevention by diltiazem or angiotensin-converting enzyme inhibitors

Objectives. This study attempted to determine whether long-term treatment with cyclosporine in rats affects cardiac beta1-adrenoceptors and whether this can be prevented by angiotensinconverting enzyme inhibitors or calcium-entry blocking agents. Background. In the transplanted human heart the density of beta1-adrenoceptors decreases with time after transplantation, whereas that of beta2-adrenoceptors does not. Because heart transplant recipients are treated with cyclosporine A, we studied whether administration of cyclosporine in rats might cause this beta1-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 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 caused significant decrease in cardiac beta1-adrenoceptor density without affecting beta2-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 beta1-adrenoceptors. Conclusions. In normotensive Wistar rats, cyclosporine causes significant decrease in cardiac beta1-adrenoceptors without affecting beta2-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 very similar beta1-adrenoceptor down-regulation with time after transplantation. Thus, administration of cyclosporine may cause these beta-adrenoceptor subtype alterations.