title: Selective downregulation of rat cardiac beta 1-adrenoceptors by cyclosporine A: prevention by diltiazem or angiotensin-converting enzyme inhibitors.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Internal Medicine, University of Essen, Germany.
authors.forename: O E
authors.initials: OE
authors.lastname: Brodde
authors.forename: M
authors.initials: M
authors.lastname: Adamczyk
authors.forename: F
authors.initials: F
authors.lastname: Busch
authors.forename: C
authors.initials: C
authors.lastname: Bossaller
authors.forename: E
authors.initials: E
authors.lastname: Duske
authors.forename: E
authors.initials: E
authors.lastname: Fleck
authors.forename: S
authors.initials: S
authors.lastname: Götze
authors.forename: W
authors.initials: W
authors.lastname: Auch-Schwelk
mesh_terms: D000818:Animals; D016572:Cyclosporine / Q000008:administration & dosage / Q000494:pharmacology*; D004110:Diltiazem / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects*; D004656:Enalapril / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018342:Receptors, Adrenergic, beta-1 / Q000502:physiology*
chemical_list: D018342:Receptors, Adrenergic, beta-1; D004656:Enalapril; D016572:Cyclosporine; D004110:Diltiazem