Tissue- and subtype-specific modulation of angiotensin II receptors by chronic treatment with cyclosporin A, angiotensin-converting enzyme inhibitors and AT1 antagonists.
We wished to determine whether chronic treatment of rats with cyclosporin A (CSA), an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor antagonists modulates the angiotensin receptor density. In rats treated chronically with CSA, the vasoconstrictor response to angiotensin II (AII) is increased and this increase is modulated by ACEI and angiotensin receptor antagonists. Rats were treated for 6 weeks orally with CSA (15 mg/kg/day), the ACE inhibitor lisinopril (10 mg/kg/day), the angiotensin receptor antagonists DUP 753 (10 mg/kg/day), and D 8731 (10 mg/kg/day) and the combinations CSA + lisinopril, CSA + DUP 753, and CSA + D 8731. Olive oil was used as a control. The number of total AII receptors (Bmax) was determined by Scatchard analysis of [125I]Sar1 Ile8 AII binding in kidney, liver, adrenal cortex, and adrenal medulla. The receptor subtypes were analyzed with the specific antagonists DUP 753 (subtype 1) and PD 123319 (subtype 2). CSA upregulated angiotensin receptors in all organs studied. Lisinopril alone downregulated angiotensin receptors and abolished the effect of CSA in liver and adrenal cortex and medulla, but not in the kidney, where it had no effect. DUP 753 alone downregulated the angiotensin receptor subtype 1 in kidney, liver and adrenal cortex; its effect on the adrenal medulla in which 89% of angiotensin receptors are subtype 2, did not quite reach significance. The combination of DUP 753 and cyclosporin CSA abolished the CSA-induced increase in angiotensin receptor density in all four organs. The angiotensin receptor antagonists D 8731 downregulated the angiotensin receptors (subtype 1) in liver and kidney and upregulated angiotensin receptors (subtype 2) in the adrenal medulla.(ABSTRACT TRUNCATED AT 250 WORDS)
Regitz-Zagrosek
V
V
Department of Internal Medicine/Cardiology and Angiology, Free University Berlin, University Hospital Rudolf Virchow, Germany.
Auch-Schwelk
W
W
Hess
B
B
Klein
U
U
Duske
E
E
Steffen
C
C
Hildebrandt
A G
AG
Fleck
E
E
D000284:Administration, Oral; D000302:Adrenal Cortex / Q000187:drug effects / Q000378:metabolism; D000313:Adrenal Medulla / Q000187:drug effects / Q000378:metabolism; D000804:Angiotensin II / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000378:metabolism / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000378:metabolism / Q000494:pharmacology; D016572:Cyclosporine / Q000008:administration & dosage / Q000494:pharmacology*; D015536:Down-Regulation; D004347:Drug Interactions; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D017706:Lisinopril / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D019808:Losartan; D008297:Male; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011945:Receptors, Angiotensin / Q000187:drug effects* / Q000378:metabolism; D013777:Tetrazoles / Q000378:metabolism / Q000494:pharmacology; D015854:Up-Regulation
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D011725:Pyridines; D011804:Quinolines; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; C073402:PD 123319; C081112:ICI D8731; C032651:angiotensin II, Sar(1)-Ile(5)-; D016572:Cyclosporine; D017706:Lisinopril; D019808:Losartan