TISSUE-SPECIFIC AND SUBTYPE-SPECIFIC MODULATION OF ANGIOTENSIN-II RECEPTORS BY CHRONIC TREATMENT WITH CYCLOSPORINE-A, ANGIOTENSIN-CONVERTING ENZYME-INHIBITORS AND AT1 ANTAGONISTS

We wished to determine whether chronic treatment of rats with cyclospo rin A (CSA), an angiotensin-converting enzyme inhibitor (ACEI) or angi otensin receptor antagonists modulates the angiotensin receptor densit y. 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 we eks orally with CSA (15 mg/kg/day), the ACE inhibitor lisinoprir (10 m g/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 num ber of total AII receptors (B-max) was determined by Scatchard analysi s of [I-125]Sar(1) Ile AII binding in kidney, liver, adrenal cortex, a nd adrenal medulla. The receptor subtypes were analyzed with the speci fic antagonists DUP 753 (subtype 1) and PD 123319 (subtype 2). CSA upr egulated angiotensin receptors in all organs studied. Lisinopril alone downregulated angiotensin receptors and abolished the effect of CSA i n liver and adrenal cortex and medulla, but not in the kidney, where i t had no effect. DUP 753 alone downregulated the angiotensin receptor subtype 1 in kidney, liver and adrenal cortex; its effect on the adren al medulla in which 89% of angiotensin receptors are subtype 2, did no t quite reach significance. The combination of DUP 753 and cyclosporin CSA abolished the CSA-induced increase in angiotensin receptor densit y in all four organs. The angiotensin receptor antagonists D 8731 down regulated the angiotensin receptors (subtype 1) in liver and kidney an d upregulated angiotensin receptors (subtype 2) in the adrenal medulla . Angiotensin receptors are upregulated by treatment with CSA and, in most cases, downregurated by the ACEI lisinopril and two different sub type 1 antagonists. Regulation is organ and subtype specific. Most of our results could be explained by a positive feedback mechanisms in th e regulation of angiotensin receptors by AII.