ANGIOTENSIN-II RECEPTOR SUBTYPES AND PHOSPHOINOSITIDE HYDROLYSIS IN RAT ADRENAL-MEDULLA

Angiotensin II (ANG) receptor subtypes were characterized by quantitative autoradiography after incubation with the ANG agonist [I-125]Sar(1)-ANG in rat adrenal medulla. ANG receptors are highly localized in adrenal medulla. Specific binding was displaced by 4% and by 95% with the AT(1) receptor blocker losartan and the AT(2) receptor competitor CGP 42112A, respectively. Analysis of competition curves indicated relative binding potencies for the AT(2) population of CGP 42112A>PD 123319> PD 123177. ANG stimulated inositol phosphate formation in a dose-dependent manner in rat adrenal medulla. Losartan at concentrations of 10(-9) to 10(-5) M antagonized the effect of ANG, whereas PD 123177 or PD 123319 had no antagonistic action, However, at a higher concentration (10(-5) M) PD 123177 or PD 123319 potentiated the effect of ANG on InsP(1)-accumulation. In the presence of PO 123319 (10(-5) M) ANG dose-response curve was shifted to the left with no change in the maximal effect. This affect was blocked by the addition of losartan (10(-5) M). On the contrary, the addition of CGP 42112A (10(-6) M) inhibited ANG-induced increase in InsP(1)-accumulation. On the other hand, ANG and CGP 42112A reduced basal cyclic GMP formation, this effect was partially reverted by sodium orthovanadate, a phosphotyrosine phosphatase inhibitor, Our results further demonstrate the presence of two ANG receptor subtypes in adrenal medulla: ANG binding to AT(1) receptor stimulates inositol phospholipid metabolism, whereas ANG binding to AT(2) receptors decreases both inositol phosphate production and cGMP formation.