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 [124I]Sar1-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, receptor blocker losartan and the AT2 receptor competitor CGP 42112A, respectively. Analysis of competition curves indicated relative binding potencies for the AT2 population of CGP 42112A>PD 123319> PD 123177. ANG stimulated +-nositol 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 InsP1-accumulation. In the presence of PD 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 InsP1-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, receptor stimulates inositol phospholipid metabolism, whereas ANG binding to AT2 receptors decreases both inositol phosphate production and cGMP formation.
Israel
A
A
Section on Pharmacology, National Institute of Mental Health, Bethesda, MD 20892, USA.
Strömberg
C
C
Tsutsumi
K
K
Garrido
M R
MR
Torres
M
M
Saavedra
J M
JM
D000313:Adrenal Medulla / Q000378:metabolism*; D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001667:Binding, Competitive; D001713:Biphenyl Compounds / Q000494:pharmacology*; D006152:Cyclic GMP / Q000096:biosynthesis; D006868:Hydrolysis; D007093:Imidazoles / Q000494:pharmacology*; D019808:Losartan; D008297:Male; D010716:Phosphatidylinositols / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000032:analysis*; D013777:Tetrazoles / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D007093:Imidazoles; D010716:Phosphatidylinositols; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; D006152:Cyclic GMP; D019808:Losartan