Angiotensin II inhibits glomerular adenylate cyclase via the angiotensin II receptor subtype 1 (AT1).
We examined the role of angiotensin II (AII) receptor subtypes in the regulation of hormone-stimulated cyclic AMP (cAMP) accumulation in isolated rat glomeruli. All inhibited cAMP formation induced by histamine, serotonin and parathyroid hormone, but not by prostaglandin E2 or calcitonin gene-related peptide. Angiotensin III but not the angiotensin fragments (1-7) and (3-8) also showed inhibitory activity. The inhibition of histamine-induced cAMP accumulation by AII was concentration-dependent and was absent in glomeruli isolated from pertussis toxin-treated rats. The effect of AII on histamine-induced cAMP levels was not mimicked by the protein kinase C activator, phorbol-12-myristate-13-acetate, nor was the effect of AII inhibited by the protein kinase C inhibitors, staurosporine and H-7. The angiotensin II receptor subtype 1 (AT1) antagonists, SK&F 108566 and losartan, attenuated the inhibitory effect of AII on histamine-stimulated cAMP accumulation, whereas the AT2 selective antagonists, CGP 42112A, WL-19 and PD 123319, had no effect. Displacement of [125I]AII from glomerular membrane using the subtype-selective antagonists confirmed that the glomerular AII receptor has characteristics of an AT1 subtype. The results suggest that AII, through activation of the AT1 receptor, may act to maintain the contractile state of glomerular mesangial cells by attenuating the increase in cAMP levels induced by some hormones.
Department of Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania.
R M
RM
Edwards
E J
EJ
Stack
D000067956:Adenylyl Cyclase Inhibitors; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D007678:Kidney Glomerulus / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000032:analysis / Q000187:drug effects*
D000067956:Adenylyl Cyclase Inhibitors; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D000242:Cyclic AMP; D011493:Protein Kinase C