title: Stimulation of renin secretion by angiotensin II blockade is Gsalpha-dependent.
abstract: Angiotensin II converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB) presumably stimulate renin secretion by interrupting angiotensin II feedback inhibition. The increase in cytosolic calcium caused by activation of Gq-coupled AT1 receptors may mediate the renin-inhibitory effect of angiotensin II at the cellular level, implying that ACEI and ARB may work by reducing intracellular calcium. Here, we investigated whether angiotensin II blockade acts predominantly through Gs-mediated stimulation of adenylyl cyclase (AC) by testing the effect of ACEI and ARB in mice with juxtaglomerular cell-specific deficiency of the AC-stimulatory Gsalpha. The ACEI captopril and quinaprilate and the ARB candesartan significantly increased plasma renin concentration (PRC) to 20 to 40 times basal PRC in wild-type mice but did not significantly alter PRC in Gsalpha-deficient mice. Captopril also completely abrogated renin stimulation in wild-type mice after co-administration of propranolol, indomethacin, and L-NAME. Treatment with enalapril and a low-NaCl diet for 7 days led to a 35-fold increase in PRC among wild-type mice but no significant change in PRC among Gsalpha-deficient mice. Three different pharmacologic inhibitors of AC reduced the stimulatory effect of captopril by 70% to 80%. In conclusion, blockade of angiotensin II stimulates renin synthesis and release indirectly through the action of ligands that activate the cAMP/PKA pathway in a Gsalpha-dependent fashion, including catecholamines, prostaglandins, and nitric oxide.
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 9000 Rockville Pike, Building 31, Room 2B11, Bethesda, MD 20892, USA.
authors.forename: Limeng
authors.initials: L
authors.lastname: Chen
authors.forename: Soo Mi
authors.initials: SM
authors.lastname: Kim
authors.forename: Christoph
authors.initials: C
authors.lastname: Eisner
authors.forename: Mona
authors.initials: M
authors.lastname: Oppermann
authors.forename: Yuning
authors.initials: Y
authors.lastname: Huang
authors.forename: Diane
authors.initials: D
authors.lastname: Mizel
authors.forename: Lingli
authors.initials: L
authors.lastname: Li
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Sequeira Lopez
authors.forename: Lee S
authors.initials: LS
authors.lastname: Weinstein
authors.forename: Roberto A
authors.initials: RA
authors.lastname: Gomez
authors.forename: Jurgen
authors.initials: J
authors.lastname: Schnermann
authors.forename: Josephine P
authors.initials: JP
authors.lastname: Briggs
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism*; D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D002216:Captopril / Q000494:pharmacology; D002395:Catecholamines / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004656:Enalapril / Q000494:pharmacology; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics / Q000378:metabolism*; D007606:Juxtaglomerular Apparatus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009569:Nitric Oxide / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism; D012083:Renin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D002395:Catecholamines; D011453:Prostaglandins; D044005:Tetrahydroisoquinolines; D013777:Tetrazoles; D000804:Angiotensin II; D009569:Nitric Oxide; C054501:quinaprilat; D004656:Enalapril; D002216:Captopril; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D012083:Renin; D019205:GTP-Binding Protein alpha Subunits, Gs; D000262:Adenylyl Cyclases; C081643:candesartan
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