Stimulation of renin secretion by angiotensin II blockade is Gsalpha-dependent.
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.
Chen
Limeng
L
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 9000 Rockville Pike, Building 31, Room 2B11, Bethesda, MD 20892, USA.
Kim
Soo Mi
SM
Eisner
Christoph
C
Oppermann
Mona
M
Huang
Yuning
Y
Mizel
Diane
D
Li
Lingli
L
Chen
Min
M
Sequeira Lopez
Maria Luisa
ML
Weinstein
Lee S
LS
Gomez
Roberto A
RA
Schnermann
Jurgen
J
Briggs
Josephine P
JP
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
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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