This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Laredo, J. Articles by Hamlyn, J. M. Search for Related Content PubMed PubMed Citation Articles by Laredo, J. Articles by Hamlyn, J. M. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB HYDROCORTISONE OUABAIN

(Hypertension. 1997;29:401.)
© 1997 American Heart Association, Inc.

State-of-the-Art-Lecture

Angiotensin II Stimulates Secretion of Endogenous Ouabain From Bovine Adrenocortical Cells via Angiotensin Type 2 Receptors

James Laredo; Jui R. Shah; Zhuo-ren Lu; Bruce P. Hamilton; John M. Hamlyn

From the Departments of Physiology (J.L., J.R.S., Z.L., J.M.H.) and Medicine (B.P.H.), University of Maryland School of Medicine, Baltimore.

Correspondence to John Hamlyn, Department of Physiology, School of Medicine, University of Maryland, 655 W Baltimore St, Baltimore, MD 21201

Angiotensin II stimulates secretion of corticosteroids and ouabain-like activity from adrenocortical cells. Distinct adrenocortical angiotensin II receptor subtypes (AT₁, AT₂) have been described, and the present studies investigated their roles in steroid secretion. Using primary bovine adrenocortical cell cultures under serum free conditions, angiotensin II stimulated the secretions of aldosterone, cortisol, and endogenous ouabain as verified by high-performance chromatography. The dose-response curves for stimulated steroid secretion were parallel with unitary slopes while the half-maximally effective concentrations of angiotensin II were 0.31 to 0.38 nmol/L for secretions of aldosterone and cortisol and 2.3 nmol/L for endogenous ouabain. The nonselective mammalian antagonist (Sar¹-Ile⁸) angiotensin II blocked stimulated secretion of all three steroids without affecting basal output. In the presence of the AT₁ antagonist DuP753, angiotensin II—stimulated secretions of aldosterone and cortisol were blocked while secretion of endogenous ouabain was unaffected. In the presence of the AT₂ antagonist PD123319, both basal and angiotensin II-stimulated secretions of aldosterone and cortisol were normal while stimulated secretion of endogenous ouabain was inhibited. The secretion of endogenous ouabain was activated maximally by the AT₂ agonist CGP42112 under conditions in which aldosterone secretion was unaffected. These results demonstrate that AT₂ receptors stimulate secretion of endogenous ouabain from bovine adrenocortical cells. The specificity of AT₁ and AT₂ receptor stimulation indicates that separate signaling mechanisms having minimal cross talk control the adrenocortical secretions of corticosteroids and cardiac-active steroids. Adrenocortical AT₂ receptors may be important in the adaptation to low salt diets and other conditions in which angiotensin II is increased.

Key Words: adrenal • cardiac glycosides • angiotensin and antagonists • losartan • DuP753 • PD 123319 • CGP42112

Abbreviations: AGEO = aglycone of endogenous ouabain • AII = angiotensin II • AT₁, AT₂ = angiotensin type 1, angiotensin type 2 • CDMEM = complete DMEM • CGP = nicotinic acid-tyr-(N-benzoxycarbonyl-Arg)-Lys-His-Pro-Ile-OH • CV = coefficient of variation • DTFA = ditrifluoroacetate • DuP753 = 2-n-butyl-4-chloro-5-(hydroxymethyl)-1-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}imidazole • EO = endogenous ouabain • HPLC = high-performance liquid chromatography • PD = (s)-1-{[4-(dimethylamino)-3-methylphenyl]methyl}-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo(4,5-c)pyridine-6-carboxylic acid • RIA = radioimmunoassay • SI-AII = Sar¹, Ile⁸-angiotensin II • SM = secretion medium

This article has been cited by other articles:

				J. W. Funder The Off-Target Effects of Torcetrapib Endocrinology, May 1, 2009; 150(5): 2024 - 2026. [Full Text] [PDF]

				A. Y. Bagrov, J. I. Shapiro, and O. V. Fedorova Endogenous Cardiotonic Steroids: Physiology, Pharmacology, and Novel Therapeutic Targets Pharmacol. Rev., March 1, 2009; 61(1): 9 - 38. [Abstract] [Full Text] [PDF]

				W. Schoner and G. Scheiner-Bobis Role of endogenous cardiotonic steroids in sodium homeostasis Nephrol. Dial. Transplant., September 1, 2008; 23(9): 2723 - 2729. [Full Text] [PDF]

				W. Schoner and G. Scheiner-Bobis Endogenous and exogenous cardiac glycosides: their roles in hypertension, salt metabolism, and cell growth Am J Physiol Cell Physiol, August 1, 2007; 293(2): C509 - C536. [Abstract] [Full Text] [PDF]

				O. Kotova, L. Al-Khalili, S. Talia, C. Hooke, O. V. Fedorova, A. Y. Bagrov, and A. V. Chibalin Cardiotonic Steroids Stimulate Glycogen Synthesis in Human Skeletal Muscle Cells via a Src- and ERK1/2-dependent Mechanism J. Biol. Chem., July 21, 2006; 281(29): 20085 - 20094. [Abstract] [Full Text] [PDF]

				I. Dostanic-Larson, J. W. Van Huysse, J. N. Lorenz, and J. B Lingrel From The Cover: The highly conserved cardiac glycoside binding site of Na,K-ATPase plays a role in blood pressure regulation PNAS, November 1, 2005; 102(44): 15845 - 15850. [Abstract] [Full Text] [PDF]

				J. R. Murrell, J. D. Randall, J. Rosoff, J.-l. Zhao, R. V. Jensen, S. R. Gullans, and G. T. Haupert Jr Endogenous Ouabain: Upregulation of Steroidogenic Genes in Hypertensive Hypothalamus but Not Adrenal Circulation, August 30, 2005; 112(9): 1301 - 1308. [Abstract] [Full Text] [PDF]

				N. Bauer, J. Muller-Ehmsen, U. Kramer, N. Hambarchian, C. Zobel, R. H.G. Schwinger, H. Neu, U. Kirch, E.-G. Grunbaum, and W. Schoner Ouabain-Like Compound Changes Rapidly on Physical Exercise in Humans and Dogs: Effects of {beta}-Blockade and Angiotensin-Converting Enzyme Inhibition Hypertension, May 1, 2005; 45(5): 1024 - 1028. [Abstract] [Full Text] [PDF]

				H. Lin, S. Ozaki, N. Fujishiro, K. Takeda, I. Imanaga, G. D Prestwich, and M. Inoue Subunit composition and role of Na+,K+-ATPases in adrenal chromaffin cells J. Physiol., April 1, 2005; 564(1): 161 - 172. [Abstract] [Full Text] [PDF]

				R. I. Dmitrieva and P. A. Doris Ouabain Is a Potent Promoter of Growth and Activator of ERK1/2 in Ouabain-resistant Rat Renal Epithelial Cells J. Biol. Chem., July 18, 2003; 278(30): 28160 - 28166. [Abstract] [Full Text] [PDF]

				Z. Xie and T. Cai Na+-K+-ATPase-Mediated Signal Transduction: From Protein Interaction to Cellular Function Mol. Interv., May 1, 2003; 3(3): 157 - 168. [Abstract] [Full Text] [PDF]

				R. I. Dmitrieva and P. A. Doris Cardiotonic Steroids: Potential Endogenous Sodium Pump Ligands with Diverse Function Experimental Biology and Medicine, September 1, 2002; 227(8): 561 - 569. [Abstract] [Full Text] [PDF]

				B. Parhami-Seren, R. Haberly, M. N. Margolies, and G. T. Haupert Jr Ouabain-Binding Protein(s) From Human Plasma Hypertension, August 1, 2002; 40(2): 220 - 228. [Abstract] [Full Text] [PDF]

				H. E. De Wardener The Hypothalamus and Hypertension Physiol Rev, October 1, 2001; 81(4): 1599 - 1658. [Abstract] [Full Text] [PDF]

				H. Peng, J. Moffett, J. Myers, X. Fang, E. K. Stachowiak, P. Maher, E. Kratz, J. Hines, S. J. Fluharty, E. Mizukoshi, et al. Novel Nuclear Signaling Pathway Mediates Activation of Fibroblast Growth Factor-2 Gene by Type 1 and Type 2 Angiotensin II Receptors Mol. Biol. Cell, February 1, 2001; 12(2): 449 - 462. [Abstract] [Full Text]

				B. Parhami-Seren, C. Bell, M. N. Margolies, and G. T. Haupert Jr. Monoclonal Antibodies That Distinguish Between Two Related Digitalis Glycosides, Ouabain and Digoxin J. Immunol., October 15, 1999; 163(8): 4360 - 4366. [Abstract] [Full Text] [PDF]

				E. K. Jackson, W. A. Herzer, S. J. Vyas, and C. K. Kost Jr Angiotensin II-Induced Renal Vasoconstriction in Genetic Hypertension J. Pharmacol. Exp. Ther., October 1, 1999; 291(1): 329 - 334. [Abstract] [Full Text]

				M. P. Blaustein and W. J. Lederer Sodium/Calcium Exchange: Its Physiological Implications Physiol Rev, July 1, 1999; 79(3): 763 - 854. [Abstract] [Full Text] [PDF]

				R. Antolovic, H. Kost, M. Mohadjerani, D. Linder, M. Linder, and W. Schoner A Specific Binding Protein for Cardiac Glycosides Exists in Bovine Serum J. Biol. Chem., June 26, 1998; 273(26): 16259 - 16264. [Abstract] [Full Text] [PDF]

				L. F. Santana, A. M. Gómez, and W. J. Lederer Ca2+ Flux Through Promiscuous Cardiac Na+ Channels: Slip-Mode Conductance Science, February 13, 1998; 279(5353): 1027 - 1033. [Abstract] [Full Text]

				R. Schneider, V. Wray, M. Nimtz, W. D. Lehmann, U. Kirch, R. Antolovic, and W. Schoner Bovine Adrenals Contain, in Addition to Ouabain, a Second Inhibitor of the Sodium Pump J. Biol. Chem., January 9, 1998; 273(2): 784 - 792. [Abstract] [Full Text] [PDF]

				J. R. Shah, J. Laredo, B. P. Hamilton, and J. M. Hamlyn Different Signaling Pathways Mediate Stimulated Secretions Of Endogenous Ouabain and Aldosterone From Bovine Adrenocortical Cells Hypertension, January 1, 1998; 31(1): 463 - 468. [Abstract] [Full Text] [PDF]