title: Glucocorticoid-induced hypertension and cardiac injury: effects of mineralocorticoid and glucocorticoid receptor antagonism.
abstract: Glucocorticoids are widely administered for the treatment of various disorders, although their long-term use results in adverse effects associated with glucocorticoid excess. We investigated the pathophysiological roles of glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs) in the cardiac changes induced by exogenous corticosterone in rats. Corticosterone or vehicle was injected twice daily in rats from 8 to 12 weeks of age. The effects of the GR antagonist RU486, the MR antagonist spironolactone, or both agents on corticosterone action were also determined. Corticosterone induced hypertension, left ventricular (LV) fibrosis, and LV diastolic dysfunction. Neither RU486 nor spironolactone affected corticosterone-induced hypertension, whereas spironolactone, but not RU486, attenuated the effects of corticosterone on LV fibrosis and diastolic function. Corticosterone also increased cardiac oxidative stress and inflammation in a manner sensitive to spironolactone but not to RU486. The corticosterone-induced LV atrophy was not affected by either RU486 or spironolactone. Our results implicate MRs in the cardiac fibrosis and diastolic dysfunction, but not MRs or GRs in the cardiac atrophy, induced by corticosterone. Neither MRs nor GRs appear to contribute to corticosterone-induced hypertension.
authors.affiliation: Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Hattori
authors.forename: Tamayo
authors.initials: T
authors.lastname: Murase
authors.forename: Erika
authors.initials: E
authors.lastname: Iwase
authors.forename: Keiji
authors.initials: K
authors.lastname: Takahashi
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ohtake
authors.forename: Koji
authors.initials: K
authors.lastname: Tsuboi
authors.forename: Mayuko
authors.initials: M
authors.lastname: Ohtake
authors.forename: Masaaki
authors.initials: M
authors.lastname: Miyachi
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
authors.forename: Kohzo
authors.initials: K
authors.lastname: Nagata
mesh_terms: D000818:Animals; D001284:Atrophy; D001794:Blood Pressure / Q000187:drug effects; D003345:Corticosterone; D004195:Disease Models, Animal; D005355:Fibrosis; D006331:Heart Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D015735:Mifepristone / Q000494:pharmacology*; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000187:drug effects* / Q000378:metabolism; D013148:Spironolactone / Q000494:pharmacology*; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D018836:Inflammation Mediators; D000451:Mineralocorticoid Receptor Antagonists; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D015735:Mifepristone; D003345:Corticosterone
references.citation: J Clin Invest. 1995 Nov;96(5):2113-9
references.pmid: 7593595
references.citation: Hypertens Res. 1996 Mar;19(1):1-8
references.pmid: 8829818
references.citation: Biochem J. 1982 Jun 15;204(3):663-72
references.pmid: 6181774
references.citation: Anesth Analg. 2000 Aug;91(2):322-8
references.pmid: 10910842
references.citation: Joint Bone Spine. 2011 Jan;78(1):41-4
references.pmid: 20471889
references.citation: J Steroid Biochem Mol Biol. 2005 Feb;93(2-5):121-5
references.pmid: 15860254
references.citation: N Engl J Med. 1996 Dec 19;335(25):1897-905
references.pmid: 8948566
references.citation: J Hypertens. 1999 Mar;17(3):419-26
references.pmid: 10100081
references.citation: Circulation. 2001 Aug 7;104(6):658-63
references.pmid: 11489771
references.citation: Horm Res. 2009 Nov;72 Suppl 1:36-41
references.pmid: 19940494
references.citation: Proc Natl Acad Sci U S A. 1990 Dec;87(24):10043-7
references.pmid: 1702214
references.citation: Circulation. 2004 May 4;109(17):2143-9
references.pmid: 15051632
references.citation: Heart. 2004 Aug;90(8):859-65
references.pmid: 15253953
references.citation: Hypertension. 1999 Apr;33(4):981-6
references.pmid: 10205234
references.citation: Curr Opin Nephrol Hypertens. 2004 Jul;13(4):451-8
references.pmid: 15199296
references.citation: J Clin Endocrinol Metab. 1988 Oct;67(4):824-31
references.pmid: 2843562
references.citation: Hypertens Res. 2011 Jul;34(7):809-16
references.pmid: 21471973
references.citation: Am J Physiol Endocrinol Metab. 2000 Nov;279(5):E1185-90
references.pmid: 11052975
references.citation: Cardiovasc Res. 1999 Jan;41(1):55-64
references.pmid: 10325953
references.citation: J Cardiol. 1995 Dec;26(6):357-66
references.pmid: 8558414
references.citation: J Cell Physiol. 2006 Nov;209(2):501-14
references.pmid: 16883577
references.citation: Clin Exp Pharmacol Physiol. 2008 Apr;35(4):477-82
references.pmid: 18307745
references.citation: Cell Mol Life Sci. 2006 Mar;63(5):565-78
references.pmid: 16416027
references.citation: Am J Physiol Endocrinol Metab. 2003 Aug;285(2):E363-71
references.pmid: 12721153
references.citation: Hypertension. 2005 Feb;45(2):283-7
references.pmid: 15623539
references.citation: Hypertension. 2012 Mar;59(3):694-704
references.pmid: 22275535
references.citation: J Hypertens. 2000 Dec;18(12):1849-55
references.pmid: 11132610
references.citation: Physiology (Bethesda). 2008 Jun;23:160-70
references.pmid: 18556469
references.citation: Hypertension. 2002 Aug;40(2):168-74
references.pmid: 12154108
references.citation: Hypertens Res. 2009 Aug;32(8):649-57
references.pmid: 19521418
references.citation: Br J Nutr. 1998 Mar;79(3):297-304
references.pmid: 9577308
references.citation: Hypertension. 2000 Nov;36(5):912-6
references.pmid: 11082166
references.citation: Hypertension. 2009 Apr;53(4):701-7
references.pmid: 19255362
references.citation: Circ Res. 2003 Jan 10;92(1):81-7
references.pmid: 12522124
references.citation: Lancet. 1982 Sep 18;2(8299):646-9
references.pmid: 6125785
references.citation: Am J Physiol Endocrinol Metab. 2006 Mar;290(3):E409-15
references.pmid: 16219664
references.citation: J Endocrinol. 2008 Apr;197(1):1-10
references.pmid: 18372227
references.citation: Am J Respir Crit Care Med. 1999 Jan;159(1):283-9
references.pmid: 9872851
references.citation: Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13357-62
references.pmid: 10557325
references.citation: Hypertension. 2006 Apr;47(4):656-64
references.pmid: 16505208
references.citation: J Cell Biol. 2003 Sep 15;162(6):1135-47
references.pmid: 12963705