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Semin Vasc Med 2004; 4(2): 121-128
DOI: 10.1055/s-2004-835369
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001 USA.

Cortisol, 11β-Hydroxysteroid Dehydrogenases, and Hypertension

Stan H.M van Uum1 , Jacques W.M Lenders2 , Ad R.M.M Hermus3
  • 1Division of Endocrinology and Metabolism, Department of Medicine, University of Western Ontario, London, Ontario, Canada
  • 2Division of General Internal Medicine
  • 3Division of Endocrinology, Deptartment of Medicine, University Medical Center, Nijmegen, The Netherlands
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Publication History

Publication Date:
11 October 2004 (online)

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Hypersecretion of cortisol is associated with hypertension. In addition, an abnormal cortisol metabolism may play a role in the pathogenesis of hypertension. The 11β-hydroxysteroid dehydrogenase (11β-HSD) isozymes catalyze interconversion of cortisol and cortisone and play an important role in the regulation of the effects of cortisol. Activity of 11β-HSD type 2, converting active cortisol in inactive cortisone, is crucial in preventing access of cortisol to the renal mineralocorticoid receptors (MRs). Decreased activity of this isozyme in the kidney, either congenitally in Apparent Mineralocorticoid Excess syndrome or acquired following licorice consumption, allows cortisol access to the MRs, resulting in hypokalemic hypertension. In normotensive subjects, an association has been demonstrated between blood pressure increase on a high-salt diet and a mild decrease of renal 11β-HSD2 activity. In ectopic adrenocorticotropic hormone (ACTH), plasma cortisol levels are very high, resulting in mineralocorticoid hypertension caused by saturation of the available renal 11β-HSD2 capacity. Activity of the 11β-HSDs has also been demonstrated in many extrarenal sites. Several studies have demonstrated extrarenal effects of cortisol on blood pressure, as well as a possible role for altered extrarenal 11β-HSD activities in the pathogenesis of hypertension. More studies are needed to clarify the role of 11β-HSDs in the pathogenesis of hypertension.

KEYWORDS

Cortisol - 11β-hydroxysteroid dehydrogenases - hypertension - licorice

REFERENCES

  • 1 Danese R D, Aron D C. Cushing's syndrome and hypertension.  Endocrinol Metab Clin North Am. 1994;  23 299-324
    PubMedGoogle Scholar
  • 2 Fallo F, Paoletta A, Tona F et al.. Response of hypertension to conventional antihypertensive treatment and/or steroidogenesis inhibitors in Cushing's syndrome.  J Intern Med. 1993;  234 595-598
    PubMedGoogle Scholar
  • 3 Connell J M, Whitworth J A, Davies D L et al.. Effects of ACTH and cortisol administration on blood pressure, electrolyte metabolism, atrial natriuretic peptide and renal function in normal man.  J Hypertens. 1987;  5 425-433
    PubMedGoogle Scholar
  • 4 Vermeulen A, van der Straeten M. Adrenal cortical function in benign essential hypertension.  J Clin Endocrinol Metab. 1963;  23 574-578
    PubMedGoogle Scholar
  • 5 Filipovsky J, Ducimetiere P, Eschwege E et al.. The relationship of blood pressure with glucose, insulin, heart rate, free fatty acids and plasma cortisol levels according to degree of obesity in middle-aged men.  J Hypertens. 1996;  14 229-235
    CrossrefPubMedGoogle Scholar
  • 6 Whitworth J A, Gordon D, McLachlan Troup N et al.. Dexamethasone suppression in essential hypertension: effects on cortisol and blood pressure.  Clin Exp Hypertens A. 1989;  11 323-335
    PubMedGoogle Scholar
  • 7 Lakshmi V, Monder C. Evidence for independent 11-oxidase and 11-reductase activities of 11 beta-hydroxysteroid dehydrogenase: enzyme latency, phase transitions, and lipid requirements.  Endocrinology. 1985;  116 552-560
    PubMedGoogle Scholar
  • 8 Monder C, White P C. 11 beta-hydroxysteroid dehydrogenase.  Vitam Horm. 1993;  47 187-271
    PubMedGoogle Scholar
  • 9 Walker B R, Campbell J C, Williams B C et al.. Tissue-specific distribution of the NAD(+)-dependent isoform of 11 beta-hydroxysteroid dehydrogenase.  Endocrinology. 1992;  131 970-972
    CrossrefPubMedGoogle Scholar
  • 10 Whorwood C B, Mason J I, Ricketts M L et al.. Detection of human 11 beta-hydroxysteroid dehydrogenase isoforms using reverse-transcriptase-polymerase chain reaction and localization of the type 2 isoform to renal collecting ducts.  Mol Cell Endocrinol. 1995;  110 R7-12
    CrossrefPubMedGoogle Scholar
  • 11 Stewart P M, Murry B A, Mason J I. Human kidney 11 beta-hydroxysteroid dehydrogenase is a high affinity nicotinamide adenine dinucleotide-dependent enzyme and differs from the cloned type I isoform.  J Clin Endocrinol Metab. 1994;  79 480-484
    CrossrefPubMedGoogle Scholar
  • 12 Agarwal A K, Tusie-Luna M T, Monder C et al.. Expression of 11 beta-hydroxysteroid dehydrogenase using recombinant vaccinia virus.  Mol Endocrinol. 1990;  4 1827-1832
    PubMedGoogle Scholar
  • 13 Brown R W, Chapman K E, Kotelevtsev Y et al.. Cloning and production of antisera to human placental 11beta-hydroxysteroid dehydrogenase type 2.  Biochem J. 1996;  313 1007-1017
    PubMedGoogle Scholar
  • 14 Smith R E, Maguire J A, Stein Oakley A N et al.. Localization of 11 beta-hydroxysteroid dehydrogenase type II in human epithelial tissues.  J Clin Endocrinol Metab. 1996;  81 3244-3248
    CrossrefPubMedGoogle Scholar
  • 15 Arriza J L, Weinberger C, Cerelli G et al.. Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor.  Science. 1987;  237 268-275
    CrossrefPubMedGoogle Scholar
  • 16 Palermo M, Shackleton C H, Mantero F et al.. Urinary free cortisone and the assessment of 11 beta- hydroxysteroid dehydrogenase activity in man.  Clin Endocrinol (Oxf). 1996;  45 605-611
    CrossrefPubMedGoogle Scholar
  • 17 Ulick S, Levine L S, Gunczler P et al.. A syndrome of apparent mineralocorticoid excess associated with defects in the peripheral metabolism of cortisol.  J Clin Endocrinol Metab. 1979;  49 757-764
    CrossrefPubMedGoogle Scholar
  • 18 New M I, Levine L S, Biglieri E G et al.. Evidence for an unidentified steroid in a child with apparent mineralocorticoid hypertension.  J Clin Endocrinol Metab. 1977;  44 924-933
    CrossrefPubMedGoogle Scholar
  • 19 Quinkler M, Stewart P M. Hypertension and the cortisol-cortisone shuttle.  J Clin Endocrinol Metab. 2003;  88 2384-2392
    CrossrefPubMedGoogle Scholar
  • 20 Milford D V, Shackleton C H, Stewart P M. Mineralocorticoid hypertension and congenital deficiency of 11 beta-hydroxysteroid dehydrogenase in a family with the syndrome of ‘apparent’ mineralocorticoid excess.  Clin Endocrinol (Oxf). 1995;  43 241-246
    PubMedGoogle Scholar
  • 21 Stewart P M, Corrie J E, Shackleton C H et al.. Syndrome of apparent mineralocorticoid excess. A defect in the cortisol-cortisone shuttle.  J Clin Invest. 1988;  82 340-349
    CrossrefPubMedGoogle Scholar
  • 22 Stewart P M, Wallace A M, Valentino R et al.. Mineralocorticoid activity of liquorice: 11-beta-hydroxysteroid dehydrogenase deficiency comes of age.  Lancet. 1987;  2 821-824
    PubMedGoogle Scholar
  • 23 MacKenzie M A, Hoefnagels W HL, Jansen R WMM et al.. The influence of glycyrrhetinic acid on plasma cortisol and cortisone in healthy young volunteers.  J Clin Endocrinol Metab. 1990;  70 1637-1643
    PubMedGoogle Scholar
  • 24 Stormer F C, Reistad R, Alexander J. Glycyrrhizic acid in liquorice-evaluation of health hazard.  Food Chem Toxicol. 1993;  31 303-312
    PubMedGoogle Scholar
  • 25 Walker B R, Campbell J C, Fraser R et al.. Mineralocorticoid excess and inhibition of 11 beta-hydroxysteroid dehydrogenase in patients with ectopic ACTH syndrome.  Clin Endocrinol. 1992;  37 483-492
    PubMedGoogle Scholar
  • 26 Diederich S, Quinkler M, Miller K et al.. Human kidney 11 beta-hydroxysteroid dehydrogenase: regulation by adrenocorticotropin?.  Eur J Endocrinol. 1996;  134 301-307
    PubMedGoogle Scholar
  • 27 van Uum S H, Houben A J, Hermus A R et al.. Acute intrarenal administration of cortisol has no effect on renal blood flow in hypertensive individuals.  J Hypertens. 2002;  20 2275-2283
    CrossrefPubMedGoogle Scholar
  • 28 Whitworth J A, Stewart P M, Burt D et al.. The kidney is the major site of cortisone production in man.  Clin Endocrinol (Oxf). 1989;  31 355-361
    CrossrefPubMedGoogle Scholar
  • 29 Riddle M C, McDaniel P A. Renal 11 beta-hydroxysteroid dehydrogenase activity is enhanced by ramipril and captopril.  J Clin Endocrinol Metab. 1994;  78 830-834
    CrossrefPubMedGoogle Scholar
  • 30 Burnier M, Roch-Ramel F, Brunner H R. Renal effects of angiotensin II receptor blockade in normotensive subjects.  Kidney Int. 1996;  49 1787-1790
    PubMedGoogle Scholar
  • 31 Kerstens M N, Buter H, Navis G J et al.. 11beta-hydroxysteroid dehydrogenase activity in proteinuric patients and the effect of angiotensin-II receptor blockade.  Eur J Clin Invest. 2002;  32 513-518
    CrossrefPubMedGoogle Scholar
  • 32 Soro A, Ingram M C, Tonolo G et al.. Evidence of coexisting changes in 11 beta-hydroxysteroid dehydrogenase and 5 beta-reductase activity in subjects with untreated essential hypertension.  Hypertension. 1995;  25 67-70
    PubMedGoogle Scholar
  • 33 Takeda Y, Miyamori I, Iki K et al.. Endogenous renal 11 beta-hydroxysteroid dehydrogenase inhibitory factors in patients with low-renin essential hypertension.  Hypertension. 1996;  27 197-201
    PubMedGoogle Scholar
  • 34 Iki K, Miyamori I, Hatakeyama H et al.. The activities of 5 beta-reductase and 11 beta-hydroxysteroid dehydrogenase in essential hypertension.  Steroids. 1994;  59 656-660
    CrossrefPubMedGoogle Scholar
  • 35 van Uum S H, Walker B R, Hermus A R et al.. Effect of glycyrrhetinic acid on 11 beta-hydroxysteroid dehydrogenase activity in normotensive and hypertensive subjects.  Clin Sci (Lond). 2002;  102 203-211
    PubMedGoogle Scholar
  • 36 Walker B R, Stewart P M, Shackleton C H et al.. Deficient inactivation of cortisol by 11 beta-hydroxysteroid dehydrogenase in essential hypertension.  Clin Endocrinol. 1993;  39 221-227
    PubMedGoogle Scholar
  • 37 Walker B R, Phillips D I, Noon J P et al.. Increased glucocorticoid activity in men with cardiovascular risk factors.  Hypertension. 1998;  31 891-895
    PubMedGoogle Scholar
  • 38 Sigurjonsdottir H A, Franzson L, Manhem K et al.. Liquorice-induced rise in blood pressure: a linear dose-response relationship.  J Hum Hypertens. 2001;  15 549-552
    CrossrefPubMedGoogle Scholar
  • 39 Sigurjonsdottir H A, Manhem K, Axelson M et al.. Subjects with essential hypertension are more sensitive to the inhibition of 11 beta-HSD by liquorice.  J Hum Hypertens. 2003;  17 125-131
    CrossrefPubMedGoogle Scholar
  • 40 Lovati E, Ferrari P, Dick B et al.. Molecular basis of human salt sensitivity: the role of the 11beta-hydroxysteroid dehydrogenase type 2.  J Clin Endocrinol Metab. 1999;  84 3745-3749
    CrossrefPubMedGoogle Scholar
  • 41 Ferrari P, Sansonnens A, Dick B et al.. In vivo 11beta-HSD-2 activity: variability, salt-sensitivity, and effect of licorice.  Hypertension. 2001;  38 1330-1336
    PubMedGoogle Scholar
  • 42 Kerstens M N, van der Kleij F G, Boonstra A H et al.. Salt loading affects cortisol metabolism in normotensive subjects: relationships with salt sensitivity.  J Clin Endocrinol Metab. 2003;  88 4180-4185
    CrossrefPubMedGoogle Scholar
  • 43 Kornel L, Ramsay C, Kanamarlapudi N et al.. Evidence for the presence in arterial walls of intracellular- molecular mechanism for action of mineralocorticoids.  Clin Exp Hypertens A. 1982;  4 1561-1582
    PubMedGoogle Scholar
  • 44 Ullian M E. The role of corticosteroids in the regulation of vascular tone.  Cardiovasc Res. 1999;  41 55-64
    CrossrefPubMedGoogle Scholar
  • 45 Kalsner S. Mechanism of hydrocortisone potentiation of responses to epinephrine and norepinephrine in rabbit aorta.  Circ Res. 1969;  24 383-395
    PubMedGoogle Scholar
  • 46 Besse J C, Bass A D. Potentiation by hydrocortisone of responses to catecholamines in vascular smooth muscle.  J Pharmacol Exp Ther. 1966;  154 224-238
    PubMedGoogle Scholar
  • 47 Beilin L J, Wade D N, Honour A J et al.. Vascular hyper-reactivity with sodium loading and with desoxycorticosterone induced hypertension in the rat.  Clin Sci. 1970;  39 793-810
    PubMedGoogle Scholar
  • 48 Angelo Khattar M M, Thulesius O. Vascular effects of glucocorticosteroids, with special reference to budesonide.  Gen Pharmacol. 1983;  14 125-127
    PubMedGoogle Scholar
  • 49 Berecek K H, Bohr D F. Whole body vascular reactivity during the development of deoxycorticosterone acetate hypertension in the pig.  Circ Res. 1978;  42 764-771
    PubMedGoogle Scholar
  • 50 Grunfeld J P, Eloy L. Glucocorticoids modulate vascular reactivity in the rat.  Hypertension. 1987;  10 608-618
    PubMedGoogle Scholar
  • 51 Sudhir K, Jennings G L, Esler M D et al.. Hydrocortisone-induced hypertension in humans: pressor responsiveness and sympathetic function.  Hypertension. 1989;  13 416-421
    PubMedGoogle Scholar
  • 52 Mangos G J, Walker B R, Kelly J J et al.. Cortisol inhibits cholinergic vasodilation in the human forearm.  Am J Hypertens. 2000;  13 1155-1160
    CrossrefPubMedGoogle Scholar
  • 53 Pirpiris M, Sudhir K, Yeung S et al.. Pressor responsiveness in corticosteroid-induced hypertension in humans.  Hypertension. 1992;  19 567-574
    PubMedGoogle Scholar
  • 54 Walker B R, Yau J L, Brett L P et al.. 11 beta-hydroxysteroid dehydrogenase in vascular smooth muscle and heart: implications for cardiovascular responses to glucocorticoids.  Endocrinology. 1991;  129 3305-3312
    PubMedGoogle Scholar
  • 55 Walker B R, Connacher A A, Webb D J et al.. Glucocorticoids and blood pressure: a role for the cortisol/cortisone shuttle in the control of vascular tone in man.  Clin Sci Colch. 1992;  83 171-178
    PubMedGoogle Scholar
  • 56 Jamieson P M, Chapman K E, Edwards C R et al.. 11 beta-hydroxysteroid dehydrogenase is an exclusive 11 beta- reductase in primary cultures of rat hepatocytes: effect of physicochemical and hormonal manipulations.  Endocrinology. 1995;  136 4754-4761
    CrossrefPubMedGoogle Scholar
  • 57 Seckl J R, Walker B R. Minireview: 11beta-hydroxysteroid dehydrogenase type 1- a tissue-specific amplifier of glucocorticoid action.  Endocrinology. 2001;  142 1371-1376
    CrossrefPubMedGoogle Scholar
  • 58 Smith R E, Little P J, Maguire J A et al.. Vascular localization of the 11 beta-hydroxysteroid dehydrogenase type II enzyme.  Clin Exp Pharmacol Physiol. 1996;  23 549-551
    PubMedGoogle Scholar
  • 59 Hadoke P W, Christy C, Kotelevtsev Y V et al.. Endothelial cell dysfunction in mice after transgenic knockout of type 2, but not type 1, 11beta-hydroxysteroid dehydrogenase.  Circulation. 2001;  104 2832-2837
    PubMedGoogle Scholar
  • 60 Christy C, Hadoke P W, Paterson J M et al.. 11beta-hydroxysteroid dehydrogenase type 2 in mouse aorta: localization and influence on response to glucocorticoids.  Hypertension. 2003;  42 580-587
    CrossrefPubMedGoogle Scholar
  • 61 Reul J M, de Kloet E R. Two receptor systems for corticosterone in rat brain: microdistribution and differential occupation.  Endocrinology. 1985;  117 2505-2511
    CrossrefPubMedGoogle Scholar
  • 62 Roland B L, Li K X, Funder J W. Hybridization histochemical localization of 11 beta-hydroxysteroid dehydrogenase type 2 in rat brain.  Endocrinology. 1995;  136 4697-4700
    CrossrefPubMedGoogle Scholar
  • 63 Gomez-Sanchez E P, Fort C M, Gomez-Sanchez C E. Intracerebroventricular infusion of RU28318 blocks aldosterone-salt hypertension.  Am J Physiol. 1990;  258 E482-E484
    PubMedGoogle Scholar
  • 64 Barker D J, Bull A R, Osmond C et al.. Fetal and placental size and risk of hypertension in adult life.  BMJ. 1990;  301 259-262
    CrossrefPubMedGoogle Scholar
  • 65 Huxley R R, Shiell A W, Law C M. The role of size at birth and postnatal catch-up growth in determining systolic blood pressure: a systematic review of the literature.  J Hypertens. 2000;  18 815-831
    CrossrefPubMedGoogle Scholar
  • 66 Reinisch J M, Simon N G, Karow W G et al.. Prenatal exposure to prednisone in humans and animals retards intrauterine growth.  Science. 1978;  202 436-438
    CrossrefPubMedGoogle Scholar
  • 67 Benediktsson R, Lindsay R S, Noble J et al.. Glucocorticoid exposure in utero: new model for adult hypertension.  Lancet. 1993;  341 339-341
    CrossrefPubMedGoogle Scholar
  • 68 Lindsay R S, Lindsay R M, Waddell B J et al.. Prenatal glucocorticoid exposure leads to offspring hyperglycaemia in the rat: studies with the 11 beta-hydroxysteroid dehydrogenase inhibitor carbenoxolone.  Diabetologia. 1996;  39 1299-1305
    CrossrefPubMedGoogle Scholar
  • 69 Stewart P M, Rogerson F M, Mason J I. Type 2 11 beta-hydroxysteroid dehydrogenase messenger ribonucleic acid and activity in human placenta and fetal membranes: its relationship to birth weight and putative role in fetal adrenal steroidogenesis.  J Clin Endocrinol Metab. 1995;  80 885-890
    CrossrefPubMedGoogle Scholar
  • 70 Strandberg T E, Jarvenpaa A L, Vanhanen H et al.. Birth outcome in relation to licorice consumption during pregnancy.  Am J Epidemiol. 2001;  153 1085-1088
    CrossrefPubMedGoogle Scholar

Stan H.M van UumM.D. Ph.D.  Assistant Professor

Endocrinology and Metabolism, Department of Medicine, University of Western Ontario

St. Joseph's Health Centre, Room G401, 268 Grosvenor St.

London, Ontario N6A 4V2, Canada