zyxwvutsrqpo zyxwvuts zyxwv zyxwv Clinical und Experimental Pharmacology and Physiology (1998) 25 (Suppl.), SSl-S56 zyxwvuts zyxwvuts CORTISOL AND HYPERTENSION JJ Kelly, G Mangos, PM Williamson and JA Whitworth" Departments of Medicine and Renal Medicine, St George Hospital, University of New South Wales, Sydney, New South Wales and "Chief Medical OfJicer, Department of Health and Family Services, Canberra, Australian Capital Territory, Australia SUMMARY reproduced by infusion of the major ovine adrenal product cortisol at rates appropriate to achieve blood concentrations of cortisol similar to those found under conditions of ACTH stimulation.3 The dose of cortisol used in these studies was 5 mg/h or around 3 mgkg per day. At this infusion rate, cortisol did increase mean arterial pressure (MAP), but the effect was not equivalent to that produced by ACTH. Blood pressure was elevated within 24 h, but the rise in pressure was of the order of 10 mmHg compared with the 20 mmHg rise seen with ACTH.4 We then looked at the effects of a higher infusion rate (20 mg/h or approximately 12 mgkg per day) and found that this raised pressure by almost 30 mmHg over a 5 day period (Fig. 1) and that the metabolic effects of cortisol at this dose were very similar to those of ACTH! Thus, it was apparent from these early studies that cortisol, given at a high enough dose, could elevate BP substantially in the sheep, but that the BP-raising effects of ACTH could not be explained simply in terms of ACTH-induced cortisol secretion. zyxwvu 1. In humans, the hypertensive effects of adrenocorticotropic hormone (ACTH) infusion are reproduced by intravenous or oral cortisol. Oral cortisol increases blood pressure in a dosedependent fashion. At a dose of 80-200mg/day, the peak increases in systolic pressure are of the order of 15mmHg. Increases in blood pressure are apparent within 24 h. 2. Cortisol-inducedhypertensionis accompanied by a significant sodium retention and volume expansion. Co-administration of the type I (mineralocorticoid) receptor antagonist spironolactone does not prevent the onset of cortisol-induced hypertension. Thus, sodium retention is not the primary mechanism of cortisol-induced hypertension. 3. Direct and indirect measures of sympathetic activity are unchanged or suppressed during cortisol administration, suggesting that cortisol-induced hypertension is not mediated by increased sympathetic tone. 4. Preliminary evidencein humans suggests that suppression of the nitric oxide system may play a role in cortisol-induced hypertension. 5. These potential mechanisms of cortisol action may be relevant in a number of clinical contexts, including Cushing's syndrome, apparent mineralocorticoidexcess, the hypertension of liquorice abuse and chronic renal failure. There is also preliminary evidence suggesting a role for cortisol in essential hypertension. Key words: cortisol, Cushing's syndrome, hypertension. STUDIES I N HUMANS INTRODUCTION This work had its origins in studies undertaken by the senior author (JAW) at the Howard Florey Institute from 1975 on, originally as a PhD student under the supervision of John Coghlan' and from 1978 as a research associate. Early studies at the Howard Florey Institute in the late 1960s and early 1970s on the effects of adrenocorticotrophic hormone (ACTH) on steroidogenesis showed that ACTH administration produced a rapid-onset sustained hypertension in conscious sheep; but the blood pressure (BP)-raising effects of ACTH in sheep could not be Early studies of the effects of ACTH in human subjects (normal, essential hypertension and Addison's disease) at the Royal Melbourne Hospital, in association with the Howard Florey Institute, showed that ACTH produced effects similar to those seen in sheep, with a rapid-onset sustained adrenally dependent hypertension accompanied by salt and water retention, hypernatraemia and hyp~kalaemia.~ The key difference was that in humans the hypertension produced by ACTH administration could be reproduced by cortisol, whether administered intravenously6or orally7at doses that produced plasma concentrations seen with ACTH treatment. Cortisol increases BP in a dose-dependent fashion.' At a physiological replacement dose (40 mg/day) no change in BP is apparent, whereas at doses of 80 and 200 mg/day significant increases in systolic BP (SBP; 10-16 mmHg), MAP(10-12 mmHg) and diastolic BP(DBP; 4-10 mmHg) occur over a 5 day peri~d.~.' Increases in BP occur within 24 h and the peak response is usually observed on day 4 or S of treatment. Accordingly, our more recent studies have focused on mechanisms of cortisol-induced hypertension in humans. zyxwvut MECHANISMS OF CORTISOL-INDUCED HYPERTENSION Role of sodium -~ Correspondence:Dr John Kelly, Department of Renal Medicine, St George Hospital, Kogarah, NSW 2217, Australia. Email: <jkelly@s056.aone.net.au> Received 31 October 1998; accepted 30 June 1998. Significant sodium retention accompanies the rise in BP during cortisol treatment. Bodyweight increases by 1-2 kg on average and there are initial reductions in urine sodium e~cretion.~.' In both S52 zyxwvutsrqpo zyxwvuts JJ Kelly et al. zyxwvutsr z ACTH- and cortisol-treated subjects, plasma volume, extracellular fluid volume and exchangeable sodium are significantly increased?,* In keeping with this positive sodium balance and volume expansion, plasma renin, angiotensin I1 (AngII) and aldosterone concentrations are reduced and atrial natriuretic ~. peptide is i n ~ r e a s e d . ~ , ~ h rn I E E v Q. m v) Despite these changes, cortisol-induced hypertension is not primarily mediated by sodium retention, as demonstrated by coadministration of the type I (mineralocorticoid) receptor antagonist spironolactone at 400 mg/day,8 a dose that antagonizes the sodium retaining effects of the synthetic mineralocorticoid 9'-fludrocortisone at 3 mg/day. Blood pressure rose with cortisol and spironolactone treatment, despite evidence of adequate type I receptor blockade (i.e. no change in bodyweight and no suppression of plasma renin and aldosterone concentrations; Fig. 2). This is analogous to changes observed in ACTH hypertension in humans, where reducing dietary sodium from high (200 mmoyday) to average (150 mollday) or low (15 mmoUday) intakes reduces, but does not abolish, the increase in BP observed (ASBP 30,20 and 12 mmHg at these sodium intakes, respectively).' Thus, while sodium retention amplifies the hypertensive effects of ACTH or cortisol, it is not the primary mechanism by which hypertension occurs. zyxwvu zyxwvutsrqp Haemodynamic effects E2 E3 E4 Treatment day Increases in cardiac output of approximately 1 L/min during cortisol treatment have been demonstrated using the Fick technique or echocardiography Doppler." Heart rate (HR) is unchanged and the increase in cardiac output is primarily due to an increase in stroke volume accompanying the expansion of plasma volume. Calculated total peripheral resistance (CTPR) does not change;" however, significant changes in regional circulation do occur with an increase in vascular (Fig. 3).7 zyxwvutsrqp zyxwvutsrqpon E5 Fig. 1 Systolic blood pressure (SBP)-raising effects of cortisol infusions (0, 20mgih; B, Smgih) in sheep (from Whitworth et ~ 1 . 4 ) .*P<0.05, **P<0.01 compared with control. C, control; El, E2, E3, E4, E5, treatment days I , 2, 3, 4 and 5 with cortisol; P,values 2 days after cessation of all treatment. However' cortisol-induced hypertension is not dependent On increased Cardiac output. fietreatment with the P-adrenoreceptor antagonist atenolol prevents the increase in cardiac output, but does . . . . . . . . . . . . . . . . . . . . . . . . . . . ; Spironolactone (400 mg/day) ; Fig. 2 Systolic blood pressure (SBP), bodyweight and plasma renin concentration (PRC) during co-administrationof PRC AngI/mL per Control Sp El €3 E5 P spironolactone and cortisol. Sp, first day of spironolactone treatment; El, E3, ES, treatment days 1, 3 and 5 with cortisol (80 mg/day); P, values 2 days after cessation of all treatment. *P<O.OS compared with control. zyxwvutsr zyxwvu z s53 Cortisol and hypertension not prevent the rise in BP." In this experimental setting, the rise in BP is associated with an increase in CTPR, but when the increase in CTPR is prevented by pretreatment with the calcium channel antagonist felodipine, no effect on cortisol-induced hypertension is observed." These studies are open to several interpretations. One is that the hypertensive effects of cortisol are mediated centrally (e.g. by increased sympathetic activity) so that in ordinary circumstances the rise in BP is mediated by an increase in cardiac output but, if the rise in cardiac output is prevented, then the central signal is translated to an increase in vascular resistance. Another interpretation is that the rise in BP is critically dependent on an increase in regional vascular resistance rather than in TPR. For example, renal vascular resistance is increased by cortisol and, although felodipine at the dose of 5 mg/day used in the aforementioned study prevented the increase in CTPR," the dose may not have been sufficient to prevent a rise in renal vascular resistance. Sympathetic nervous system The role of the sympathetic nervous system (SNS) has been examined using a variety of direct and indirect measurements of resting sympathetic tone. Early studies demonstrated that plasma noradrenaline (NA) and adrenaline concentrations are not altered by cortisol admini~tration.~ Similarly, measurement of plasma immunoreactivity of the cotransmitter neuropeptide Y (NPY) is also unchanged by cortisol, although there is a rebound in plasma NPYlike immunoreactivity following cortisol withdrawal.'* These results argue against an increase in SNS activity and have been confirmed by forearm NA spillover measurements, which are unchanged by cortiso~.'~ We have also examined reflex sympathetic responses to passive head tilt, isometric exercise (30%maximal hand grip), mental arithmetic and cold pressor s t i m ~ l u s .There ' ~ was no increase in the pulse or BP responses to these stimuli and the BP response to cold pressor stimulus was slightly attenuated by cortisol, suggesting a reduction in sympathetic tone. This is supported by observations that the pressor response and baroreflex HR response to phenylephrine (PE) are augmented during cortisol treatment. More recently, we have demonstrated significant suppression of resting muscle sympathetic nerve activity using microneurographic recordings from the common peroneal nerve.I5 Collectively, these observations demonstrate that cortisol-induced hypertension is not mediated by increased sympathetic tone. In fact, autonomic blockade in supine young subjects treated with cortisol produced significant elevation of BP and HR, suggesting that autonomic tone modulates the rise in BP that occurs during cortisol treatment.I6 z Vascular reactivity zyxwvutsrq zyxwvuts zyxwvut * zyxwvutsrqpo zyxwvu I h I" € E v a cn loo- 50 - 0 0.12 (b) i 0.10 0.08 I (I > Ix A role for glucocorticoids in modulating vascular function is suggested by a number of observations. Glucocorticoid receptors are widely distributed in the vasculature and, in the rat, 11P-hydroxy steroid dehydrogenase (1 1PHSD) is distributed in resistance vessels where it is appropriately sited to modulate access of glucocorticoids to vascular receptor^.'^ Topical application of glucocorticoids results in dermal vasoconstriction, supporting an interaction between glucocorticoid administration and enhanced vascular reactivity." Our studies in humans point to alterations in vascular responsiveness to endogenous pressor and dilator agonists as a possible pathophysiological mechanism of cortisol-induced hypertension. Pressor responsiveness to systemic administration of PE and, to a lesser extent, AngII is enhanced and forearm vascular responsiveness to intraarterial NA is also enhanced.I3 These effects do not appear to be sufficient, in themselves, to cause hypertension. Increased pressor responsiveness to these agonists may simply reflect compensatory responses to suppression of the SNS and reninangiotensin system. Our more recent data'9.20suggest a role for the nitric oxide system in ACTH and cortisol-induced hypertension. Experiments in this area have been prompted by observations in rats, where ACTH treatment suppresses plasma reactive nitrogen intermediates in comparison with sham treatment. l 9 Feeding L-arginine to ACTH-treated rats prevents ACTH hypertension but not ACTH metabolic effects, whereas D-arginine has no effect." In cortisol-treated humans, we have preliminary evidence of suppression of the nitric oxide (NO) system. In subjects placed on a nitrate-exclusion diet (to reduce the confounding effects of dietary nitrate on measurements of plasma reactive nitrogen intermediates), significant reductions in plasma nitratehitrite concentrations are apparent during cortisol treatment.20 As well as assessing these biochemical markers of the NO system, we have studied a physiological end-point of NO action, 0.08 0.04 0.02 0.00 Fig. 3 Changes in (a) systolic blood pressure (SBP) and (b) renal vascular resistance (RVR; resistance units) during cortisol treatment (200 mg/day for 5 days; M). *P<0.05compared with control (0). s54 zyxwvutsrqp zyxwvutsrqp JJ Kelly et al. acetylcholine (ACh)-induced vasodilatation in the forearm vascular bed (GJ Mangos et aZ., unpubl. data). In crossover studies, forearm blood flow measured by venous occlusion plethysmography was compared on day 5 of cortisol and placebo treatment in response to intrabrachial artery infusions of ACh. Significant suppression of the ACh vasodilator response was observed in cortisol-treated subjects that was similar in degree to the reduction in ACh-induced vasodilatation observed following infusion of the NO synthase (NOS) antagonist I@-monomethyl -L-arginine. Collectively, these observations point to a role for the NO system as a possible mediator of cortisol-induced hypertension. The mechanism by which cortisol inhibits the NO system in vivo is unclear. In subjects on a low-nitrate diet, we did not observe any reduction in plasma arginine concentration or any increase in the endogenous NOS inhibitor asymmetrical dimethyl arginine.20These observations suggest that substrate availability or induction of NOS inhibitors are not the mechanisms by which cortisol suppresses the NO system. Glucocorticoids have complex effects on the NO system in vitro, including inhibition of the inducible NOS isoform (iNOS), inhibition of transmembrane arginine transport and inhibition of the enzymes involved in de novo synthesis of arginine.21*22 While the iNOS has not been implicated in the basal regulation of vascular tone, inhibition of transmembrane arginine transport or de novo intracellular arginine synthesis are possible mechanisms by which cortisol may suppress vascular NO system activity and, thus, elevate BP. APPARENT MINERALOCORTICOID EXCESS Apparent mineralocorticoid excess (AME) is a rare form of hypertension associated usually with defects of the enzyme complex 11pHSD.3"*3'Apparent mineralocorticoid excess is characterized by decreased metabolic clearance of cortisol with prolonged cortisol half-life. The enzyme llPHSD functions as a tissue-specific protector of the type I mineralocorticoid receptor by exclusion of endogenous glucocorticoid. In the absence of this protection, tissues are exposed locally to excess cortisol. In the kidney, excess cortisol produces sodium retention and it has been assumed that this is the mechanism of the h y p e r t e n ~ i o n ? ~ ~ ~ However, there are features of AME that are not explained by the action of cortisol on the type 1 glucocorticoid receptor. First, the classic mineralocorticoid receptor agonists, such as aldosterone and deoxycorticosterone, produce profound and rapid urinary sodium retention, but the rise in BP is very gradual, appearing over ~ e e k s . 3 ~ The BP-raising effects of cortisol, in contrast, are apparent within 24h6s7 in normal subjects and, in subjects with AME, they are apparent within a few days?4 Second, although spironolactone can ameliorate the hypertension in AME, its effects are incomplete and may not be s u ~ t a i n e dThe . ~ partial ~ ~ ~ ~effects ~ ~ ~of spironolactone in AME could be explained simply by the natriuretic effect of the drug, which is known to be effective in non-steroid forms of hypertenion:^ As outlined previously, while sodium retention may amplify ACTH- or cortisol-induced hypertension, it is not the primary mechanism by which hypertension occurs. Thus, the spironolactone effect in AME could be due to modification of the sodium-dependent component of the hypertension. Third, we have shown that synthetic steroids with glucocorticoid activity but no in vivo mineralocorticoid activity can raise BP in the absence of any sodium retention or volume expansion38 so, clearly, the rise in BP can be independent of urinary sodium retention. Thus, the BP-raising effects of cortisol in AME are not simply a consequence of sodium retention. zyxwvut zyxwvutsrqpo zyx zyxwvuts CUSHING'S SYNDROME Cushing's syndrome is a condition of cortisol excess with clinical features of hypertension, susceptibility to infection, moon face, truncal obesity, abdominal striae, hirsutism, plethora, hyperglycaemia, glucose intolerance and diabetes, cataracts, purpura, myopathy, osteoporosis and renal calculi. It is usually due to ACTH excess, which may be either from pituitary oversecretion or ectopic production, or, less commonly, due to an adrenal tumour with excess steroid production. The most common cause of naturally occurring Cushing's syndrome is pituitary ACTH excess or Cushing's disease, responsible for some two-thirds of cases. The excess ACTH secretion leads to bilateral adrenal hyperplasia. The pituitary usually contains a micro-adenoma, either chromophobe or basophil, hut approximately 10% will have adenomas of sufficient size to enlarge the pituitary fossa.23The iatrogenic form due to therapy with synthetic glucocorticoids or ACTH administration is frequent. Although hypertension is common in Cushing's syndrome Cushing's syndrome is a rare cause of clinical hypertension, affecting less than 0.1% of the population.23The diagnosis is usually obvious clinically in the patient presenting with hypertension, but the obese hypertensive patient with glucose intolerance or Syndrome X may provide diagnostic difficulty. Cardiovascular morbidity and mortality is very high and prolonged corticosteroid excess is associated not only with hypertension, but also hypercholesterolaemia, hypertriglyceridaemia, impairment of glucose tolerance and accelerated ather~sclerosis?~ The hypertension of Cushing's syndrome is explicable in terms of the cortisol excess.26327 In patients with ectopic ACTH production, hypertension is less of a feature2*and is thought to be a consequence of cortisol inactivation overload giving rise to mineralocorticoid effects through cortisol occupancy of mineralocorticoid receptor^.'^ LICORICE ABUSE Regular intake of licorice has long been known to ameliorate the symptoms of Addison's disease and produce hypokalaemic alkalosis and hypertension in otherwise normal subjects. The active component, glycyerrhetinic acid, was originally thought to act through weak binding to type 1 mineralocorticoid receptor but, more recently, abnormalities of 11 PHSD activity or cortisol metabolism have been shown in the hypertension of liquorice abuse.39 This form of hypertension differs in some respects from cortisolinduced hypertension, as described earlier, in that it is slow in onset and has features of a mineralocorticoid-type hypertension. Thus, the evidence suggests that, in this condition, cortisol is exerting its effects through occupancy of mineralocorticoid receptor. CHRONIC RENAL FAILURE Hypertension is extremely common in chronic renal failure and most patients entering end-stage renal failure programmes are hypertensive. It has been known for many years that cortisol half-life is prolonged in chronic renal failure.4o34'We found an inverse correlation between plasma creatinine and cortisol concentrations in 88 patients with proven renal disease and concluded that the kidney is the major site of conversion of cortisol to cortisone in humans.42 We speculated that renal parenchymal disease z zyxwvutsrq s55 Cortisol and hypertension and hypertension may be related through loss of renal llPHSD activity and functional cortisol excess. ESSENTIAL HYPERTENSION Evidence implicating adrenocorticoidsin the pathogenesis of essential hypertension remains preliminary, but intriguing. Patients with essential hypertension do not have obvious signs of mineralocorticoid excess; however, some observers have noted a positive correlation between BP and body sodium and a negative correlation between BP and potassium in essential hyperten~ion?~ Moreover, the insulin resistance syndrome (elevated BP, central obesity, dyslipidaemia and impaired glucose tolerance)44in some patients with essential hypertension bears similarities to the metabolic abnormalities of Cushing’s syndrome. Patients with essential hypertension demonstrate small but significant reductions in BP in response to ACTH suppression by dexamethasone (0.5 mg nocte), suggesting that the hypothalamicpituitary-adrenal axis may contribute to the hyperten~ion.~~ Intriguing observations have been made with regard to 11PHSD activity in essential hypertension. Walker et a1!6 have reported prolonged cortisol half-life in patients with essential hypertension. Skin vasoconstrictor response to topical glucocorticoids was enhanced, but there was no biochemical evidence of mineralocorticoid excess.46 In a population of subjects with untreated hypertension, Soro et al. demonstrated an increased ratio of urinary cortisol to cortisone metabolites, suggesting a significantly lower 11 PHSD activity?’ Furthermore, an association has been noted between low birth weight or a low foeta1:placental weight ratio and the subsequent risk of developing hyperten~ion.~~ In rat models, there is a negative correlation between placental weight and placental 11PHSD activity and a positive correlation between birthweight and placental 11PHSD Rats treated with dexamethasone, which is not metabolized by 11PHSD, had offspring with lower birthweights and higher BP. These observations suggest that, in the rat, placental 1 1 PHSD may protect the foetoplacental unit against the glucocorticoid effects of corticosterone. Therefore, it has been hypothesized that variations in llPHSD activity may be one factor influencing foetal growth and, ultimately, adult BP.49350 Abnormalities of the glucocorticoid receptor in essential hypertension were observed in a study by Watt et al. using a novel ‘fourcomer’ study design to investigate familial influences on BP.5’ Subjects whose parents had high BP and whose personal BP was at the high end of their peer group had an increased frequency of a glucocorticoid receptor restriction fragment length polymorphism genotype (AA) compared with subjects whose parents had a low BP and whose personal BP was also REFERENCES 1. Whitworth JA. Steroids and hypertension in sheep. PhD thesis, University of Melbourne, Melbourne, Vic., Australia. 1978. 2. Scoggins BA, Coghlan JP, Denton DA et al. Metabolic effects of ACTH in the sheep. Am. J. Physiol. 1974; 226: 198-205. 3. Fan JS, Coghlan JP, Denton DA, Oddie C, Scoggins BA, Shulkes AA. Effects of intravenous infusion of corticosteroids on blood pressure, electrolytes, and water metabolism in sheep.Am J. Physiol. 1975; 228: 1695-701. 4. Whitworth JA, Coghlan JP, Denton DA, Graham WF, Humphery TJ, Scoggins BA. Comparisons of the effects of glucocorticoid and mineralocorticoid infusions on blood pressure in sheep. Clin. Exp. Hypertens. 1979; 1: 649-63. 5. Whitworth JA, Thatcher R, Scoggins BA. Blood pressure and metabolic effects of ACTH in normotensive and hypertensive man. Clin. Exp. Hypertens. 1983; 5: 501-22. 6. Whitworth JA, Saines D, Scoggins BA. Blood pressure and metabolic effects of cortisol and deoxycorticosterone in man. Clin.Exp. Hypertern. 1984; 6: 795-809. 7. Connell JMC, Whitworth JA, Davis DL, LeverAF, Richards AM, Fraser R. The effects of ACTH and cortisol administration on blood pressure, electrolyte metabolism, atrial natriuretic peptide and renal function in normal man. J. Hypertens. 1987; 5 : 425-33. 8. Williamson PM, Kelly JJ, Whitworth JA. Dose response relationships and mineralocorticoid activity in cortisol induced hypertension in humans. J. Hypertens. (Suppl.) 1996; 1 4 537-41. 9. Connell JMC, Whitworth JA, Davies DL, Richards AM, Fraser R. Haemodynamic hormonal and renal effects of ACTH in sodium restricted man. J. Hypertens. 1988; 6: 17-23. 10. Pirpiris M, Yeung S, Dewar E, Jennings GL, Whitworth JA. Hydrocortisone-inducedhypertension in man: The role of cardiac output. Am. J. Hypertens. 1993; 6: 287-94. 11. Whitworth JA, Williamson PM, Ramsay D. Haemodynamic responses to cortisol in man: Effects of felodipine. Hypertens. Res. 1994; 17: 13742. 12. Whitworth JA, Williamson PM, Brown MA, Morris MJ. Neuropeptide Y in cortisol-induced hypertension in male volunteers. Clin. Exp. Phannacol. Physiol. 1994; 21: 435-8. 13. Pirpiris M, Sudhir K, Yeung S, Jennings G, Whitworth JA. Pressor responsiveness in cortisol-induced hypertension in humans. Hypertension 1991; 19: 1129-36. 14. 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L-Arginine prevents corticotrophin-induced increases in blood pressure in the rat. Hypertension 1996; 27: 184-9. 20. Kelly JJ, Tam SH, Williamson PM, Lawson J, Whitworth JA. The nitric oxide system and cortisol induced hypertension in humans. Clin. Exp. Pharmacol. Physiol. 1998 (in press). 21. Radonski MW, Palmer RMJ, Moncada S. Glucocorticoids inhibit the expression of an inducible but not constitutive nitric oxide synthase in vascularendothelial cells. Proc. NatlAcad. Sci. USA 1990;8 2 10043-7. 22. Simmons WW, Ungureanu-Longrois D, Smith GK, Smith TW, Kelly zyx zyxwv zyxwv zyxwvutsrq CONCLUSION Cortisol-induced hypertension may be much more common than previously thought. Our studies of the role of cortisol in the production of hypertension have become of increasing relevance with the discovery that relative or local cortisol excess may be responsible for hypertension in a variety of clinical situations. 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