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Effect of Aminoglutethimide on Blood Pressure and Steroid Secretion in Patients with Low Renin Essential Hypertension

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Effect of Aminoglutethimide on Blood Pressure and Steroid Secretion in Patients with Low Renin Essential Hypertension Effect of Aminoglutethimide on Blood Pressure and Steroid Secretion in Patients with Low Renin Essential Hypertension Addison A. Taylor, … , John R. Gill Jr., Ronald B. Franklin J Clin Invest. 1978;62(1):162-168. https://doi.org/10.1172/JCI109101. Research Article An inhibitor of adrenal steroid biosynthesis, aminoglutethimide, was administered to seven patients with low renin essential hypertension, and the antihypertensive action of the drug was compared with its effects on adrenal steroid production. In all patients aldosterone concentrations in plasma and urine were within normal limits before the study. Mean arterial pressure was reduced from a pretreatment value of 117±2 (mean±SE) mm Hg to 108±3 mm Hg after 4 days of aminoglutethimide therapy and further to 99±3 mm Hg when drug administration was stopped (usually 21 days). Body weight was also reduced from 81.6±7.2 kg in the control period to 80.6±7.0 kg after 4 days of drug treatment and to 80.1±6.7 kg at the termination of therapy. Plasma renin activity was not significantly increased after 4 days of treatment but had risen to the normal range by the termination of aminoglutethimide therapy. Mean plasma concentrations of deoxycorticosterone and cortisol were unchanged during aminoglutethimide treatment whereas those of 18- hydroxydeoxycorticosterone, progesterone, 17α-hydroxyprogesterone, and 11-deoxycortisol were increased as compared to pretreatment values. In contrast, aminoglutethimide treatment reduced mean plasma aldosterone concentrations to about 30% of control values. Excretion rates of 16β-hydroxydehydroepiandrosterone, 16-oxo-androstenediol, 17- hydroxycorticosteroids and 17-ketosteroids, and the secretion rate of 16β-hydroxydehydroepiandrosterone were not significantly altered by aminoglutethimide treatment whereas the excretion rate of aldosterone was reduced from 3.62±0.5 (mean±SE) in the control period […] Find the latest version: https://jci.me/109101/pdf Effect of Aminoglutethimide on Blood Pressure and Steroid Secretion in Patients with Low Renin Essential Hypertension ADDISON A. TAYLOR, JERRY R. MITCHELL, FREDERIC C. BARTTER, WAYNE R. SNODGRASS, RANDOLPH J. MCMURTRY, JOHN R. GILL, JR., and RONALD B. FRANKLIN, Section on Steroid and Mineral Metabolism, Hyper- tension-Endocrine Branch, and Section on Clinical Pharmacology and Metabolism, Office of Director of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland 20014 A B S T R A C T An inhibitor of adrenal steroid bio- rate of 16,8-hydroxydehydroepiandrosterone were not synthesis, aminoglutethimide, was administered to significantly altered by aminoglutethimide treatment seven patients with low renin essential hypertension, whereas the excretion rate of aldosterone was re- and the antihypertensive action of the drug was duced from 3.62+0.5 (mean+SE) in the control period compared with its effects on adrenal steroid produc- to 0.9+0.2 ,ug/24 h after 4 days and to 1.1±0.3 ,ug/24 h tion. In all patients aldosterone concentrations in at the termination of aminoglutethimide treatment. plasma and urine were within normal limits before The gradual lowering of blood pressure and body the study. Mean arterial pressure was reduced from a weight during aminoglutethimide therapy is consistent pretreatment value of 117+2 (mean±SE) mm Hg to with the view that the antihypertensive effect of 108±3 mm Hg after 4 days of aminoglutethimide the drug is mediated through a reduction in the pa- therapy and further to 99±3 mm Hg when drug tients' extracellular fluid volume, probably secondary administration was stopped (usually 21 days). Body to the persistent decrease in aldosterone production. weight was also reduced from 81.6±7.2 kg in the The observation that chronic administration of amino- control period to 80.6±7.0 kg after 4 days of drug glutethimide lowered blood pressure in these patients treatment and to 80.1±6.7 kg at the termination and elevated their plasma renin activity to the normal of therapy. Plasma renin activity was not significantly range without decreasing production of the adrenal increased after 4 days of treatment but had risen to steroids, deoxycorticosterone, 18-hydroxydeoxycorti- the normal range by the termination of amino- costerone, and 16,3-hydroxydehydroepiandrosterone, glutethimide therapy. Mean plasma concentrations of makes it unlikely that these steroids are responsible deoxycorticosterone and cortisol were unchanged dur- either for the decreased renin or the elevated blood ing aminoglutethimide treatment whereas those of pressure in patients with low renin essential hyper- 18-hydroxydeoxycorticosterone, progesterone, 17a-hy- tension. droxyprogesterone, and 1 1-deoxycortisol were in- creased as compared to pretreatment values. In INTRODUCTION contrast, aminoglutethimide treatment reduced mean plasma aldosterone concentrations to about 30% of Patients with hypertension and low plasma renin control values. Excretion rates of 16,8-hydroxydehydro- activity (PRA)' can be subdivided further into those epiandrosterone, 16-oxo-androstenediol, 17-hydroxy- with an elevated, normal, or reduced aldosterone ex- corticosteroids and 17-ketosteroids, and the secretion cretion rate. Patients in the first category have primary aldosteronism (1) whereas those in the last two categories mainly have low renin essential Part of this work has been published in abstract form. 1976. hyper- Clin. Res. 24: 424A. (Abstr.) Dr. Wayne Snodgrass was supported by a staff fellowship, 1Abbreviations used in this paper: DOC, deoxycortico- Pharmacology Research Associate Training Program, National sterone 17KS, 17-ketosteroids; 170HCS, 17-hydroxycortico- Institute of General Medical Sciences. steroids; 16,/-OH DHEA, 16,8-hydroxydehydroepiandroster- Received for publication 31 May 1977 and in revised form one; 18-OH DOC, 18-hydroxydeoxycorticosterone; PRA, 9 March 1978. plasma renin activity. 162 The Journal of Clinical Investigation Volume 62 July 1978 *162 -168 tension (2-5). The finding that low renin hyperten- was approved by the clinical research review committee of the sion was present in 9-50% of hypertensive patients, National Heart, Lung, and Blood Institute, and all patients gave written informed consent before participating in the study. depending upon the age of the population studied The patients were hospitalized and given a daily diet contain- (6, 7), generated considerable interest in the patho- ing 209 meq sodium to avoid stimulation of PRA. Urine was physiologic mechanisms which might contribute to a collected contintuously in 24-h aliquots for determinations of' low plasma renin. The report by \VToods et al. (8) creatiniine, sodium, potassiumil, 1 7-hvdroxycorticosteroids (170HCS), 17-ketosteroids (17KS) and aldosterone excretion that aminoglutethimide, an inhibitor of adrenal steroid rates. After overnight recumbency, blood was collected at 8 biosynthesis, normalized blood pressture in hyper- a.m. on the 3rd hospital day for PRA and f'or plasma steroids tensive patients wvith low PRA raised the possibility including aldosterone, progesterone, 17 a-hydroxyprogesterone, that these patients could be treated specifically. This DOC, 18-OH DOC, 11-deoxvcortisol, and cortisol. Patients possibility was supported by the finding that spiro- then stood until 12 noon at wlhich time blood was obtained f'or PRA and plasma steroids. Blood f'or measurement of'plasma nolactone, an antagonist of the renal action of aldo- steroids \vas obtained at 6 p.m. while posture was not con- sterone and other mineralocorticoid hormones, more trolled and again at 12 midnight and 6 a.m. after the patients effectively lowered blood pressure in patients with had retired to bed at 10 p.m. Blood xvas collected in tubes low vs. normal renin essential hypertension (9). Be- containing disodium EDTA for PRA determinations and in tubes containing heparin sodiutm for measurements of' plasma cause aldosterone production is not elevated in patients steroids. On the morning of'the 4th hospital day, each patient with low renin essential hypertension, an intensive was then given an intravenous injection of[3H]16,8-OH DHEA search for a new sodium retaining steroid other than and urine wvas collected for the subsequent 3 days for de- aldosterone was instituted. Subse(quently, increased termination of' secretory and excretory rates. Patients were secretion or excretion of (DOC) then given aminoglutethlimide, 250 mg, by mouth every 6 h, deoxycorticosterone and on the 4th day of adminoglutethimide treatment, blood (10), 18-hydroxydeoxycorticosterone (18-OH DOC) was again collected at the times and in the postures indicated (11, 12), and 16,3-hydroxydehydroepiandrosterone above f'or measurement of PRA and plasma steroids, and the (16,B-OH DHEA) (13) has been reported in groups of injection of' [3H]16,3-OH DHEA intravenously for determina- patients with low renin hypertension as compared to tion of' secretory and exeretory rates was repeated. Patients were then disciharged and followed in the outpatient clinic groups of patients with normal renin hypertension or at weeklv intervals f'or 3 wk. Patients recorded their blood normotensive subjects. However, no cause-and-effect pressures at home 2-4 times per day throughout the outpatient stuidies have been carried out to compare blood phase of the study. Patients cointinued to ingest a high sodium pressure changes and steroid secretion in the same diet at home. Two of the seven patients were readmitted to patients. In the present study, therefore, the effect of the hospital
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