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The role of renal II β-HSD2 deficiency on hypokalemia induced by furosemide and essential hypertensive disease

Author: YaoBing
Tutor: ZhangYinZuo
School: Nanjing Medical University
Course: Pharmacology
Keywords: 11 β -hydroxysteroid dehydrogenase apparent mineralocorticoid excess essential hypertension HPLC hypokalemia furosemide indapamide glycyrrhizic acid cortisol cortisone corticosterone dehydrocorticosterone
CLC: R965
Type: PhD thesis
Year: 2001
Downloads: 63
Quote: 0
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Abstract


The role of renal 1113 -H7SD2 deficiency inhypokalemia induced by furosemideand essential hypertensive diseaseABSTRACTBackgroundThe 1113 -hydroxysteroid dehydrogenase (11 13 -HSD) is an important microsome enzyme which converts of glucocorticoids [corticosterone(B) or cortisol(F)] to their inactive metabolites [11dehydrocorticosterone(A) and cortisone(E)], protects the nonselective mineralo-corticoid receptor from occupation by cortisoL The congenital deficiency of 11 13 -HSD induced hypertension and hypokalemia. This disorder is called “apparent mineralocorticoid excess”(AME). There have been reported about 50 cases of AME patients worldwide since Ulick reported the first AME case in 1977. Benediktsson reported that one-third of essential hypertensives had deficient 1113 -HSD in 1994. So that recent studies have been thrown more light on the pathological roles played by the 1113 -HSD deficiency in essential hypertension. The patients suffering from essential hypertension has been estimated approximately a hundred million in our country, The investigation on the renal 1113 -HSD activity not only enables us to discover the congenital deficiency of 1113 -HSD in Chinese people, but also provide good evidence to elucidate the role of 1113 -HSD in essential hypertensive pathogenesis. Otherwise several endo- and xenobiotics including glycyrrhizic acid, gossypol and bile acids have been found to modulate the activity of 11 f3 -HSD and caused excess mineralocorticoid effect and hypokalemia. Our previous study showed that furosemide (Fur) inhibited 1113 -HSD activity in guinea pig kidney. But it has not beenreported that the correlation betWeen the change of 1l 0 -HSDactivity and hyPokalemia by furosemide in intact rats and its effect onhuman renal microsome preparation. The aim of this study is also toestablish the possible new mechanism of hypokalemia induced byFurosmide.Objectives1. To investigate 1l 0 -hydroxystYoid dehydrogenase activity in vivoand in vitYo Stlldies, an exact precision reproducible HPLC assaywas developed for measuring the ratio of cortisol to cortisone (F/E)or dehydrocorticosterone to corticosterone (Mi).2. Furosemide was given by gavage to rats in order to evaluate theeffect of furosemide on l1 6 -hydroXysteroid dehydrogenaseactivity and blood pressure, serum electrolyte in intact rats, and toinvestigate the novel mechanism of hypokalemia by furosemide.3. Human renal cortex microsome preparation was used as anenZyme source to study the effects of furosemide, indopamide(Ind) and caPtopril on l l 0 -HSD activity.4. The urinary ratio of F/E was assayed in essential hyPertensionand healthy volunteers to investigate their difference ofrena1 l l 0-HSD activity and discover the cases of apparent minealocorticoidexcess by epidemio1ogical survery.5. To study the effect of indaPamide on human serum potassium andrenal 1l 0 -HSD activity after long term medication.Methods1. The HPLC aPparatus consisted of a mode1 Shidzu LC-l0ADsolvent delivery system, SPD-l0A ultraviolet detector and C-R2AX IntergraPh, the stainless steel Zorbax ODS column. Themobile phase contained methano1-water gradient delivery intemalstandard quanitative calculation method. The activity of l1 0 -HSD was evaluated by measuring the ratio ofdehydrocorticosterone to corticosterone or cortisol to cortisone.72. SD rats were given Fur single dose (40, 100, and 250 mg’ kg’) or. esuccessive dose (10, 20, and l00 mg kg-’, bid x 20 d) by gavage.The activity of l l 0 -HSD was eva1uated by measuring the fatio ofdehydrocorticoSterone to corticosterone in urine andconversion rate of corticosterone to dehydrocorticosterone onrenal cortex microsome preparation with above method.Autobiochemical aPparatus assayed the serum electrolytes. Theblood pressure of rat was measured by tail-cuff pulse-sphygmograPhic method using HX- II sphygmomanometers. Theaim was to study the iflteraction and relation betWeen the cha

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