原发性高血压患者醛固酮逃逸现象与左心室肥厚的关系

目的探讨原发性高血压(EH)患者使用血管紧张素转换酶抑制剂(ACEI)依那普利后并发的醛固酮逃逸及与左心室肥厚(LVH)的关系,并观察ACEI联合使用螺内酯后对醛固酮逃逸和LVH的效果。方法65例EH患者分为左心室肥厚组(LVH组)和非左心室肥厚组(NLVH组),使用依那普利。分别于治疗前及治疗后1、3、6个月采血检测血管紧张素Ⅱ(AngⅡ)、醛固酮(Ald)浓度,并用超声心动图测定左心室重量指数(LVMI)。根据3个月时的Ald浓度,判断有无醛固酮逃逸,对有醛固酮逃逸者,联合用螺内酯3个月,观察效果。结果依那普利治疗后1个月,AngⅡ、Ald与治疗前相比均下降,但3个月时,AngⅡ有所升高,Ald明显增高,65例中有28例并发醛固酮逃逸。治疗前LVH组的Ald明显高于NLVH组,LVMI与Ald呈明显的正相关;LVH组治疗3个月,无醛固酮逃逸者的LVMI与治疗前比较有显著下降,有醛固酮逃逸者LVMI变化不显著。结论EH患者长期使用ACEI后会出现醛固酮逃逸现象,Ald与EH合并的LVH有明显的相关性,ACEI能逆转EH所合并的LVH,但醛固酮逃逸能阻碍ACEI对LVH的逆转作用,ACEI联合使用螺内酯可能会改善醛固酮逃逸。     

The effect of saluretics and spironolactone on aldosterone production and electrolyte excretion in man

Summary Healthy volunteers received orally the saluretics furosemide (40 mg/day) and thiabutazide (10 mg/day) over a 5-day period, and the aldosterone antagonist spironolactone (5 mg and 10 mg/kg per day) over 7-and 3-day periods, respectively. On the first day of treatment both saluretics induced a marked increase in sodium and water excretion, but only a moderate increase in potassium excretion. On the second day, however, the sodium and water excretion had already returned to almost normal values, reaching a minimum after discontinuation of the saluretics. Under saluretic therapy, a steep increase in plasma aldosterone concentration and in urinary aldosterone was observed. After the saluretics were discontinued, both the markedly elevated plasma aldosterone concentration and the aldosterone excretion returned to normal within two days. Under saluretic therapy potassium excretion appeared to be aldosterone-dependent, since potassium excretion paralleled aldosterone excretion. Spironolactone (5 mg/kg oder a 7-day period) caused a moderate increase in sodium excretion and a moderate decrease in potassium excretion. Spironolactone (10 mg/kg over a 3-day period) caused a distinct increase in sodium excretion and a slight decrease in potassium excretion. Neither of the two spironolactone doses used here produced an increase in aldosterone excretion. After discontinuation of spironolactone, a rebound in aldosterone excretion was observed. The increase in aldosterone excretion was associated with corresponding changes in electrolyte excretion.The increase in aldosterone excretion and in plasma aldosterone concentration induced by the saluretic thiabutazide was markedly reduced by the administration of spironolactone (10 mg/kg). The sodium and water retention which was caused by the hyperaldosteronism, was almost completely abolished, and the increased potassium excretion returned to normal.This study was supported by the Deutsche Forschungsgemeinschaft     

Metabolic effects of high dose amiloride and spironolactone: a comparative study in normal subjects.

Amiloride (75 mg daily) and spironolactone (300 mg daily) were given to five normal subjects for 7 days in order to compare metabolic effects at maximal doses. Blood pressure, body weight, Na+ and K+ balance, and plasma concentrations of Na+, K+, active and total renin, angiotensin II, aldosterone, 11-deoxycorticosterone (DOC), 18-hydroxydeoxycorticosterone (18-OH DOC), corticosterone (B), 18-hydroxycorticosterone (18-OH B) and cortisol were measured before and on each day of treatment. Natriuresis and K+ retention were significantly greater with amiloride. Plasma K+ increased from 4.1 +/- 0.2 to 4.9 +/- 0.2 mmol/l (mean +/- s.d.) on amiloride and from 4.0 +/- 0.2 to 4.4 +/- 0.2 mmol/l with spironolactone. Stimulation of renin, angiotensin II, aldosterone and 18-OH B occurred with both drugs but was greater with amiloride in each case. A transient decrease in systolic and diastolic blood pressure was observed after 2 days of spironolactone treatment but not with amiloride. The slope of the regression of aldosterone on angiotensin II during spironolactone treatment was less than that with amiloride, consistent with partial blockade of aldosterone synthesis by spironolactone. These data suggest that the maximum metabolic effects of amiloride exceed those of spironolactone.     

伊贝沙坦对高血压患者醛固酮逃逸现象的影响

目的 探讨伊贝沙坦对高血压患者使用血管紧张素抑制剂(ACEI)后并发醛固酮(Ald)逃逸现象的影响.方法 166例高血压患者使用ACEI治疗3个月,放射免疫法测血浆醛固酮及血管紧张素Ⅱ浓度,根据醛固酮水平,判断有无并发醛固酮逃逸,对逃逸者加用伊贝沙坦治疗6个月,观察伊贝沙坦治疗后1、3、6个月对醛固酮逃逸现象的影响.结果 使用伊贝沙坦治疗后1个月,血浆醛固酮及血管紧张素Ⅱ浓度明显下降(P<0.01),3个月及6个月时回升,但仍然低于治疗前水平(P<0.01).至6个月时已经明显高于治疗后1、3个月水平(P<0.01),但是3个月与1个月时相比并无明显差异(P>0.05).结论 伊贝沙坦治疗后6个月内,可减少高血压患者并发醛固酮逃逸现象的发生;但6个月后可能再次出现醛固酮逃逸现象.     

Raised aldosterone to renin ratio predicts antihypertensive efficacy of spironolactone: a prospective cohort follow-up study

AIMS: Aldosterone/renin ratio is an index for inappropriate aldosterone activity, and it is increasingly being used to screen for primary aldosteronism within the hypertensive population. It may also be a good index to help predict the response to spironolactone. To assess the blood pressure response to oral spironolactone in hypertensive patients with primary aldosteronism identified with raised aldosterone to renin ratio. METHODS: We conducted a prospective cohort study of hypertensive patients with raised aldosterone/renin ratio, who failed to suppress plasma aldosterone with salt loading and fludrocortisone suppression test. These patients were treated with spironolactone and were followed-up for a period of up to 3 years. RESULTS: We studied 28 (12 male) subjects with a mean age of 55 (s.d. 10) years who were followed up for a mean period of 12.9 (7) months. At baseline, the patients were taking a mean of 2.1 (1.2) antihypertensive drugs, but despite this 16/28 (57%) had diastolic BP >90 mmHg, 39% with systolic BP >160 mmHg. After commencing spironolactone, three patients complained of breast tenderness but continued treatment and one patient was intolerant of spironolactone and had to stop treatment. Of the remaining 27 patients, the mean number of antihypertensive drugs used dropped to spironolactone plus 0.7 (s.d. 0.9). All but one patient (96%) achieved a diastolic BP相似文献   

The influence of enalapril or spironolactone on experimental cyclosporin nephrotoxicity

Adult Sprague-Dawley rats treated daily for 14 days with 50 mg/kg cyclosporin A (CsA) exhibited nephrotoxicity, characterized by reduced glomerular filtration rate, decreased urinary sodium and potassium flow, tubular enzymuria and proximal tubular structural damage. Elevations in plasma renin activity (PRA) were observed on day 4, but returned to normal within 7 days. Co-treatment of animals for the 14 day period with enalapril (8 mg/kg/day), a potent inhibitor of angiotensin converting enzyme (ACE), or spironolactone (25 mg/kg/day), the distal tubular antagonist of aldosterone, reduced the nephrotoxicity, although PRA remained elevated. Neither enalapril nor spironolactone affected circulating CsA levels. These data suggest that the action of aldosterone on the distal tubule may be important in the pathogenesis of CsA nephrotoxicity.     

贝那普利和螺内酯联合治疗糖尿病肾病的临床研究

目的:比较血管紧张素转换酶抑制剂(ACEIs)贝那普利和醛固酮受体阻滞剂螺内酯单独及联合治疗糖尿病肾病的疗效。方法:40例糖尿病肾病病人随机分为两组:联合治疗组20例,用贝那普利10 mg/d联合螺内酯20 mg/d治疗;贝那普利组20例,单用贝那普利10 mg/d。比较两组治疗前、治疗后1个月、治疗后3个月尿蛋白、血清肌酐、血钾变化。结果:治疗1个月后两组病人尿蛋白水平均明显下降,3个月后联合治疗组尿蛋白水平进一步下降,贝那普利组尿蛋白水平回升。两组病人的血清肌酐、血钾治疗前后均无明显变化。结论:糖尿病肾病病人长期应用ACEIs药物可出现尿蛋白定量水平反跳,该现象可能与醛固酮逃逸有关,联合服用醛固酮受体拮抗剂可改善该现象。     

Efficacy and safety of lasilactone,a new combination diuretic,in essential hypertension

1. Lasilactone, a new combination diuretic (furosemide 20 mg and spironolactone 50 mg) was evaluated in 30 patients with mild-to-moderate essential hypertension. Each patient received one capsule of lasilactone daily.2. Significant changes in BP were observed 1 week after initiation of therapy and were sustained during the observation period of 1 year.3. Supine and standing BP fell from 148.6 ± 2.6/102.1 ± 1.9 to 120.8 ± 1.4/91.7 ± 1.2 and from 154.4 ± 2.1/106.1 ± 1.6 to 125.7 ± 2.2/90.7 ± 1.5 mm Hg respectively.4. There were no changes in the concentrations of plasma glucose, lipids, uric acid and potassium. On the other hand, levels of plasma renin activity rose from 0.69 ± 0.06 to 3.95 ± 0.47 ng/ml/hr and urinary aldosterone excretory rate increased from 9.6 ± 1.6 to 42.8 ± 4.2 μg/day.5. This study suggests that addition of spironolactone to furosemide improves the hypotensive potency and minimizes the metabolic and electrolyte alterations of the latter.     

Anti-aldosteronergic effect of torasemide.

The diuretic actions of torasemide and furosemide were studied in normotensive rats and in deoxycorticosterone acetate (DOCA)-saline-loaded hypertensive rats. Torasemide (0.3-3 mg/kg) and furosemide (3-30 mg/kg) had a dose-dependent and significant diuretic action in normotensive rats. Potassium retention was only observed in the case of torasemide. Torasemide also had a dose-dependent and significant diuretic action in DOCA-saline-loaded hypertensive rats, whereas furosemide did not. Higher doses of torasemide (10 mg/kg) and furosemide (100 mg/kg) increased both plasma renin activity and aldosterone concentration in normotensive rats in a similar manner. In vivo aldosterone receptor binding was determined to test the possible anti-aldosteronergic effect of torasemide. Torasemide inhibited the binding of aldosterone to its receptor in the cytoplasmic fraction of rat kidney in a dose-dependent manner, while furosemide produced no effect. These results suggest strongly that an anti-aldosteronergic action of torasemide contributes to producing less kaliuresis.     

Combined effects of low-dose spironolactone and captopril therapy in a rat model of genetic hypertrophic cardiomyopathy

For several years, the severe side effects associated with the use of high doses of the aldosterone antagonist, spironolactone, limited its clinical use. Studies have recently shown efficacy and minimal side effects of low-dose spironolactone combined with standard therapy in the treatment of heart failure and hypertensive patients. The authors evaluated the effects of low-dose spironolactone alone or in combination with angiotensin-converting enzyme (ACE) inhibitors on the progression of left ventricular dysfunction and remodeling in a congenic rat model of hypertrophic cardiomyopathy.The congenic SS-16/Mcwi rats developed severe cardiac hypertrophy despite being normotensive even on high-salt diet. SS-16/Mcwi and SS/Mcwi rats were fed a low-salt (0.4% NaCl) diet and were treated with vehicle (CON), spironolactone (20 mg/kg/d subcutaneously), captopril (100 mg/kg/d drinking water), or both spironolactone and captopril for 4 weeks. Blood pressure, plasma peptides, cardiac fibrosis, and echocardiography measurements were evaluated.Spironolactone at a low dose had no effect on blood pressure, cardiac hypertrophy, and fibrosis in either strain. However, in combination with captopril, spironolactone decreased the cardiac hypertrophy more than captopril treatment alone. In the SS-16/Mcwi rats, the combined therapy significantly preserved the cardiac index when compared with control.These data indicate that the addition of low-dose spironolactone to captopril treatment was more effective in preventing the progression of heart hypertrophy and ventricular dysfunction in the SS-16/Mcwi than captopril alone. This study suggests that combined spironolactone and captopril therapy may be useful in the treatment of hypertrophic cardiomyopathy.     

Relative potency of prorenoate potassium and spironolactone in attenuating diuretic induced hypokalaemia

The plasma potassium responses to the aldosterone antagonists prorenoate K (10 mg/day and 40 mg/day) and spironolactone (25 mg/day and 100 mg/day) were compared following treatment for 11 days in combination with the diuretic metolazone (2.5 mg/day) in a double-blind crossover study in twelve healthy men. The best estimate of the potency of prorenoate K relative to spironolactone in attenuating metolazone induced hypokalaemia was 5.6 with 95% confidence limits 2.4-35.2. The method employed allowed a statistically valid quantitative comparison of the potassium sparing properties of the mineralocorticoid antagonists after repeated doses and may be useful in the preclinical evaluation of these drugs.     

Diuretic induced hypokalaemia: relationship to dosage interval and plasma aldosterone.

Plasma potassium and aldosterone responses to 9 days treatment with hydrochlorothiazide (100 mg/day) alone or in combination with spironolactone (100 mg/day), prescribed once daily or in doses 12 h apart, were examined in a double-blind, crossover study in twelve healthy subjects. Plasma potassium concentrations were lower when the drugs were administered 12 h apart (P less than 0.01). Spironolactone attenuated significantly hydrochlorothiazide induced hypokalaemia--mean rise in plasma potassium, 0.36 mmol/l (P less than 0.001). The increase in plasma aldosterone was greater following combination therapies (P less than 0.001), but there were no significant differences between once daily and twice daily regimens. We conclude that plasma potassium concentration is better maintained when diuretics are given once daily and that this is not related closely to differences in plasma aldosterone responses.     

血管紧张素转换酶抑制剂的肝脏水平醛固酮逃逸现象及其干预作用研究

目的 观察依那普利联合安体舒通(螺内酯)干预肝纤维化的作用是否伴有肝脏水平的“醛固酮逃逸”现象及醛固酮选逸对肝脏纤维化的影响.方法 应用40％四氯化碳(CCl4)灌胃建立大鼠肝纤维化模型,将60只雄性SD大鼠随机分为对照组(NC组)、模型组(Mo组)、依那普利组[En组,20 mg/(kg·d)]、依那普利联合安体舒通组[En+Sp组,20mg/(kg·d)+20 mg/(kg·d)].依那普利与安体舒通于造模同时连续灌胃给药,20周后处死大鼠.用放免法检测血浆、肝组织中血管紧张素Ⅱ( AngⅡ)、醛固酮水平.取肝组织,分别行苏木素伊红染色和马松三色染色,光镜下观察组织学改变.结果 En组、En+Sp组肝匀浆中AngⅡ和醛固酮的含量、肝纤维化程度明显低于Mo组.结论 依那普利在肝纤维化的防治中若长期使用同样存在肝脏水平的“醛固酮逃逸”现象,安体舒通与依那普利联用可以防止肝脏水平的“醛固酮逃逸”,并加强对肝纤维化的防治作用.     

Multiple dose kinetics of spironolactone and canrenoate-potassium in cardiac and hepatic failure

Summary Plasma concentrations of canrenone and canrenoate were measured in 43 patients treated with spironolactone 50–400 mg/day, and in one patient treated with canrenoate-K 3×200 mg/day. The cumulation of canrenone and canrenoate was followed in 9 patients recovering from myocardial infarction, without congestive heart failure or cirrhosis, who received spironolactone 2×100 mg/day. The cumulation half-life was 1–4 days, which may partly explain the delayed clinical action of spironolactone. The plasma elimination half-life of canrenone and canrenoate in six of these patients lay between 13.5 and 24 h. After 10 doses it was unchanged in three patients and had decreased only slightly in three others. Steady state minimum plasma levels of canrenone and canrenoate were measured in 33 patients with congestive heart failure or cirrhosis who received spironolactone 50–400 mg/day for at least three weeks. There was up to 15 fold inter-individual variation in the plasma levels of canrenone amongst those receiving spironolactone 200 mg/day. No statistically significant correlation was found between steady state levels of canrenone and plasma creatinine or the results of bromsulphalein liver function tests. In one patient with severe congestive heart failure given canrenoate-K 3×200 mg/day, cumulation of canrenone and canrenoate occurred for seven days, followed by a gradual decline in their plasma levels until the eleventh day of therapy. A loading dose is recommended for initiation of spironolactone therapy.     

Evaluation of the ASPIRANT trial

Several pathophysiological, clinical, and therapeutic features of resistant hypertension are far from being clearly defined. This is the case also for the efficacy of aldosterone receptor antagonists as an add-on treatment of resistant hypertension. The Addition of Spironolactone in Patients with Resistant Arterial Hypertension (ASPIRANT) trial evaluated, with a double-blind, placebo-controlled design, the effects of low-dose (25 mg/day) spironolactone as compared with placebo on clinic and ambulatory blood pressure in 117 resistant hypertensive obese patients, already under treatment with at least four antihypertensive drugs. The primary study endpoint was the achievement of a statistically significant difference in the systo-diastolic blood pressure reduction during the daytime period between the spironolactone-treated and the placebo-treated group. The results show that aldosterone blockade was associated with a significant reduction in clinic, 24-h and daytime systolic (but not in diastolic) blood pressure as compared with the placebo-treated group, the systo-diastolic blood pressure difference between the two treatment regimens amounting to 5.4/1.0 mmHg. Although a number of limitations weaken some of the study conclusions, ASPIRANT trial provides the first controlled evidence on the blood pressure-lowering effects of low-dose spironolactone in resistant hypertensive patients.     

Influence of spironolactone treatment on gentamicin-induced nephrotoxicity in rats

The effect of treatment of rats with gentamicin (80 mg/kg/day for 6 days), oral doses of spironolacatone (20 mg/kg/day for 6 days), and the combined treatment (spironolactone + gentamicin) on renal histology and reduced glutathione (GSH) concentration, and some serum constituents indicative of kidney function were studied. The serum concentrations of creatinine and urea were not significantly affected by spironolactone treatment, but were significantly elevated (P<0.05) by gentamicin administration. The antibiotic treatment also reduced GSH concentration and caused a moderate renal cortical necrosis. However, rats exposed to spironolactone + gentamicin revealed drastic increases in the serum urea and creatinine concentrations amounting to about 1.8 and 2.1 times those of rats treated with gentamicin alone, respectively. The histological examination of slides of the renal cortex of rats exposed to the combined drugs exhibited more extensive necrosis in the tubules when compared to those treated with gentamicin alone. The reduction in GSH induced by gentamicin was unaffected by the concomitant treatment of gentamicin and spironolactone. The concentration of gentamicin accumulated in the renal cortex was significantly larger (twofold) in rats treated concomitantly with spironolactone + gentamicin than in rats treated with gentamicin alone. The present results indicate that spironolactone aggravates gentamicin-induced nephrotoxicity in the rat.     

The efficacy and safety of furosemide and a combination of spironolactone and hydrochlorothiazide in congestive heart failure.

The therapeutic and biochemical effects of two commonly employed diuretic preparations were compared in a double-blind fashion in 32 patients with congestive heart failure. At the doses employed, furosemide and a fixed combination of spironolactone and hydrochlothiazide maintained control of the clinical manifestations of congestive heart failure to about the same degree. However, significant biochemical changes in the renin-aldosterone system were found in patients receiving the spironolactone/thiazide combination therapy. A significant increase in plasma renin activity and a significantly greater increase in aldosterone excretion were found in the spironolactone/thiazide group compared to the furosemide group. No significant differences were observed in serum potassium levels or 24-hour potassium excretion rates in patients treated with the two diuretic preparations.     

Effect of benazepril monotherapy in subjects with hypertension associated with renal dysfunction

Nine hypertensive patients with mild to moderate renal dysfunction were entered into a protocol to assess the blood pressure, humoral and renal effects of the angiotensin converting enzyme inhibitor, Benazepril (CGS14824A, 2 to 20 mg twice daily) in patients with hypertension and moderate renal insufficiency (mean creatinine clearance 56 ml/min/1.73 m2). Specifically monitored, prior to and following 12 weeks of Benazepril monotherapy, were plasma renin activity and plasma aldosterone, the clearances of creatinine, Tc99m-diethylenetriaminepentaacetic acid (TC99m-DTPA) and para-amino-hippurate, and the 24-hour urinary excretion of protein. Blood pressure was well controlled. Plasma renin activity was stimulated, and plasma aldosterone was suppressed. Mean serum potassium increased from 3.9 to 4.2 mEq/L. Benazepril monotherapy had no adverse renal hemodynamic effect. Benazepril appears to be an effective antihypertensive agent in hypertensive patients with moderately impaired renal function.     

Effects of valsartan and perindopril combination therapy on left ventricular hypertrophy and aortic arterial stiffness in patients with essential hypertension

Objective To compare the effects of combined therapy of an angiotensin II receptor blocker (ARB; valsartan) and an angiotensin converting enzyme inhibitor (ACEI; perindopril) on blood pressure (BP), metabolic profiles, plasma brain natriuretic peptide (BNP) levels, echocardiographic findings, and aortic pulse wave velocity (PWV) with those of respective monotherapy in never-treated patients with essential hypertension.Methods This was a prospective randomized trial, in which there were 31 patients with essential hypertension and left ventricular hypertrophy (LVH) who visited the outpatient clinic of Oita Red Cross Hospital (14 women and 17 men; mean±SD age, 59±5 years). Each patient was randomly assigned to receive valsartan (160 mg/day, V group, n=10), perindopril (8 mg/day, P group, n=11), or a combination of valsartan (80 mg/day) and perindopril (4 mg/day, V+P group, n=10) for 40 weeks. Ambulatory BP monitoring (ABPM), echocardiographic findings, metabolic findings, plasma BNP levels, and brachial-ankle PWV (baPWV) were evaluated before and after the 40-week therapy.Results The baseline and post-therapeutic BP levels were similar among the three groups. At baseline ABPM, non-dipping was observed in 80, 82, and 80% in the V, P, and V+P groups, respectively. Each 40-week therapy regimen comparably reduced ABP. The plasma BNP levels (P<0.0001 for each), left ventricular mass index (LVMI) (P<0.01 for each), and PWV values (P<0.0001 for each) were also reduced. However, when compared with either V or P group, the percentage reduction in LVMI (P<0.05 and P<0.005, respectively), BNP (P<0.05 for each), and baPWV values (P<0.005 and P<0.001, respectively) was greater in the V+P group.Conclusions Our findings suggest that, when compared with each monotherapy, perindopril and valsartan combination therapy exerts greater beneficial effects regarding the regression of LVH, reduction in BNP, and improvement of PWV in a selected group of essential hypertensive patients with LVH and high prevalence of non-dipping patterns.