***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    ***EXAMPLES*** 
    Input: Background —Specific treatments targeting the pathophysiology of hypertensive heart disease are lacking . As aldosterone has been implicated in the genesis of myocardial fibrosis , hypertrophy , and dysfunction , we sought to determine the effects of aldosterone antagonism on myocardial function in hypertensive patients with suspected diastolic heart failure by using sensitive quantitative echocardiographic techniques in a r and omized , double-blinded , placebo-controlled study . Methods and Results —Thirty medically treated ambulatory hypertensive patients ( 19 women , age 62±6 years ) with exertional dyspnea , ejection fraction > 50 % , and diastolic dysfunction ( E/A < 1 , E deceleration time > 250m/sec ) and without ischemia were r and omized to spironolactone 25 mg/d or placebo for 6 months . Patients were overweight ( 31±5 kg/m2 ) with reduced treadmill exercise capacity ( 6.7±2.1 METS ) . Long-axis strain rate ( SR ) , peak systolic strain , and cyclic variation of integrated backscatter ( CVIB ) were averaged from 6 walls in 3 st and ard apical views . Mean 24-hour ambulatory blood pressure at baseline ( 133±17/80±7 mm Hg ) did not change in either group . Values for SR , peak systolic strain , and CVIB were similar between groups at baseline and remained unchanged with placebo . Spironolactone therapy was associated with increases in SR ( baseline : −1.57±0.46 s−1 versus 6-months : −1.91±0.36 s−1 , P<0.01 ) , peak systolic strain ( −20.3±5.0 % versus −26.9±4.3 % , P<0.001 ) , and CVIB ( 7.4±1.7dB versus 8.6±1.7 dB , P=0.08 ) . Each parameter was significantly greater in the spironolactone group compared with placebo at 6 months ( P=0.05 , P=0.02 , and P=0.02 , respectively ) , and the increases remained significant after adjusting for baseline differences . The increase in strain was independent of changes in blood pressure with intervention . The spironolactone group also exhibited reduction in posterior wall thickness ( P=0.04 ) and a trend to reduced left atrial area ( P=0.09 ) . Conclusions —Aldosterone antagonism improves myocardial function in hypertensive heart disease Summary Since there is only scanty , indirect information about the mechanism of the hypotensive effect of spironolactone , 9 patients with essential hypertension were studied according to a r and omised double-blind , cross-over protocol . Spironolactone 100 mg b.i.d . and placebo were each given for one month and the following parameters were studied : blood pressure , heart rate , response to cold pressure and h and -grip tests , as well as blood flow in the calf and finger vessels . Flow in the calf and fingers representing muscle and skin arteries , respectively , was measured semicontinuously with an ECG-triggered venous occlusion plethysmograph . After spironolactone there was a significant decrease in the systolic and diastolic blood pressures in the supine , sitting and st and ing positions ; the sitting systolic and diastolic blood pressure decreased by ( mean ± SE ) 27±4 mm Hg ( p<0.001 ) and 11±4 mm Hg ( p<0.02 ) , respectively . No orthostatic response was observed . Heart rate remained unchanged . Blood flow through muscle and skin vessels increased in 6 out of 9 patients , and in these patients calculated vascular resistance in these areas decreased . Spironolactone did not significantly change the response of systemic blood pressure to the h and grip and cold pressure tests . The present data confirm the hypotensive properties of spironolactone and show that this effect is associated with dilatation of muscle and skin arteries in many but not in all the patients . The data do not support the hypothesis that spironolactone decreases the responsiveness of systemic blood pressure to orthosympathetic stimulation The relative blood pressure response and side effects of spironolactone ( S ) , 400 mg/day , and hydrochlorothiazide ( H ) , 100 mg/day , were evaluated in a double‐masked crossed comparison . Subjects were 24 essential hypertensives , 13 normal and 11 with low renin activity . Upright renin levels were determined in the am after 3 days of moderately low sodium diet ( < 100 mEq/day ) and at the end of each drug treatment period . The values were not revealed to one investigator until completion of the study . After 4‐week placebo control periods , either S or H was given in divided doses for 6 weeks . Blood pressure measurements and side effects were evaluated at biweekly intervals . The fall in blood pressure from control was the same for each drug and was independent of renin activity . Side effects occurred more often in patients treated with S , and H was judged superior by risk/benefit analysis . We conclude that S is no more beneficial than H in hypertensive patients with either low or normal renin activity but induces a higher incidence of adverse effects in the dose used in this study . We found no evidence for a greater effectiveness of S in low‐renin essential hypertension The effects of inhibiting angiotensin converting enzyme with perindopril and aldosterone with spironolactone were tested in hypertensive patients over fifty . Accordingly , 75 patients with mild hypertension aged 50 to 70 were r and omly divided into three groups for a double-blind 8 week comparison of the actions of placebo , 4 to 8 mg/day perindopril , and 37.5 to 75 mg/day spironolactone .  Side-effects caused one patient to withdraw from placebo and one from spironolactone treatment . Mean blood pressure rose by 2.4 mm Hg after placebo but dropped by 7.4 and 8.6 after perindopril and spironolactone ( P less than .01 ) . Placebo , perindopril , and spironolactone did not alter blood glucose or plasma potassium , but induced , respectively , variations of -0.09 , 0 , and + 0.34 mmol/L in cholesterol ( P = .04 ) , and -0.02 , -0.05 , and + 0.27 mmol/L in triglycerides ( P less than .01 ) . After the three treatments , changes in angiotensin converting enzyme activity averaged -1 , -6 , and -1 mU/mL ( P less than .01 ) , in active renin -2 , + 18 , and + 28 pg/mL ( P less than .01 ) , and in aldosterone , + 15 , + 8 , and + 95 pg/mL ( P less than .01 ) . Placebo , perindopril , and spironolactone did not alter microalbuminuria , but reduced urinary kallikrein activity by 0.9 , 1.8 , and 5.4 mU/mmol creatinine ( P = .04 ) . Although short-term administration of spironolactone  raised renin and aldosterone markedly and lipids moderately ( possibly because of volume contraction ) , the present results show that perindopril and spironolactone are both safe and effective for treating hypertension at the age of 50 or older Twenty-seven patients with hypertension were r and omly allocated to a 10 month crossover study . Treatment consisted of spironolactone ( 200 mg/day for 2 months ) , propranolol ( 320 mg/day for 2 months ) and combined administration of both drugs at half the dosage . Between treatment periods placebo was given for 2 months . Fourteen patients were previously untreated . The average pretreatment  blood pressure  for the entire group was 188/114 + /- 16/7(mean + /- st and ard deviation ) mm Hg supine and 188/118 + /- 20/9 mm Hg st and ing . Both spironolactone and propranolol reduced blood pressure significantly in both the supine and st and ing positions . Upright plasma renin activity was determined by radioimmunoassay of angiotensin I. The average initial level was 1.9 + /- 1.2 ( range 0.4 to 5.0 ) ng/ml/hr . There was a close correlation between plasma renin activity and the effects of the drugs : With increasing renin level the response to propranolol was better whereas the opposite was true for spironolactone . The combination of spironolactone and propranolol decreased the blood pressure still further in the supine and st and ing positions , irrespective of initial plasma renin activity . All patients achieved a normal supine pressure . Blood pressure and plasma renin activity returned toward pretreatment values during placebo administration . It is concluded that pretreatment levels of plasma renin activity can predict the antihypertensive response to propranolol and spironolactone . The combination of the two drugs , which have different modes of action , will effectively reduce blood pressure in hypertension . The results support the concept that the renin-angiotensin-aldo-sterone system may be involved in primary hypertension In a prospect i ve , double-blind , intraindividual , cross-over , placebo-controlled multicenter study , clinical and biochemical effects of once daily postpr and ial dose regimens of 50 , 100 , and 200 mg spironolactone were investigated in 45 out patients with primary hypertension , WHO ( World Health Organization ) Stage I-II . Each of the three active therapy periods , which were r and omly allocated to patients , were of 2 months ' duration , with intervening placebo periods , Clinical and biochemical parameters , including furosemide-stimulated plasma renin activity ( PRA ) , were recorded at regular intervals . All three spironolactone doses result ed in statistically significant blood pressure ( BP ) reductions independent of initial pretreatment levels and yielded satisfactory BP control in more than half of the patients . The 200 mg daily dose of spironolactone was found to be more effective than 50 but not 100 mg . When , correlating blood pressure response ( delta MAP ) to PRA , the profiling for positive spironolactone responders was characterized by high age and low PRA , irrespective of sex . Spironolactone therapy result ed in decreased serum sodium and magnesium values ; potassium , creatinine , urate , and triglyceride levels were increased . However , all treatment values were within normal ranges . Side effects were infrequent and mainly of endocrine nature In a crossover study 32 patients with hypertension were r and omly allocated to treatment with spironolactone 200 mg/day for two months , propranolol 320 mg/day for two months , and a combination of both drugs at half the dose . Between the treatments placebo was given for two months . Both spironolactone and propranolol lowered the blood pressure significantly in both positions . The initial plasma renin activity ( PRA ) levels ranged from 0 - 4 to 5 - 0 mug angiotensin I l-1 h-1 , and there was a close correlation between these levels and the effects of the drugs : with increasing PRA the response to propranolol was better while the opposite was true for spironolactone . Spironolactone reduced the blood pressure more at eight than at four weeks , while no such difference could be shown for propranolol . Spironolactone and propranolol together decreased the blood pressure still further irrespective of the initial PRA . All patients achieved a normal supine blood pressure Aims /hypothesisAldosterone antagonism improves endothelial function ( and reduces deaths ) in chronic heart failure . It is not known whether similar effects occur in other high-risk groups such as patients with diabetes and hypertension . We therefore assessed the full effects of aldosterone blockade in poorly controlled hypertensive patients with type 2 diabetes , focussing on blood pressure , endothelial function , glycaemic control and key hormones . Methods We performed a r and omised , placebo-controlled , double-blind , crossover study on 50 patients with type 2 diabetes and treated but poorly controlled hypertension , comparing spironolactone versus placebo . Patients had their endothelial function assessed by st and ard forearm venous occlusion plethysmography . Results There was no significant improvement in endothelium-dependent vasodilatation in response to acetylcholine , despite highly significant reductions in systolic and diastolic blood pressure . However , spironolactone significantly worsened glycaemic control , plasma angiotensin II and cortisol . Conclusions /interpretationSpironolactone is highly effective in lowering blood pressure in patients with type 2 diabetes and poorly controlled hypertension on st and ard treatment , but does not improve vascular endothelial function in this group . We speculate that any tendency for the spironolactone-induced lowering of blood pressure to improve endothelial function is offset by its tendency to worsen glycaemic control and increase the levels of angiotensin II and even possibly cortisol . Trials Registry no. : IS RCT N The long-term efficacy and tolerance of spironolactone in essential hypertension was evaluated among 20,812 patients referred to the Broussais and St. Joseph systemic hypertension clinics between 1976 and 1985 by using information prospect ively collected in the computerized ARTEMIS data bank . In 182 patients ( 51 men , 131 women ) treated with spironolactone alone  during 
    Output:
    
In other words , it appears that doses > 50mg/day do not produce further reductions in either SBP or DBP .
From the limited available evidence , spironolactone appears to lower blood pressure compared to placebo to a similar degree in patients with primary ( essential ) hypertension when doses of 100 - 500 mg/day are given .
A dose of 25 mg/day did not statistically significantly reduce systolic or diastolic blood pressure , compared to placebo .
Given the lack of a dose-response , coupled with a possible increased risk in adverse events with higher doses , doses of 25 to 100 mg/day are reasonable .
There is no evidence of the effect of spironolactone on clinical outcomes in hypertensive patients