Renin status does not predict the anti-hypertensive response to angiotensin-converting enzyme inhibition in African–Americans Blood Pressure Lowering in Essential Hypertension With an Oral Renin Inhibitor, Aliskiren Safety and tolerability of the direct renin inhibitor aliskiren: a pooled analysis of clinical experience in more than 12,000 patients with hypertension. Effects of renin-angiotensin-aldosterone system inhibitors and beta-blockers on markers of arterial stiffness. Effect of candesartan and lisinopril alone and in combination on blood pressure and microalbuminuria Comparison of the angiotensin II antagonist losartan with the angiotensin converting enzyme inhibitor enalapril in patients with essential hypertension The rapidity of drug dose escalation influences blood pressure response and adverse effects burden in patients with hypertension: the Quinapril Titration Interval Management Evaluation (ATIME) Study. ATIME Research Group. Additive hypotensive effect of angiotensin-converting enzyme inhibition and angiotensin-receptor antagonism in essential hypertension. Effect of indomethacin on blood pressure in elderly people with essential hypertension well controlled on amlodipine or enalapril. Gene polymorphisms of the renin-angiotensin system and age-related changes in systolic and diastolic blood pressure in subjects with hypertension. Effects of the Oral Direct Renin Inhibitor Aliskiren in Patients With Symptomatic Heart Failure Clinical variables, not RAAS polymorphisms, predict blood pressure response to ACE inhibitors in Sardinians. Efficacy of Eplerenone Added to Renin-Angiotensin Blockade in Hypertensive Patients Angiotensin converting enzyme gene polymorphism predicts blood pressure response to angiotensin II receptor type 1 antagonist treatment in hypertensive patients Effects of enalapril alone, and in combination with hydrochlorothiazide, on renin-angiotensin-aldosterone, renal function, salt and water excretion, and body fluid composition. Dual blockade of the rennin–angiotensin system versus maximal recommended dose of angiotensin II receptor blockade in chronic glomerulonephritis Efficacy, tolerance and hormonal effects of a new oral angiotensin converting enzyme inhibitor, ramipril (HOE 498), in mild to moderate primary hypertension. Renal vascular responses to renin inhibition with zankiren in men ADEPT: Addition of the AT1 receptor antagonist eprosartan to ACE inhibitor therapy in chronic heart failure trial: hemodynamic and neurohormonal effects. Safety and tolerability of losartan potassium, an angiotensin II receptor antagonist, compared with hydrochlorothiazide, atenolol, felodipine ER, and angiotensin-converting enzyme inhibitors for the treatment of systemic hypertension. Efficacy of low-dose spironolactone in subjects with resistant hypertension. Aliskiren, an oral renin inhibitor, provides dose-dependent efficacy and sustained 24-hour blood pressure control in patients with hypertension. Comparison of the efficacy and tolerability of telmisartan and enalapril in patients of mild to moderate essential hypertension Low-dose dual blockade of the renin-angiotensin system in patients with primary glomerulonephritis. Evaluation of blood pressure response to the combination of enalapril (single dose) and diltiazem ER (four different doses) in systemic hypertension. Antihypertensive efficacy and tolerability of once daily losartan potassium compared with captopril in patients with mild to moderate essential hypertension Comparison of blood pressure and angiotensin responses to the renin inhibitor Ro 42-5892 and the angiotensin converting enzyme inhibitor enalapril in essential hypertension Practitioner's Trial on the Efficacy of Antihypertensive Treatment in the Elderly Hypertension (The PATE-Hypertension Study) in Japan. First dose response and 24-hour antihypertensive efficacy of the new once-daily angiotensin converting enzyme inhibitor, ramipril. Blood pressure effects of acute intravenous renin or oral angiotensin converting enzyme inhibition in essential hypertension Antihypertensive efficacy of the angiotensin receptor blocker azilsartan medoxomil compared with the angiotensin-converting enzyme inhibitor ramipril Renin‐angiotensin system gene polymorphisms influence blood pressure and the response to angiotensin converting enzyme inhibition Efficacy of a Very‐low‐dose Combination of Perindopril and Indapamide—Preterax Compared with Cilazapril Monotherapy in Patients with Inadequate Blood Pressure Control—A Randomized, Double‐blind, Add‐on Study Combination of half doses of angiotensin type 1 receptor antagonist and angiotensin-converting enzyme inhibitor in diabetic nephropathy. Angiotensinergic Versus Nonangiotensinergic Hemodynamic Effects of Converting Enzyme Inhibition in Patients With Chronic Heart Failure: Assessment by Acute Renin and Converting Enzyme Inhibition Comparison of valsartan 160 mg with lisinopril 20 mg, given as monotherapy or in combination with a diuretic, for the treatment of hypertension: the Blood Pressure Reduction and Tolerability of Valsartan in Comparison with Lisinopril (PREVAIL) study. Comparative studies: enalapril versus hydrochlorothiazide as first-step therapy for the treatment of primary hypertension. Targeting albumin excretion rate in the treatment of the hypertensive diabetic patient with renal disease.
The angiotensin-converting enzyme ( ACE ) inhibitor tr and olapril , a non-sulfhydryl prodrug which is hydrolysed into tr and olaprilat , was studied in 322 hypertensives of African – American descent using a double-blind , r and omised , placebo-controlled , parallel study design . Following 6 weeks of double-blind treatment with placebo or 0.25 to 16 mg/day tr and olapril , an analysis of drug effect on trough blood pressure ( BP ) stratified by age , gender , weight , pre-treatment plasma renin activity , and tr and olaprilat concentration was performed . Two mg was the lowest effective tr and olapril dose , whereas doses above 4 mg did not significantly reduce trough BP . Reduction in BP did not correlate with trough plasma tr and olaprilat concentration . Pre-treatment plasma renin activity was not a reliable indicator of antihypertensive response , as similar reductions in BP occurred even in patients with the lowest renin levels . There were no observable differences based on age , gender or measurements of the renin-angiotensin- aldosterone axis . In conclusion , neither age , gender or plasma renin activity influenced anti-hypertensive response to angiotensin-converting enzyme inhibition in African – Abstract —Inhibition of the first and rate-limiting step of the renin-angiotensin system has long been an elusive therapeutic goal . Aliskiren , the first known representative of a new class of completely nonpeptide , orally active , renin inhibitors , has been shown to inhibit the production of angiotensin I and II in healthy volunteers and to reduce blood pressure ( BP ) in sodium-depleted marmosets . The aim of this r and omized , double-blind , active comparator trial study was to assess the BP-lowering efficacy and safety of aliskiren .  Two hundred twenty-six patients , 21 to 70 years of age , with mild to moderate hypertension , were r and omly assigned to receive 37.5 mg , 75 mg , 150 mg , or 300 mg aliskiren or 100 mg losartan daily for 4 weeks . Dose-dependent reductions in daytime ambulatory systolic pressure ( mean change , mm Hg [ SD of change ] ; −0.4 [ 11.7 ] , −5.3 [ 11.3 ] , −8.0 [ 11.0 ] , and −11.0 [ 11.0 ] , P = 0.0002 ) and in plasma renin activity ( median change % [ interquartile range ] ; −55 [ −64 , −11 ] , −60 [ −82 , −46 ] , −77 [ −86 , −72 ] , and −83 [ −92 , −71 ] , P = 0.0008 ) were observed with 37.5 , 75 , 150 , and 300 mg aliskiren . The change in daytime systolic pressure with 100 mg losartan ( −10.9 [ 13.8 ] ) was not significantly different from the changes seen with 75 , 150 , and 300 mg aliskiren . Aliskiren was well tolerated at all doses studied . This study demonstrates that aliskiren , through inhibition of renin , is an effective and safe orally active BP-lowering agent . Whether renin inhibition results in protection from heart attack , stroke , and nephropathy , similar to angiotensin-converting enzyme inhibition and angiotensin receptor blockade , needs to be research ed While the safety of renin-angiotensin system (RAS)-blocking drugs such as angiotensin-converting enzyme ( ACE ) inhibitors and angiotensin receptor blockers is well known , less is known about the new direct renin inhibitor aliskiren . The authors pooled data from 12 r and omized controlled trials of aliskiren in patients with hypertension and analyzed the incidence and types of adverse events ( AEs ) and laboratory abnormalities . Studies were characterized as short-term ( ≤2 months ) placebo-controlled or long-term ( > 2 months ) active-controlled . Relative risks for AEs of particular interest for RAS blockers were calculated . In short-term studies , AEs occurred in similar proportions of aliskiren 150 mg and 300 mg ( 33.6 % and 31.6 % , respectively ) and placebo treatment groups ( 36.8 % ) . In long-term studies , a lower proportion of patients treated with aliskiren 150 mg and 300 mg had AEs ( 33.7 % and 43.2 % , respectively ) than those treated with ACE inhibitors ( 60.1 % ) , angiotensin receptor blockers ( 53.9 % ) , and thiazide diuretics ( 48.9 % ) . Events of special interest , including angioedema , hyperkalemia , and diarrhea occurred in similar proportions of patients taking aliskiren , placebo , and comparator agents . In studies of up to 36 weeks , patients treated with aliskiren were significantly less likely to develop cough than those treated with ACE inhibitors . At the registered doses of 150 mg and 300 mg daily , aliskiren  has safety and tolerability profiles  similar to placebo , other RAS blockers , and diuretics . Cough rates are lower with aliskiren compared with ACE inhibitors Antihypertensive agents may , even within the same class , exert variable effects on arterial stiffness variables .  Nebivolol could have a better impact than atenolol on arterial stiffness , by increasing the bioavailability of endothelium-derived nitric oxide . Angiotensin-converting enzyme inhibitors ( ACEIs ) and angiotensin receptor blockers ( ARBs ) increase plasma renin activity ( enhancing the production of angiotensin II via non-ACE-related pathways ) whereas aliskiren does not , potentially affecting central hemodynamics differently . We compared the effects of two renin-angiotensin-aldosterone system ( RAAS ) inhibitors ( quinapril and aliskiren ) and 2 beta-blockers ( atenolol and nebivolol ) on arterial stiffness variables . Treatment-naïve patients ( n = 72 ; 68.1 % males ; age , 47.6 ± 10.6 years ) with uncomplicated stage I-II essential hypertension were r and omly assigned to quinapril , aliskiren , atenolol , or nebivolol for 10 weeks . Central systolic and diastolic blood pressure ( BP ) , central pulse pressure ( PP ) , augmentation index ( AIx ) , and pulse wave velocity ( PWV ) were measured at baseline , 2 , and 10 weeks . The same measurements were performed in 20 normotensive subjects ( 65.0 % males ; age , 40.0 ± 8.9 years ) . Peripheral and central systolic and diastolic BP , peripheral PP , and PWV were significantly and similarly reduced by all agents . However , PWV continued to decline between the second and last visit in patients on quinapril and aliskiren but did not change in those on nebivolol or atenolol  . Central PP and AIx decreased in patients on quinapril , aliskiren , and nebivolol but did not change in those taking atenolol . The decrease in central PP and AIx did not differ between patients on quinapril , aliskiren , and nebivolol . Despite similar reductions in peripheral BP , atenolol is less effective than nebivolol and RAAS inhibitors in improving central pulsatile hemodynamics . Aliskiren exerts similar effects on markers of arterial stiffness  as quinapril . The clinical relevance of these differences remains to be established Background Angiotensin-converting enzyme ( ACE ) inhibitors and angiotensin receptor blocking drugs ( ARB ) block the effect of angiotensin II by different mechanisms . It has been suggested that combined therapy may be more effective at reducing blood pressure ( BP ) than higher doses of either drug . Methods Twenty-three elderly patients with systolic hypertension completed a double-blind crossover study comparing placebo , c and esartan ( C ) 16 mg , C32 mg , lisinopril ( L ) 20 mg , L40 mg and C16 mg + L20 mg . Treatment periods were one month and ambulatory BP measurements were performed at the end of each period . The effects on albumin excretion in eight patients with microalbuminuria  were determined . Results All treatments lowered BP . The falls in systolic and diastolic BP with C16 , C32 , L20 and L40 were similar . Plasma renin rose to a similar extent . A plateau effect was reached with C16 and L20 . Systolic BP on the combination of C16 + L20 was lower than on each monotherapy ( C16 , 3.8 mmHg [ p=0.002 ] ; C32 , 6.4 [ 0.0003 ] ; L20 , 2.9 [ 0.05 ] ; L40 , 3.3 [ 0.003 ] ) . The additional fall in BP with the combination appeared to be due to recruitment of non-responders , rather than to an additive effect in most patients . All treatments reduced microalbuminuria to a similar extent . The combination was well tolerated and there was no deterioration in renal function . Conclusion When patients are on a plateau dose of an ACE inhibitor or an ARB , addition of the other drug class has a small but significant incremental effect on BP in the overall group . However , some patients respond better to one drug class than to the other and this may explain the results . This study lends no support to the use of these two drugs in combination to treat hypertension Objective : To evaluate the blood pressure lowering efficacy as well as tolerability and safety of the angiotensin II antagonist losartan compared with that of the angiotensin converting enzyme inhibitor enalapril in patients with mild-to-moderate essential hypertension . Design and methods : The study was a multicentre , double-blind , double-dummy , r and omized , parallel study . Patients ( n=407 ) with diastolic blood pressure > 95 and < 120mmHg at the end of a 2-week baseline placebo period were r and omly allocated to receive either 50 mg losartan once a day or 20 mg enalapril once a day for 12 weeks . Blood pressure , clinical and laboratory safety , specific symptoms including coughing determined using a symptoms question naire and metabolic variables were examined at baseline and at weeks 6 and 12 . Results : Both losartan and enalapril decreased systolic and diastolic blood pressure from baseline at weeks 6 and 12 . Blood pressure changes from baseline at trough ( 22 - 26 h after the dose ) did not differ between the two groups in the per- protocol analysis . Response to treatment at trough was excellent or good ( diastolic blood pressure < 90mmHg or reduction in diastolic blood pressure of lOmmHg ) in 51 and 53 % of the patients in the losartan and enalapril groups , respectively . Enalapril administration increased dry coughing symptoms whereas losartan did not . The incidence of dry coughing was 1.0 and 12.2 % as a spontaneously reported discomfort at week 12 and 3.0 and 15.1 % as a clinical adverse experience in the losartan and enalapril groups , respectively . The difference from baseline at week 12 in the incidence of dry coughing between the two groups was 14.9 % as a specific symptom in the symptoms question naire . Losartan reduced serum uric acid concentration , whereas effects on other metabolic parameters did not differ between the groups . Conclusions : Losartan is an effective and we 11-tolerated antihypertensive drug showing similar blood-pressure-lowering efficacy to that of enalapril at trough . However , in contrast to enalapril , losartan does not increase the incidence of dry coughing . Thus , the angiotensin II antagonist losartan provides a promising new approach to treatment of hypertension BACKGROUND Antihypertensive medication doses are typically increased within several weeks after initiation of therapy because of inadequate blood pressure ( BP ) control and /or adverse effects . METHODS We conducted a parallel-group clinical trial with 2935 subjects ( 53 % women , n=1547 ) aged 21 to 75 years , with Joint National Committee on Prevention , Detection , Evaluation , and Treatment of High Blood Pressure VI stages 1 to 2 hypertension , recruited from 365 physician practice s in the southeastern United States . Participants were r and omized either to a fast ( every 2 weeks ; n=1727 ) or slow ( every 6 weeks ; n=1208 ) drug titration . Therapy with quinapril , an angiotensin-converting enzyme inhibitor , was initiated at 20 mg once daily . The dose was doubled at the next 2 clinic visits until the BP was lower than 140/90 mm Hg or a dose of 80 mg was reached . RESULTS Pretreatment BP averaged 152/95 mm Hg . Patients with stage 2 hypertension reported more symptoms than those with stage 1 . The BP averaged 140/86 , 137/84 , and 134/83 mm Hg in the slow group compared with 141/88 , 137/85 , and 135/84 mm Hg in the fast group at the 3 respective clinic visits . The BP control rates to lower than 140/90 mm Hg at the 3 clinic visits were ( slow , fast , respectively ) 41.3 % , 35.7 % ( P<.001 ) ; 54.3 % , 51.5 % ( P=.16 ) ; and 68 % , 62.3 % ( P=.02 ) . In the fast group , 10.7 % of participants experienced adverse events vs 10.8 % in the slow group ; however , 21.0 % of adverse events in the fast group were " serious " vs only 12 % in the slow group . CONCLUSION Slower dose escalation of the angiotensin-converting enzyme inhibitor quinapril provides higher BP control rates and fewer serious adverse events than more rapid drug dose escalation The study was design ed to assess the antihypertensive effect of combined angiotensin-converting enzyme ( ACE ) inhibition and angiotensin II type 1 receptor ( AT1 ) antagonism in patients with essential hypertension . Twenty patients with uncontrolled ambulatory diastolic blood pressure ( BP ) after 6 weeks of ACE inhibitor monotherapy ( benazepril , 20 mg , o.d . ) were r and omized to receive double-blind valsartan , 80 mg , o.d . ( AT1 antagonist ) or matching placebo for 5 weeks while continuing to receive background benazepril . Then patients crossed over to the alternative regimen for a second 5-week period . The 24-h ambulatory BP was monitored on the final day of the benazepril monotherapy period and on the final day of each double-blind treatment period . Valsartan added to benazepril produced a significant antihypertensive effect with a benefit over placebo of 6.5 + /- 12.6/4.5 + /- 8.0 mm Hg ( systolic/diastolic ) for average awake ambulatory BP ( p < 0.05 ) , 7.1 + /- 9.4/5.6 + /- 6.5 mm Hg for asleep BP ( p < 0.01 ) , and 6.8 + /- 9.7/4.9 + /- 6.8 mm Hg for average 24-h ambulatory BP ( p < 0.01 ) . Pulse rate was unaffected . Plasma active renin was higher on the benazepril-valsartan combination compared with benazepril-placebo ( p < 0.05 ) . There was no change in routine biochemical variables when valsartan was added to benazepril . Six patients reported mild dizziness or fatigue ( three also with placebo ) . These data suggest that in hypertensive patients uncontrolled with an ACE inhibitor , the addition of an AT1 antagonist provides a powerful and safe antihypertensive drug combination Arthritis and hypertension are frequent comorbidities in the elderly hypertensive population .  Nonsteroidal anti-inflammatory drugs are often used to relieve pain in arthritic patients but a side effect is sodium retention and consequent elevation of blood pressure ( BP ) . The effect of dihydropyridine calcium blocking drugs is relatively independent of sodium intake , whereas the angiotensin-converting enzyme ( ACE ) inhibitors ' effects can be blunted by a high-sodium diet . This study compared the effects of indomethacin with placebo in elderly patients with essential hypertension who had been controlled with amlodipine or enalapril . Indomethacin 50 mg twice daily or placebo was administered for 3 weeks in a double-blind crossover study to patients controlled with amlodipine or enalapril . The response was assessed by ambulatory BP measurement .  Indomethacin  raised BP and lowered pulse rates in patients taking enalapril but had little effect in patients receiving amlodipine . The difference caused by indomethacin between the two groups was 10.1/4.9 mm Hg increase in BP and a 5.6 beats/min fall in pulse in people taking enalapril . Addition of indomethacin to patients taking either drug caused a rise in weight and a fall in plasma renin . It is postulated that the effect is due to inhibition of prostagl and in synthesis , which causes sodium retention . In patients taking amlodipine , the fall in plasma renin ameliorates the effect of sodium retention on BP . In patients taking enalapril , plasma renin falls but this is not translated into an effect because of the blockage of converting enzyme . Thus , the full effect of sodium retention on BP is expressed . In patients treated with indomethacin , fewer patients may respond to ACE inhibitors . However , the major problem is the patient who intermittently takes indomethacin or other nonsteroidal anti-inflammatory drugs , which , if a person is treated by an ACE inhibitor causes BP to go out of control . In such patients amlodipine would appear to be a preferred choice to enalapril BACKGROUND Few studies have examined to what extent genes might modulate the changes of systolic and diastolic blood pressure ( BP ) with age although , in older population s , systolic BP and diastolic BP vary with age in opposite directions . METHODS This study involved 205 men and 99 women with either systolic-diastolic or isolated systolic hypertension . Age was > 50 years . Using polymerase chain reaction , four gene polymorphisms related to the renin-angiotensin system were independently investigated in men and women . Adjustments to cardiovascular and renal risk factors as well to the sodium/potassium extracellular space ratio were performed . RESULTS Regarding the angiotensin-converting enzyme ( ACE ) gene polymorphism , in men > 50 years of age , the slope ( mm Hg per unit of age ) of the age-diastolic BP ( and not age-systolic BP ) relationships significantly ( P = .0092 ) differed between genotypes : - 0.79 + /- 0.15 ( P < .0001 ) for the DD genotype , -0.53 + /- 0.10 for the ID genotype ( P < .0001 ) , and -0.23 + /- 0.11 for II genotypes ( P = NS ) . Such findings were not observed in the female population in which the age-diastolic BP curves were substantially flatter than in men . No comparable results were observed for gene polymorphisms related either to angiotensinogen or to angiotensin II type 1 receptor . CONCLUSIONS In men > 50 years of age , the ACE gene polymorphism modulates the physiologic age-induced reduction of diastolic BP . The D allele might contribute to enhance this reduction , a finding that needs confirmation using prospect i ve studies Background —Loss of negative feedback inhibition of renin release during chronic treatment with an angiotensin-converting enzyme ( ACE ) inhibitor leads to a compensatory rise in renin secretion and downstream components of the renin-angiotensin-aldosterone ( RAAS ) cascade . This may overcome ACE inhibition but should be blocked by a direct renin inhibitor . We studied the effects of adding the direct renin inhibitor aliskiren to an ACE inhibitor in patients with heart failure . Methods and Results — Patients with New York Heart Association class II to IV heart failure , current or past history of hypertension , and plasma brain natriuretic peptide ( BNP ) concentration > 100 pg/mL who had been treated with an ACE inhibitor ( or angiotensin receptor blocker ) and β-blocker were r and omized to 3 months of treatment with placebo  ( n=146 ) or aliskiren 150 mg/d ( n=156 ) . The primary efficacy outcome was the between-treatment difference in N-terminal pro-BNP ( NT-proBNP ) . Patients ’ mean age was 68 years , mean ejection fraction was 31 % , and mean±SD systolic blood pressure was 129±17.4 mm Hg . Sixty-two percent of the patients were in New York Heart Association functional class II , and 33 % were taking an aldosterone antagonist . Plasma NT-proBNP rose by 762±6123 pg/mL with placebo and fell by 244±2025 pg/mL with aliskiren  ( P=0.0106 ) . BNP and urinary ( but not plasma ) aldosterone were also reduced by aliskiren . Clinical ly important differences in blood pressure and biochemistry were not seen between aliskiren and placebo . Conclusions —Addition of aliskiren to an ACE inhibitor ( or angiotensin receptor blocker ) and β-blocker had favorable neurohumoral effects in heart failure and appeared to be well tolerated AIM No definite factors predict blood pressure response to angiotensin-converting enzyme-inhibitors . The aim of this study was to test the association of gene polymorphisms of the renin-angiotensin-aldosterone system with essential hypertension and anthropometric variables , intermediate phenotypes and gene polymorphisms with blood pressure after fosinopril in a genetically homogeneous cohort . METHODS A total of 630 essential hypertension patients , not previously treated or out of antihypertensive treatment for at least 6 months versus 219 normotensives ( genotype frequencies , chi(2 ) ) . A total of 191 patients were r and omly assigned to fosinopril 20 mg/day . Sample s for plasma renin activity and aldosterone , 24-h urinary sodium ( flame photometry ) were collected . Gene polymorphisms -- angiotensin-converting enzyme ( insertion/deletion ) , angiotensin II type 1-receptor ( A1166C ) , aldosterone synthase ( -344C/T ) and angiotensinogen (-6A/G)--were analyzed by st and ard techniques . The association of anthropometric variables , intermediate phenotypes and gene polymorphisms with blood pressure after 4 weeks therapy was tested by univariate analysis and analysis of covariance model ( Intercooled Stata SE 9.2 ) . RESULTS No genetic polymorphisms were associated with essential hypertension , blood pressure response and intermediate phenotypes ( p > 0.05 ) . Systolic blood pressure after therapy was associated with baseline systolic blood pressure , age and sex . CONCLUSIONS Our results confirm the difficulty in dissecting both essential hypertension and pharmacogenomics when analyzing the effect of single genes in complex multifactorial traits The  efficacy and tolerability of eplerenone , a selective aldosterone blocker , was assessed when added to existing antihypertensive therapy with an ACE inhibitor or an angiotensin II receptor blocker ( ARB ) . Hypertensive patients ( n=341 ) whose blood pressure ( BP ) was not controlled despite ACE inhibitor or ARB  were r and omized ( double-blind ) to receive 50 mg eplerenone ( increasing to 100 mg if required ) once daily or placebo for 8 weeks . Diastolic and systolic BP and adverse events were recorded . By study end ( week 8) , mean seated diastolic BP was significantly reduced from week 0 among patients receiving eplerenone/ARB ( −12.7±0.81 mm Hg ) compared with those receiving placebo/ARB ( −9.3±0.83 mm Hg ) . The change in mean seated diastolic BP was −9.9±0.88 mm Hg in eplerenone/ACE inhibitor patients and −8.0±0.86 mm Hg in placebo/ACE inhibitor patients ( P = NS ) . Systolic BP levels were also significantly lower at week 8 for eplerenone/ACE inhibitor ( −13.4±1.35 mm Hg ) and eplerenone/ARB ( −16.0±1.37 mm Hg ) patients , respectively , compared with placebo/ACE inhibitor ( −7.5±1.31 mm Hg ) and placebo/ARB patients ( −9.2±1.41 mm Hg ) . Adverse events were generally nonsevere and not significantly different between eplerenone and placebo . This study demonstrated that in patients whose BP was not controlled with an ACE inhibitor or ARB , the addition of eplerenone over an 8-week period significantly lowered systolic BP in both groups and diastolic BP in ARB patients . Selective aldosterone blockade with eplerenone , therefore , may be useful add-on therapy in hypertensive patients inadequately controlled on ACE inhibitor or ARB alone Objectives To determine whether polymorphisms in the renin – angiotensin system can predict blood pressure-lowering response to antihypertensive treatment ; more specifically , in response to treatment with irbesartan or atenolol . Design and methods Eighty-six patients with hypertension were r and omized to double-blind treatment with either the angiotensin II type 1 receptor antagonist irbesartan or the β1 adrenergic receptor blocker atenolol and followed for 3 months . We analysed angiotensinogen T174 M and M235 T , angiotensin converting enzyme ( ACE ) I/D and angiotensin II type 1 receptor A1166C polymorphisms and related them to blood pressure reduction . Results The mean reductions in blood pressure were similar for both treatments . In the irbesartan group , individuals homozygous for the ACE gene I allele showed a greater reduction in diastolic blood pressure , exceeding those with the D allele ( − 18 ± 11 SD versus − 7 ± 10 mmHg , P = 0.0096 ) . This was not the case during treatment  with atenolol  , and the interaction term between type of treatment and ACE II genotype was significant ( P = 0.0176 ) . The angiotensinogen and angiotensin II type 1 receptor polymorhisms were not related to the response to treatment . Conclusions ACE genotyping predicted the blood pressure-lowering response to antihypertensive treatment with irbesartan but not atenolol . Thus , specific genotypes might predict the response to specific antihypertensive treatment Enalapril is a new , oral , long-acting nonsulfhydral angiotensin converting enzyme inhibitor . Thirty-nine patients with primary hypertension were entered into a r and omized , double-blind protocol to assess the efficacy of enalapril ( 10 to 20 mg bid ) , hydrochlorothiazide ( 25 to 50 mg bid ) , or combined drug therapy . Enalapril , either alone or in combination with hydrochlorothiazide , effectively controlled blood pressure .  Enalapril monotherapy was associated with an increase in plasma renin activity and a decrease in angiotensin II concentration ; in patients with an initial inulin clearance less than or equal to 80 mL/min/1.73 m2 , inulin and para-aminohippurate clearances were markedly improved , without producing adverse effects on salt and water excretion or body fluid composition . Combination therapy was associated with a marked increase in plasma renin activity ; however , only those patients with an initial inulin clearance less than or equal to 80 mL/min/1.73 m2 demonstrated suppression of angiotensin II concentration and marked improvement in inulin and para-aminohippurate clearances . These observations suggest that enalapril , either alone or in combination with a diuretic , has the potential to reverse renal function abnormalities encountered in the hypertensive state Background Proteinuria and hypertension are predictors of poor renal outcome in chronic glomerulonephritis ( CGN ) . At the same level of blood pressure ( BP ) control , we evaluated which is superior , dual blockade of the rennin – angiotensin system ( RAS ) with both angiotensin-converting enzyme inhibitor ( ACEI ) and angiotensin II type 1 ( AT-1 ) receptor blockade ( ARB ) or single blockade of ARB to reduce proteinuria and to preserve renal function in patients with CGN . Methods In this prospect i ve , parallel , open study of 86 patients with CGN , we compared the effects on proteinuria and renal functions of 36 months with comparable blood pressure ( BP ) control achieved by c and esartan cilexetil ( c and esartan , 4–12 mg/day ) or benazepril hydrochrolide ( benazepril , 2.5–10 mg/day ) with c and esartan ( 4 mg/day ) . Aim ing at BP 125/75 mmHg or less , the dose of c and esartan ( single blockade ) or benazepril ( dual blockade ) was increased . Results Dual blockade  decreased proteinuria more than single blockade with ARB ( −42.3 vs. −60.5 % , P < 0.01 ) . Renal plasma flow ( RPF ) and glomerular filtration fraction ( GFR ) did not change significantly in either group . The filtration fraction ( FF ) decreased dual blockade more than single blockade ( −1.7 vs. −19.0 % , P < 0.05 ) . Decreased FF was associated with the reduction of proteinuria ( P < 0.05 ) . Six percent of patients with dual blockade were not able to continue the study because of a dry cough . Conclusion Long-term dual blockade  decreased proteinuria more than single blockade with ARB . Although ARB and ACEI have a glomerular size-selective function for proteinuria , a greater antiproteinuric effect may depend on renal hemodynamics , especially FF . Increased levels of bradykinin after ACEI can decrease FF and ameliorate proteinuria . Dry cough is a significant adverse effect of ACE inhibitor The immediate ( 0 to 24 hours ) and long-term ( 4 weeks ) hypotensive effects of a new long-acting angiotensin converting enzyme inhibitor , ramipril ( HOE 498 ) , as well as adverse effects and tolerance , were evaluated in 34 patients with primary hypertension . Further , effects on serum and urinary aldosterone and circulating angiotensin II concentrations were measured . After short- and long-term administration of 5 or 10 mg of ramipril , the mean blood pressure was significantly lowered compared with placebo . The mean maximum decrease in blood pressure was noted 4 to 8 hours after administration of ramipril once daily . Sustained blood pressure reduction was achieved after 4 weeks of treatment . Serum concentrations of aldosterone and plasma levels of circulating angiotensin II were reduced for up to 12 hours after drug intake , and tended to return to pretreatment levels at 24 hours . Serum angiotensin converting enzyme activity was markedly suppressed for more than 24 hours after a single dose of 5 or 10 mg ramipril . No subjective or objective adverse effects were noted , and the tolerance to the drug was very good Renin inhibition represents an alternative to angiotensin‐converting enzyme ( ACE ) inhibition for pharmacologic interruption of the renin‐angiotensin system . In addition to inhibiting the formation of angiotensin II , ACE inhibitors also inhibit the degradation of kinin and result in accumulation of powerful renal vasodilator prostagl and ins and bradykinin . We were therefore surprised by the large renal vasodilator response achieved with the renin inhibitor enalkiren , because substrate‐specific renin inhibitors reduce the formation of angiotensin II without affecting other vasodilator mechanisms . To determine whether previous findings were reflective of the renin inhibitor class , we studied 12 healthy men on a sodium‐restricted diet  , each of whom received two or three escalating oral doses of zankiren , a new agent . Plasma renin activity decreased with the smallest dose ( 5 mg ) , and this effect was sustained . The increase in renal plasma flow was clearly related to dose ( r = 0.86 , F = 9.67 ) , reaching a maximum of 134 ± 26 ml/min/1.73 m2 at 250 mg , the highest dose . Renin inhibition exerts a remarkable renal vasodilator action , perhaps reflecting the lipophilicity of the agents developed to date , an action that may have clinical implication s for the prevention of renal injury in patients at risk BACKGROUND Persistent activation of the renin-angiotensin-aldosterone-system ( RAAS ) is known to occur in patients with chronic heart failure ( CHF ) despite treatment with angiotensin-converting enzyme inhibitor ( ACE ) therapy . When added to ACE inhibitors , angiotensin II type 1 ( AT1 ) antagonists may allow more complete blockade of the RAAS and preserve the beneficial effects of bradykinin accumulation not seen with AT1 receptor blockade alone . METHODS Thirty-six patients with stable New York Heart Association class II-IV CHF receiving ACE inhibitor therapy were r and omly assigned in a double-blind manner to receive either eprosartan , a specific competitive AT1 receptor antagonist ( 400 to 800 mg daily , n = 18 ) or placebo ( n = 18 ) for 8 weeks . The primary outcome measure was left ventricular ejection fraction ( LVEF ) as measured by radionuclide ventriculography  , and secondary measures were central hemodynamics assessed by Swan-Ganz catheterization and neurohormonal effects . RESULTS There was no change in LVEF with eprosartan therapy ( mean relative LVEF percentage change [ SEM ] + 10.5 % [ 9.3 ] vs + 10.1 % [ 5.0 ] , respectively ; difference , 0.4 ; 95 % confidence interval [ CI ] , -20.8 to 21.7 ; P = .97 ) . Eprosartan was associated with a significant reduction in diastolic blood pressure and a trend toward a reduction in systolic blood pressure compared with placebo ( -7.3 mm Hg [ 95 % CI , -14.2 to -0.4 ] diastolic ; -8.9 mm Hg [ 95 % CI , -18.6 to 0.8 ] systolic ) . No significant change in heart rate or central hemodynamics occurred during treatment with eprosartan compared with placebo . A trend toward an increase in plasma renin activity was noted with eprosartan therapy . Eprosartan was well tolerated , with an adverse event profile similar to placebo , whereas kidney function remained unchanged . CONCLUSIONS When added to an ACE inhibitor , eprosartan reduced arterial pressure without increasing heart rate . There was no change in LVEF after 2 months of therapy with eprosartan This report presents data on the safety and tolerability of losartan potassium ( losartan ) , a selective antagonist of the angiotensin II AT-1 receptor , in approximately 2,900 hypertensive patients treated in double-blind clinical trials . In these studies , headache ( 14.1 % ) , upper respiratory infection ( 6.5 % ) , dizziness ( 14.1 % ) , asthenia/fatigue ( 3.8 % ) , and cough ( 3.1 % ) were the clinical adverse experiences most often reported in patients treated with losartan .  These adverse experiences were also frequently reported in patients receiving placebo : 17.2 % , 5.6 % , 2.4 % , 3.9 % , and 2.6 % , respectively . Dry cough as an adverse event was reported in 8.8 % of patients treated with angiotensin-converting enzyme inhibitors , and in 3.1 % and 2.6 % of patients treated with losartan or placebo , respectively . Only dizziness was considered " drug-related " more often in losartan-treated ( 2.4 % ) than placebo-treated ( 1.3 % ) patients . In controlled clinical trials , losartan was better tolerated than other antihypertensive agents as determined by the incidence of patients reporting any drug-related adverse experiences . Rates of discontinuation due to clinical adverse experiences in patients who received losartan monotherapy or losartan+hydrochlorothiazide were 2.3 % and 2.8 % , respectively , compared with placebo ( 3.7 % ) . No laboratory adverse experiences were unexpected or of clinical importance . First-dose hypotension rarely occurred with losartan or with losartan plus hydrochlorothiazide , and withdrawal effects such as rebound hypertension were not observed in clinical trials . There were no clinical ly important differences in the clinical or laboratory safety profiles in the demographic subgroups for age , gender , or race . In controlled clinical trials , losartan demonstrated an excellent tolerability profile BACKGROUND Previous reports have demonstrated the antihypertensive efficacy of high doses of spironolactone in subjects with primary aldosteronism and , to a lesser degree , subjects with resistant hypertension . METHODS In current analysis , we examined the antihypertensive benefit of adding low-dose spironolactone to multidrug regimens that included a diuretic and an angiotensin-converting enzyme ( ACE ) inhibitor or angiotensin receptor blocker ( ARB ) in subjects with resistant hypertension with and without primary aldosteronism . Subjects referred for resistant hypertension were evaluated with an early morning plasma renin activity , 24-h urinary aldosterone and sodium during a high dietary salt ingestion . The diagnosis of primary aldosteronism was confirmed with a renin activity < 1.0 ng/mL/h , urinary aldosterone > 12 mug/24 h and urinary sodium > 200 mEq/24 h. After biochemical evaluation , spironolactone ( 12.5 to 25 mg/d ) was added to each subject 's antihypertensive regimen . If blood pressure ( BP ) remained uncontrolled , the dose of spironolactone was titrated up to 50 mg/d . Follow-up BP was determined at 6 weeks , 3 months , and 6 months . RESULTS A total number of 76 subjects were included in the analysis , 34 of whom had biochemical primary aldosteronism . Low-dose spironolactone was associated with an additional mean decrease in BP of 21 + /- 21/10 + /- 14 mm Hg at 6 weeks and 25 + /- 20/12 + /- 12 mm Hg at 6-month follow-up . The BP reduction was similar in subjects with and without primary aldosteronism and was additive to the use of ACE inhibitors , ARBs , and diuretics . CONCLUSIONS We conclude that low-dose spironolactone provides significant additive BP reduction in African American and white subjects with resistant hypertension with and without primary aldosteronism OBJECTIVES This dose-ranging study evaluated the antihypertensive efficacy and tolerability of aliskiren in patients with mild-to-moderate hypertension . BACKGROUND Low blood pressure ( BP ) control rates among patients with hypertension indicate a need for improved treatment options . This study investigates aliskiren , the first in a new antihypertensive class called renin inhibitors . METHODS Patients with mean sitting diastolic BP 95 to 109 mm Hg were r and omized to aliskiren 150 , 300 , or 600 mg or placebo  once daily for 8 weeks . Patients completing this treatment phase entered a 2-week treatment-free withdrawal period . Office BP was recorded at baseline , weeks 2 , 4 , 6 , and 8 of treatment , and 4 days and 2 weeks after cessation of treatment . A subgroup of patients underwent ambulatory BP monitoring . RESULTS In total , 672 patients were r and omized to treatment . After 8 weeks , aliskiren 150 , 300 , and 600 mg significantly reduced mean sitting BP ( systolic/diastolic ) by 13.0/10.3 , 14.7/11.1 , and 15.8/12.5 mm Hg , respectively , versus 3.8/4.9 mm Hg with placebo ( all p < 0.0001 for systolic and diastolic BP ) . The BP-lowering effect of aliskiren persisted for up to 2 weeks after treatment withdrawal . Aliskiren significantly reduced mean 24-h ambulatory BP ( p < 0.0001 vs. placebo with all doses ) exhibiting smooth , sustained effects and high trough-to-peak ratios .  Aliskiren was well tolerated ; overall adverse event rates were 40.1 % , 46.7 % , and 52.4 % with aliskiren 150 , 300 , and 600 mg , respectively , and 43.0 % with placebo . Few patients discontinued treatment due to adverse events . CONCLUSIONS Aliskiren provides significant antihypertensive efficacy in patients with hypertension , with no rebound effects on blood pressure after treatment withdrawal Background : Theoretically , angiotensin II receptor blockers ( ARBs ) have certain advantages over angiotensin-converting enzyme inhibitors , but the contribution of these advantages to the clinical effect of ARBs is not known . Objective : To compare the efficacy and tolerability of telmisartan with enalapril in patients of essential hypertension . Material s and Methods : Patients of mild to moderate hypertension were r and omized to receive either 40 mg of telmisartan or enalapril 10 mg once a day orally for 12 weeks . At each visit , the systolic blood pressure ( BP ) , diastolic BP and heart rate of each patient were recorded . Investigations such as hemogram hemoglobin , total leucocytes count ( Hb , TLC ) , serum creatinine , serum glutamic oxaloacetic transaminase , serum glutamic pyruric transaminase ( SGOT , SGPT ) r and om blood sugar and urine examination were performed at baseline and after 12 weeks of the treatment period . Results : The mean reduction in systolic BP in the telmisartan/enalapril group was 26.38 ± 10.98/26.74 ± 8.24 mmHg while the mean reduction in diastolic BP in the telmisartan/enalapril group was 14 ± 2.98/9.71 ± 4.23 mmHg , respectively , at 12 weeks . When the reduction in systolic BP in the two groups was compared , there was no significant difference between the groups ( P > 0.05 ) . However , the mean reduction in diastolic BP achieved with telmisartan at 12 weeks was significantly higher ( P < 0.001 ) than that achieved with enalapril after the corresponding period . The overall frequency of adverse-effects was similar . However , in the enalapril group , the incidence of dry cough was higher as compared to that in the telmisartan group ( 11.43 % vs. 0 % , respectively ; P < 0.05 ) . Conclusion : Telmisartan produces a greater reduction in diastolic BP than enalapril and is free from the adverse-effect of dry cough that is commonly encountered with enalapril BACKGROUND Treatment with agents interfering with the renin-angiotensin system retards the progressive course of proteinuric chronic renal disease . However , because of unwanted effects associated with such therapy , some patients can not be treated with these drugs at all or may be administered only very small doses . To find an optimal nephroprotective strategy for these patients , we compared antiproteinuric effects of combination therapy with an angiotensin-converting enzyme inhibitor and angiotensin II type 1 receptor antagonist in very small doses with treatment with either agent alone at greater , but not maximal , doses . We compared the concomitant use of benazepril , 5 mg , and losartan , 25 mg , and monotherapy with these agents in doses 2-fold greater . METHODS This is a r and omized , open , crossover study of 3 treatments in 3 periods of 4 months each . Twenty-four patients with primary glomerulonephritis and nonnephrotic proteinuria , recognized previously as not able to be administered high doses of drugs from these classes , completed the protocol . RESULTS Combined therapy decreased 24-hour proteinuria ( -45.54 % versus baseline ) more effectively than either losartan ( -28.17 % ; analysis of variance , P < 0.01 ) or benazepril ( -20.19 % ; analysis of variance , P < 0.001 ) alone . Subgroup analysis showed that antiproteinuric effects of combination therapy , as well as losartan or benazepril alone , were significantly greater in patients with basal proteinuria greater than 2 g/24 h than in those with proteinuria less than this value ( P < 0.001 , P < 0.01 , and P < 0.05 , respectively ) . All therapies significantly decreased blood pressure ( BP ) compared with baseline , but there were no differences between treatments in BP changes . CONCLUSION The study shows that combination therapy with very small doses of losartan and benazepril was more effective in reducing proteinuria than greater doses of either agent in monotherapy , and this greater antiproteinuric efficacy was independent of changes in BP Angiotensin-converting enzyme inhibitors and calcium antagonists are 2 classes of antihypertensive agents frequently used either as monotherapy or in combination . A 6-week , multicenter , r and omized , double-blind , placebo-controlled trial was conducted in essential hypertensive patients ( diastolic blood pressures [ BP ] when seated , 95 - 115 mm Hg ) to evaluate the efficacy , dose response , and safety profiles of enalapril combined with a new once-daily formulation of diltiazem .  BP and heart rate were measured at 5 ( peak ) and 24 ( trough ) hours after dose to assess the efficacy and pharmacodynamic profile of the combination given once daily . There were 336 patients r and omly assigned to either enalapril 5 mg plus 1 of 4 dose levels of diltiazem ER ( 60 , 120 , 180 , or 240 mg ) , enalapril 5 mg alone , or placebo . Each combination dose level produced statistically significant reductions ( p < 0.05 ) in trough diastolic BP when seated , compared with placebo ( -6.8 , -8.3 , -10.1 , and -10.3 mm Hg for the diltiazem ER doses of 60 , 120 , 180 , and 240 mg , respectively ) . The 3 highest combination dose levels result ed in statistically significant ( p < 0.05 ) decreases in trough diastolic BP when seated , compared with placebo . There was a significant ( p < 0.001 ) linear dose-response relation . A trough-to-peak ratio > or = 0.5 was shown for the 3 highest combination doses . Drug-related adverse events were seen in 8.9 % to 19 % of the combination patients , 14.3 % of the enalapril patients , and 8.6 % of the placebo patients . The frequency and type of adverse events were those currently noted with each drug studied when used as monotherapy Introduction : Losartan potassium , an orally active , highly selective AT1 angiotensin II receptor inhibitor , effectively reduces blood pressure by direct receptor blockade , thereby lessening the likelihood of angiotensin converting enzyme ( ACE ) inhibitorassociated side effects such as dry cough or possibly angioedema Study design : In this multinational , double-blind , r and omized , parallel study , the efficacy and tolerability of once-daily losartan ( 50 mg ) versus once-daily ACE inhibitor ( captopril ; 50 mg ) was evaluated in 163 patients with mild to moderate hypertension . Non-responders after a 6-week treatment period had the dosage doubled for both study drugs until the end of study ( week 12 ) Results : Mean reductions in trough sitting diastolic blood pressure were significantly greater in the losartan group at week 6 ( 7.8 mmHg ) and week 12 ( 9.1 mmHg ) than in the captopril group ( 5.2 and 5.7 mmHg , respectively ) . Losartan and captopril were well tolerated . Headache was the most common adverse event reported in both groups Conclusions : It was concluded that a once-daily administration of losartan was significantly more effective in this study in lowering sitting diastolic blood pressure than once-daily administration of captopril in patients with mild to moderate essential hypertension . Both losartan and captopril regimes were well Objective : To compare the responses of angiotensin II ( Ang II ) and blood pressure to the renin inhibitor Ro 42 - 5892 and the angiotensin converting enzyme ( ACE ) inhibitor enalapril Subjects : Eight non-sodium-restricted patients with mild-to-moderate essential hypertension Design : A single-blind crossover study . Ro 42 - 5892 ( 600 mg orally , once a day ) and enalapril ( 20 mg orally , once a day ) were given for 8 days before detailed investigations were carried out . Methods : Ambulatory blood pressure was measured directly for 24 h by the Oxford technique on three occasions . Off-treatment and on day 8 of treatment with Ro 42 - 5892 and with enalapril .  Ang II was measured by radioimmunoassay after separation by high-performance liquid chromatography Results : Plasma renin activity and Ang II were lowered by 83 % [ 95 % confidence interval ( CD 61 - 105 ] and 68 % ( 95 % Cl 49 - 87 ) , respectively , 0.5 - 1 h after Ro 42 - 5892 , but after only 3h values had returned to baseline . Unlike this rapid and short-term suppression of Ang II , the maximal antihypertensive response to Ro 42 - 5892 ( fall in blood pressure 12.9/9.0 mmHg ) occurred only after 6h . Blood pressure returned to baseline after 8h . In response to enalapril , Ang II was maximally suppressed by 63 % ( 95 % Cl 32 - 94 ) after 2 h and by 83 % ( 95 % Cl 76 - 90 ) after 8 h. Despite early maximal Ang II suppression , the maximal antihypertensive response to enalapril occurred only after 12 h ( fall in blood pressure 25.3/16.3 mmHg ) . With this compound a significant antihypertensive effect was still present 24 h after dosing . Conclusions : Compared with enalapril at 20 mg once a day , repeated oral administration of a single dose of Ro 42 - 5892 at 600 mg caused only short-term suppression of Ang II and blood pressure . Suppression of Ang II and reduction in blood pressure were temporally dissociated , both with the ACE inhibitor and the renin inhibitor . This implies that the blood pressure lowering effect of these inhibitors is caused partly by Ang II suppression outside the Patients aged 60 years and older with essential hypertension were treated with an angiotensin-converting enzyme inhibitor ( ACE-I ) , delapril ( Adecut ) or a long-acting calcium (Ca)-antagonist , manidipine ( Calslot ) for 3 years . The incidences of cardiovascular events as well as drug-related side effects were compared between the two groups to investigate whether both classes of antihypertensive drugs are beneficial in elderly hypertensive patients . There were no significant differences in characteristics of patients between the two intervention groups , except for slightly lower blood pressure ( P = .08 ) in the Ca-antagonist group at the initiation of the study . There were no significant differences in total death between the two groups . Cardiovascular events ( both fatal and nonfatal ) were noted in 34 of 699 patients ( 22.5/1000 patient-years ) in the ACE-I group and 50 of 1049 patients ( 19.7/1000 patient-years ) in the Ca-antagonist group , with no significant difference found between the two groups . The correlation between cardiovascular incidence and the blood pressure attained during treatment showed a J-shaped phenomenon and suggests that an excessive reduction less than 120 mm Hg in systolic blood pressure ( SBP ) is unnecessary and may be harmful in certain cases . Side effects were more frequent in the ACE-I group than in the Ca-antagonist group ( P = .01 ) . Cough was the major adverse event , occurring in 5.0 % of patients in the ACE-I group . In conclusion , the study indicates that both ACE-I ( delapril ) and Ca-antagonist ( manidipine ) were equally beneficial for reducing cardiovascular morbidity and mortality in elderly hypertensive patients . However , tolerability of ACE-I was lower due to the adverse event of coughing The reduction in blood pressure ( BP ) after the first dose and after 8 weeks of treatment with a new once-daily angiotensin converting enzyme ( ACE ) inhibitor , ramipril , was examined in 12 untreated hypertensive patients , using ambulatory intraarterial BP monitoring . The first period of monitoring began 24 hours before the first dose was given , and continued for 24 hours afterwards . A second 24-hour period of monitoring was carried out after 8 weeks of treatment , commencing immediately after the morning dose .  Angiotensin II levels and serum drug levels were measured at 0 , 2 , 6 and 24 hours after the acute dose .  BP decreased progressively from the first hour after the first dose , reached a maximum in the fifth hour ( p less than 0.001 ) and then the effect diminished . The maximum reduction of systolic BP in any patient was 64 mm Hg , the minimum 4 mm Hg . Blood pressure was significantly ( p less than 0.05 ) reduced throughout the 24 hours after dosing , with a mean daytime reduction of 13/12 mm Hg , and a mean nighttime reduction of 15/7 mm Hg . Angiotensin II levels were significantly ( p less than 0.02 ) and maximally reduced by 2 hours after administration , but the reduction was no longer significant after 24 hours . Serum drug levels were also maximal 2 hours after administration . The trial population could be clearly divided into groups of good and poor responders on the basis of BP reduction . The angiotensin II levels were higher before treatment , and decreased further , in all patients with a good response than in those with a poor response . ( ABSTRACT TRUNCATED AT 250 WORDS Objective To assess the participation of the renin-angiotensin system in the blood pressure regulation of essential hypertensive patients through acute specific renin inhibition Design and methods Fifty-three consecutive untreated hypertensive patients ( mean ± SD age 55 ± 10 years , 42 male ) were investigated on their usual sodium diet in a 3-h protocol . The first 11 patients did not receive any drug , the following 20 patients ingested a single oral dose of captopril ( 1 mg/kg ) and the last 22 patients received a renin inhibitor infusion ( remikiren ; 1 mg/kg over 60min ) Results The maximum diastolic blood pressure fall was comparable in the two treated groups . Diastolic blood pressure changes analysed as area under the curve were similar for both drugs ( overall F1,40= 1.26 , P=0.27 ) . Even though the baseline renin levels were within the narrow range 5–80 pg/ml , the diastolic blood pressure fall analysed as area under the curve from time 32 min to time 60min was significantly correlated with the baseline active renin level in both groups ( remikiren r = 0.44 , P < 0.05 ; captopril r = 0.47 , P < 0.05 ) . The plasma active renin levels were significantly increased at 30 , 90 and 120min in both groups , and the maximum active renin levels were significantly correlated with the baseline active renin level ( remikiren r = 0.62 , P < 0.01 ; captopril r = 0.66 , P<0.01 ) . The plasma prorenin levels did not change Conclusions This study suggests that acute renin inhibition and acute angiotensin converting enzyme inhibition similarly decrease the blood pressure and increase the plasma active renin levels . Acute blockade of the renin-angiotensin system at its initial step by a renin inhibitor can therefore be used to investigate the renin dependence of the blood pressure in essential Drug therapy often fails to control hypertension . Azilsartan medoxomil ( AZL-M ) is a newly developed angiotensin II receptor blocker with high efficacy and good tolerability . This double-blind , controlled , r and omised trial compared its antihypertensive efficacy and safety vs the angiotensin-converting enzyme inhibitor ramipril ( RAM ) in patients with clinic systolic blood pressure ( SBP ) 150–180 mm Hg . Patients were r and omised ( n=884 ) to 20 mg AZL-M or 2.5 mg RAM once daily for 2 weeks , then force-titrated to 40 or 80 mg AZL-M or 10 mg RAM for 22 weeks . The primary endpoint was change in trough , seated , clinic SBP .  Mean patient age was 57±11 years , 52.4 % were male , 99.5 % were Caucasian . Mean baseline BP was 161.1±7.9/94.9±9.0 mm Hg . Clinic SBP decreased by 20.6±0.95 and 21.2±0.95 mm Hg with AZL-M 40 and 80 mg vs12.2±0.95 mm Hg with RAM ( P<0.001 for both AZL-M doses ) . Adverse events leading to discontinuation were less frequent with AZL-M 40 and 80 mg ( 2.4 % and 3.1 % , respectively ) than with RAM ( 4.8 % ) . These data demonstrated that treatment of stage 1–2 hypertension with AZL-M was more effective than RAM and better tolerated Objectives To investigate the relationship between polymorphisms in the angiotensin converting enzyme ( ACE ) , angiotensinogen ( AGT ) and type 1 angiotensin-II ( AT1R ) genes and ( 1 ) quantitative variations in blood pressure and ( 2 ) the blood pressure response to ACE inhibition in a hypertensive cohort . Design and methods We administered monotherapy with ACE inhibitors to 125 previously untreated essential hypertensives . Genotypes for ACE insertion and deletion , AGT M235 T and AT1R A1166±C polymorphisms were determined in DNA extracted from peripheral blood leucocytes . The influence of genotype on pretreatment blood pressure and the ACE inhibitor-induced decrease in blood pressure was tested by analysis of variance and multiple regression analysis , adjusting for age , sex , body mass index , alcohol intake and , where appropriate , pretreatment blood pressure . Results ACE and AT1R genotypes were independent predictors of pretreatment systolic and diastolic blood pressure , with an apparent interaction between these two gene loci . Although it did not influence pretreatment blood pressure in this population , AGT genotype was an independent predictor of the blood pressure response to ACE inhibition . Conclusions The ACE and AT1R gene loci ( chromosomes 17q and 3q , respectively ) may carry alleles influencing blood pressure variation in this hypertensive population , with a possible epistatic interaction between the two loci . The AGT T235 allele does not appear to be a marker for blood pressure variation in this group , but variants on chromosome 1q lying in or near the AGT gene may contribute to individual differences in the blood pressure response to ACE inhibition . Among essential hypertensives , differences in the ACE inhibitor response appear , in part , to be genetically determined Background : Combined regimen may be superior to monotherapy in blood pressure ( BP ) control . Since BP control is crit‐ically related to cardiovascular mortality and morbidity in hypertensive patients , this study aim ed to evaluate the efficacy and safety of a low‐dose combined regimen of preterax compared with cilazapril monotherapy for better BP control in treated hypertensive patients . Methods : Stable hypertensive patients were evaluated if their systolic BP ( SBP ) was > 130 mmHg and /or diastolic BP ( DBP ) was > 85 mmHg even with up to 2 antihypertensive drugs . Patients were excluded if they were on angiotensin‐converting enzyme inhibitors , angiotensin II receptor blockers or a diuretic . They were then r and omized to receive either preterax ( perindopril 2 mg and indapamide 0.625 mg ) or cilazapril 2.5 mg once daily in a double‐blind fashion for a period of 12 weeks after a 2‐week placebo run‐in phase . Sitting BP was recorded and the safety and efficacy were evaluated at each visit every 4 weeks . Response was defined as positive if SBP was ≤140 mmHg and DBP was ≤90 mmHg at the last visit or there was > 20 mmHg reduction in SBP and /or > 10 mmHg reduction in DBP using either treatment . Plasma biochemical analysis was performed both before and after the treatment . Results : Among the 47 patients initially enrolled , 41 completed the study ( 21 in the preterax group , 20 in the cilazapril group ) . There was no difference in the number of adverse events between the 2 groups . SBP was significantly reduced by preterax ( 13.43 ±12.48 mmHg , p < 0.0001 ) and cilazapril ( 9.00 ±13.75 mmHg , p < 0.05 ) . However , DBP was significantly reduced only by preterax ( 7.67 ±9.40 mmHg , p = 0.0009 ) but not by cilazapril ( 3.60 ±8.37 mmHg , p > 0.05 ) . The response rate was significantly higher to preterax ( 100 % ) than to cilazapril ( 70 % ) ( p = 0.0086 ) . Conclusion : Though similar in safety , combined regimen preterax was more effective than cilazapril to facilitate adequate BP control in already‐treated hypertensives . It can be added on to other antihypertensives for better BP control in clinical hypertension . [ J Chin Med Assoc 2008;71(5):247–253 BACKGROUND To investigate the renoprotective effect of combination therapy with an angiotensin I converting enzyme inhibitor and an angiotensin type I receptor blocker ( ARB ) on diabetic kidney disease , half doses of each monotherapy were given to type 2 diabetic patients with albuminuria . METHODS Urinary albumin index ( UAI ) and blood pressure ( BP ) were measured in a total of 27 out patients with type 2 diabetes mellitus receiving 10 mg imidapril or 8 mg c and esartan per day . Either agent was then substituted with a combination of 5 mg imidapril and 4 mg c and esartan . After 3 months of combination therapy , UAI and BP were measured . Changes in the parameters were assessed by paired t test . RESULTS Although BP was not significantly different prior to and at the end of combination therapy , log-transformed UAI was significantly reduced ( P = 0.003 ) from an initial UAI ( mean log-transformed UAI + /- SD ) of 79.4 (27.4 - 231)mg/g Cre to 52.5 (17.1 - 161)mg/g Cre at the end of combination therapy . The reduction was not associated with the initial UAI , initial BP , decrease in BP , pretreatment medication or other concomitant antihypertensive agents . CONCLUSIONS In patients with type 2 diabetes and nephropathy , dual blockade of the renin system with an angiotensin-converting enzyme inhibitor and angiotensin receptor blocker significantly reduces albuminuria and , thus , may be renoprotective even when the doses of the agents are reduced by one half Background The contribution of nonangiotensinergic effects of converting enzyme inhibitors to their hemodynamic effects in patients with chronic heart failure is not clear . A comparison of the effects of renin and converting enzyme inhibition should help to clarify this issue . Methods and Results Thirty-six patients with chronic heart failure ( New York Heart Association class II or III ) were r and omly assigned to receive double-blind either intravenous placebo , the renin inhibitor remikiren , or the converting enzyme inhibitor enalaprilat followed by coinfusion of a second placebo infusion , the addition of remikiren to enalaprilat , or the addition of enalaprilat to remikiren , respectively . Systemic hemodynamics ( Swan-Ganz and radial artery catheters ) were measured before ( rest and submaximal recumbent bicycle ergometry ) , during ( rest ) , and at the end ( rest and exercise ) of each 45-minute single- or combination-infusion period . Placebo did not change hemodynamics or renin activity . Effective inhibition of the renin-angiotensin system by remikiren and enalaprilat was indicated by increases of plasma immunoreactive renin together with rapid and complete inhibition of renin activity after remikiren and an increase after enalaprilat ( all P ≤ .05 ) . Remikiren and enalaprilat rapidly and to a similar extent reduced resting blood pressure through a reduction of systemic vascular resistance , and these changes were significantly correlated to baseline plasma renin activity . Both compounds also decreased pulmonary artery , pulmonary capillary wedge , and right atrial pressures to a similar extent ( P < .05 ) . During exercise , pulmonary capillary wedge and right atrial pressures were equally reduced and stroke volume index was increased with remikiren and enalaprilat ( P < .05 for both ) . The combination of converting enzyme with renin inhibition or vice versa did not cause additional hemodynamic changes . Conclusions Specific renin inhibition in patients with chronic heart failure produces short-term hemodynamic effects that are almost indistinguishable from those of converting enzyme inhibition . This finding and the lack of additional effects of converting enzyme inhibition added to renin inhibition suggest that nonangiotensinergic effects of converting enzyme inhibitors do not play a significant role in their short-term hemodynamic effects in patients with chronic heart failure BACKGROUND The goal of antihypertensive therapy is to provide good blood pressure ( BP ) control without eliciting adverse effects . OBJECTIVE This study compared the risk-benefit profile of the angiotensin II receptor blocker valsartan with that of the angiotensin-converting enzyme inhibitor lisinopril in patients with mild to severe hypertension . The primary objective was to show that the equipotent BP-lowering effect of the valsartan-based treatment is accompanied by a better tolerability profile . METHODS This 16-week , r and omized , double-blind , parallel-group study was conducted at 88 outpatient centers across Italy . After a 2-week placebo run-in period , patients aged > or = 18 years with mild to severe hypertension ( systolic BP [ SBP ] , 160 - 220 mm Hg ; diastolic BP [ DBP ] , 95 - 110 mm Hg ) were eligible . Patients were r and omized to receive once-daily , oral , self-administered treatment with valsartan 160-mg capsules or lisinopril 20-mg capsules under double-blind conditions for 4 weeks . Responders continued monotherapy , whereas nonresponders had hydrochlorothiazide 12.5 mg added for the final 12 weeks of the study . The 2 primary variables used to assess the equivalence of therapeutic efficacy of the 2 regimens were sitting SBP and sitting DBP , which were measured at weeks 0 ( baseline ) , 4 , 8 , and 16 . The rate of drug-related adverse events ( AEs ) was used to assess whether 1 treatment had a better tolerability profile than the other . Tolerability was assessed by collecting information about AEs by means of question ing the patient or physical examination at each visit . RESULTS A total of 1213 patients were enrolled ( 635 men , 578 women ; mean [ SD ] age , 54.5 [ 10.1 ] years [ range , 28 - 78 years ] ) . The study was completed by 1100 patients ( 553 receiving valsartan  and 547 receiving lisinopril ) . Fifty-one patients ( 8.4 % ) treated with valsartan and 62 ( 10.2 % ) [ corrected ] treated with lisinopril withdrew , mainly because of AEs ( 9 [ 1.5 % ] and 23 patients [ 3.8 % ] , respectively ) . The valsartan- and lisinopril-based treatments were similarly effective in reducing sitting BP , with mean SBP/DBP reductions of 31.2/15.9 mm Hg and 31.4/15.9 mm Hg , respectively . At the end of the study , BP was controlled in 82.6 % [ corrected ] of the patients receiving valsartan and 81.6 % of those receiving lisinopril .  AEs were experienced by 5.1 % of the patients treated with valsartan and 10.7 % of those treated with lisinopril ( P=.0001 ) , with dry cough observed in 1.0 % and 7.2 % of patients , respectively ( P<0.001 ) . CONCLUSIONS Valsartan and lisinopril were both highly effective in controlling BP in these patients with mild to severe hypertension , but valsartan was associated with a significantly reduced risk for AEs , especially cough Thirty-nine patients were entered into a 12-week , r and omized , double-blind , parallel protocol to assess the safety and efficacy of enalapril ( MK-421 , 10 to 20 mg bid ) , hydrochlorothiazide ( HCTZ , 25 to 50 mg bid ) , or combined drug therapy ( MK-421 + HCTZ ) for the treatment of primary hypertension . Specifically monitored were the effects of each drug program on BP and pulse , serum chemistries , body fluid composition and weight , renal function , and the renin-angiotensin-aldosterone axis . Results indicate that MK-421 , HCTZ , and combined therapy were equally effective in lowering BP ; none of the therapies significantly altered glomerular filtration rate or effective renal plasma flow . Patients on MK-421 experienced no change in volume , an increase in plasma potassium , no change in fractional sodium or potassium excretion , and a decreased urine osmolality associated with an enhanced free-water clearance . Plasma renin activity was increased , plasma angiotensin II was decreased , and plasma aldosterone was unchanged . In contrast , patients on HCTZ developed volume contraction , hypokalemia associated with an increase in fractional sodium and potassium excretion , and an increased urine osmolality associated with a decreased free-water clearance . Plasma renin activity was increased , however , plasma angiotensin II and plasma aldosterone were unchanged . Patients on combined therapy  with MK-421 + HCTZ demonstrated qualitatively similar changes in serum chemistries , body fluid volumes , and renal function compared with patients receiving HCTZ alone , whereas changes in the renin-angiotensin-aldosterone system in these patients were qualitatively similar , but more marked , compared with those occurring in patients receiving MK-421 alone . We conclude that MK-421 is an effective first-step antihypertensive agent that does not produce adverse metabolic , volume , or renal effects Combination of an angiotensin-converting enzyme inhibitor ( ACEI ) with an angiotensin II receptor blocker is advocated as a treatment option in diabetic patients with nephropathy and residual albuminuria while on antihypertensive therapy . Abrogation of albuminuria is a key treatment goal to prevent disease progression . The assumption is that albuminuria reduction is the result of more complete blockade of the renin angiotensin system ; thus , the ACEI-angiotensin II receptor blocker combination would have a greater albuminuria-lowering effect than the combination of an ACEI with a calcium channel blocker such as amlodipine , which causes similar reductions in BP but does not affect the renin angiotensin system . Twenty-eight patients who had type 1 diabetes and known diabetic renal disease and had a persistently elevated albumin creatinine ratio ( ACR ) > 10 mg/mmol despite office BP recordings < or = 140/80 mmHg on maximal recommended dose of the ACEI lisinopril were studied . Patients were allocated to receive either c and esartan ( 16 mg/d ) or amlodipine ( 10 mg/d ) in addition to preexisting ACEI inhibition and followed for 24 wk in a r and omized , double-blind , parallel-group trial . By week 24 , ACR fell by 56 % with c and esartan and 54 % with amlodipine ( P < 0.01 versus baseline for both ) with no significant difference between groups . Mean arterial BP fell between 3 and 6 mmHg similarly in both groups . In neither group was a significant correlation found between the change in ACR and the change in BP . C and esartan and amlodipine  lowered ACR and BP by a similar degree . The fall in ACR was disproportionate to the fall of systemic BP and independent of it . The mechanism of the reduction in albuminuria seen with these agents in combination with an ACEI remains to be eluci date
There was a dose-dependent decrease in blood pressure for aliskiren 75 mg , 150 mg and 300 mg .
Aliskiren had no effect on blood pressure variability .
Due to very limited information available regarding change in heart rate and pulse pressure , it was not possible to meta-analyze these outcomes .Mortality and non-fatal serious adverse events were not increased .
AUTHORS ' CONCLUSIONS Compared to placebo , aliskiren lowered BP and this effect is dose-dependent .
This magnitude of BP lowering effect is similar to that for angiotensin-converting enzyme ( ACE ) inhibitors and angiotensin receptor blockers ( ARBs ) .
There is no difference in mortality , nonfatal serious adverse events or withdrawal due to adverse effects with short term aliskiren monotherapy .
BACKGROUND Hypertension is a chronic condition associated with an increased risk of mortality and morbidity .
Renin is the enzyme responsible for converting angiotensinogen to angiotensin I , which is then converted to angiotensin II .
Renin inhibitors are a new class of drugs that decrease blood pressure ( BP ) by preventing the formation of both angiotensin I and angiotensin II .
OBJECTIVES To quantify the dose-related BP lowering efficacy of renin inhibitors compared to placebo in the treatment of primary hypertension .
To determine the change in BP variability , pulse pressure , and heart rate and to evaluate adverse events ( mortality , non-fatal serious adverse events , total adverse events , withdrawal due to adverse effects and specific adverse events such as dry cough , diarrhoea and angioedema ) .