Hemodynamic and biochemical effects of the AT1 receptor antagonist irbesartan in hypertension. Additive hypotensive effect of angiotensin-converting enzyme inhibition and angiotensin-receptor antagonism in essential hypertension. Pharmacologic demonstration of the synergistic effects of a combination of the renin inhibitor aliskiren and the AT1 receptor antagonist valsartan on the angiotensin II-renin feedback interruption. Comparison of the effects of angiotensin receptor antagonist, angiotensin converting enzyme inhibitor, and their combination on regression of left ventricular hypertrophy of diabetes type 2 patients on recent onset hemodialysis therapy. Combination is better than monotherapy with ACE inhibitor or angiotensin receptor antagonist at recommended doses Improvement of cardiac output in patients with severe heart failure by use of ACE-inhibitors combined with the AT1-antagonist eprosartan. Angiotensin II increases erythropoietin production in healthy human volunteers. A controlled, prospective study of the effects of atorvastatin on proteinuria and progression of kidney disease. ADEPT: Addition of the AT1 receptor antagonist eprosartan to ACE inhibitor therapy in chronic heart failure trial: hemodynamic and neurohormonal effects. Effects of Angiotensin II Type 1 Receptor Blocker on Blood Pressure Variability and Cardiovascular Remodeling in Hypertensive Patients on Chronic Peritoneal Dialysis Angiotensin II Type 1 Receptor Antagonist, Losartan, Causes Regression of Left Ventricular Hypertrophy in End-Stage Renal Disease An angiotensin II receptor blocker–calcium channel blocker combination prevents cardiovascular events in elderly high-risk hypertensive patients with chronic kidney disease better than high-dose angiotensin II receptor blockade alone Angiotensin-II receptor antagonist combined with calcium channel blocker or diuretic for essential hypertension Progress Report on the Hypertension Objective Treatment Based on Measurement by Electrical Devices of Blood Pressure (HOMED-BP) Study: Status at February 2004 Regression of left ventricular hypertrophy in human hypertension with irbesartan Rationale, design and patient baseline characteristics of OlmeSartan and calcium antagonists randomized (OSCAR) study: a study comparing the incidence of cardiovascular events between high-dose angiotensin II receptor blocker (ARB) monotherapy and combination therapy of ARB with calcium channel bloc Lack of association between polymorphisms of angiotensin II receptor genes and response to short‐term angiotensin II infusion Efficacy of Combination Antihypertensive Therapy with Low-Dose Indapamide: Assessment by Blood Pressure Self-Monitoring at Home Inhibition of renin–angiotensin system affects prognosis of advanced pancreatic cancer receiving gemcitabine Angiotensin converting enzyme gene polymorphism predicts blood pressure response to angiotensin II receptor type 1 antagonist treatment in hypertensive patients Progress Report on the HOMED‐BP Study: Hypertension Objective Treatment Based on Measurement by Electrical Devices of Blood Pressure Study Association of angiotensin II type 1 receptor polymorphism with resistant essential hypertension. The impact of ACE inhibitors or angiotensin II type 1 receptor blockers on the development of new-onset type 2 diabetes. Distinct time courses of renal protective action of angiotensin receptor antagonists and ACE inhibitors in chronic renal disease Hormonal and hemodynamic effects of aliskiren and valsartan and their combination in sodium-replete normotensive individuals. Long-term effects of addition of mineralocorticoid receptor antagonist to angiotensin II receptor blocker in patients with diabetic nephropathy: a randomized clinical trial. Combined angiotensin-converting enzyme inhibition and receptor blockade associate with increased risk of cardiovascular death in hemodialysis patients. Effect of angiotensin II receptor blockade on autonomic nervous system function in patients with essential hypertension. Efficacy of various antihypertensive agents as evaluated by indices of vascular stiffness in elderly hypertensive patients. Beneficial effects of candesartan, an angiotensin-blocking agent, on compensated alcoholic liver fibrosis - a randomized open-label controlled study. Antihypertensive medications and C-reactive protein in the multi-ethnic study of atherosclerosis. Angiotensin II type 1 receptor A/C1166 polymorphism. Relationships with blood pressure and cardiovascular structure. Differing anti-proteinuric action of candesartan and losartan in chronic renal disease. The Effects of Angiotensin Blocking Agents on the Progression of Liver Fibrosis in the HALT-C Trial Cohort Genome-wide response to antihypertensive medication using home blood pressure measurements: a pilot study nested within the HOMED-BP study. AT1 receptor antagonist Candesartan in selected cirrhotic patients: effect on portal pressure and liver fibrosis markers. A prospective evaluation of persistence on antihypertensive treatment with different antihypertensive drugs in clinical practice Antiproteinuric effects of combined antihypertensive therapies in patients with overt type 2 diabetic nephropathy. Influence of telmisartan on insulin response after glucose loading in obese patients with hypertension: ARB Trial of hypertension in obese patients with hyperinsulinemia assessed by oral glucose tolerance test (ATHLETE) Cardioankle Vascular Index Evaluations Revealed That Cotreatment of ARB Antihypertension Medication With Traditional Chinese Medicine Improved Arterial Functionality The Enhanced Renin-Angiotensin-Aldosteron System Pharmacological Blockade - Which is the Best?
We studied the hemodynamic , neurohumoral , and biochemical effects of the novel angiotensin type 1 ( AT1 ) receptor antagonist irbesartan in 86 untreated patients with essential hypertension on a normal sodium diet . According to a double-blind parallel group trial , patients were r and omized to a once-daily oral dose of the AT1 receptor antagonist ( 1 , 25 , or 100 mg ) or placebo after a placebo run-in period of 3 weeks . R and omization medication was given for 1 week . Compared with placebo , 24-hour ambulatory blood pressure did not change with the 1-mg dose , and it fell ( mean and 95 % confidence interval ) by 7.0 (4.2 - 9.8)/6.1 ( 3.9 - 8.1 ) mm Hg with the 25-mg dose and by 12.1 (8.1 - 16.2)/7.2 ( 4.9 - 9.4 ) mm Hg with the 100-mg dose . Heart rate did not change during either dose . With the 25-mg dose , the antihypertensive effect was attenuated during the second half of the recording , and with the 100-mg dose , it was maintained for 24 hours . Baseline values of renin and the antihypertensive response to the 25- and 100-mg doses were well correlated ( r = .68 , P < .01 ) . Renin did not change with the 1-mg dose , but it rose threefold to fourfold with the 25-mg dose and fourfold to fivefold with the 100-mg dose 4 to 6 hours after administration . With the 100-mg dose , renin was still elevated twofold 24 hours after dosing . The changes in renin induced by the AT1 receptor antagonist were associated with parallel increments in angiotensin I and angiotensin II . Aldosterone , despite AT1 receptor blockade , did not fall . ( ABSTRACT TRUNCATED AT 250 WORDS 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 Interrupting the renin-angiotensin system ( RAS ) with a usual daily dose of a single-site RAS inhibitor does not achieve complete and long-lasting pharmacologic blockade . Hormonal and BP effects were compared for 48 h after administration of single oral doses of 300 mg ( high dose ) of the renin inhibitor aliskiren ( A300 ) and 160 mg ( st and ard antihypertensive dose ) of the AT1 receptor antagonist valsartan ( V160 ) and their combination each at half dose ( A150+V80 ) in 12 mildly sodium-depleted normotensive individuals . In this double-blind , placebo-controlled , r and omized , four-period crossover study , A300 decreased plasma renin activity and angiotensin I and II levels for 48 h , stimulated immunoreactive active renin release more strongly than V160 , and decreased urinary aldosterone excretion for a longer duration than V160 . In contrast to V160 , the A150+V80 combination did not increase plasma angiotensins . The renin and aldosterone effects of the A150+V80 combination were similar to those of A300 and greater than those of V160 . When plasma drug concentrations were taken into account , the A150 + V80 combination had a synergistic effect on renin release . The A150+V80 combination lowered BP at least as effectively as either higher dose monotherapy . In conclusion , in mildly sodium-depleted normotensive individuals , the long-lasting effects of aliskiren alone or in combination with valsartan on plasma immunoreactive active renin and urinary aldosterone effects demonstrate strong and prolonged blockade of angiotensin II at the kidney and the adrenal level . Moreover , a renin inhibitor and AT1R antagonist combination may provide synergistic effects on RAS hormone levels Left ventricular hypertrophy ( LVH ) is frequently found at the initiation of dialysis therapy of diabetic and hypertensive patients , and is highly predictive of future cardiac morbidity and mortality . In patients with hypertension and LVH , both an angiotensin converting enzyme ( ACE ) inhibitor and an angiotensin type 1 receptor ( AT1 ) antagonist regress LVH . However , it remains controversial whether dual blockade of the renin-angiotensin system will regress LVH in these patients using a combination of ACE inhibitor and AT1 antagonist . Thirty-three type II diabetic patients with end-stage renal disease who had just entered into hemodialysis therapy and were diagnosed as having LVH evaluated by echocardiography were selected from three dialysis units staffed by the faculty of Saitama Medical School , Saitama , Japan between 1999 and 2001 . The study was carried out for 1 year . All patients were assigned r and omly to three groups with equal number : group I , an ACE inhibitor , enalapril 10 mg daily ; group II , an AT1 antagonist , losartan 100 mg daily ; group III , combination of enalapril 10 mg and losartan 100 mg daily . All antihypertensive drugs were given 30 min after the cessation of dialysis therapy .  LVH was evaluated by echocardiography before the start of administration of drugs , at 6 months and 12 months after the start of drug therapy . Systolic blood pressure levels less than 140 mmHg were the target for the three groups . Using repeated measures analysis of variance , applied to those with four echocardiograms , there were progressive decreases over time in left ventricular mass index , posterior wall thickness and interventricular septum thickness . There were no significant differences in regression of LVH as well as blood pressure control between enalapril and losartan groups ; however , dual blockade induced an additional 28 % reduction in left ventricular mass index compared with any type of monotherapy . Both ACE inhibitors and AT1 antagonists benefit the regression of LVH in diabetic patients who start dialysis therapy . Moreover , combination therapy with ACE inhibitors and AT1 antagonists would provide more beneficial effects on LVH in these patients than monotherapy Objective The combination of an angiotensin-converting enzyme ( ACE ) inhibitor and an angiotensin II ( Ang II ) receptor antagonist ( ARB ) could provide a higher degree of blockade of the renin-angiotensin system(RAS ) than either agent alone . The primary aim of this study was to look at the effect of three therapeutic regimens ( titrated ACE inhibitor ( ACE-I ) versus titrated ARB versus the combination of an ACE-I and an ARB ) on the attainment of adequate blood pressure ( BP ) control and antiproteinuric effect . Both ACE-I and ARB were titrated as monotherapy up to the maximal recommended dose . Methods A pilot r and omised , parallel group open-label study was conducted in 36 patients with primary renal disease , proteinuria above 1.5 g/day and BP > 140/90 mmHg while on therapy with an ACE-I.  Patients were r and omly assigned to ( 1 ) benazepril , n=12 ; ( 2 ) valsartan , n=12 ; or ( 3 ) benazepril plus valsartan , n=12 . Other antihypertensive therapies could also be added to attain goal BP ( < 140/90 mmHg ) . The primary endpoint was the change in proteinuria during six months of follow-up . Results In the presence of similar BP decreases and stable creatinine clearance values , mean proteinuria decreases were 0.5±1.7 , 1.2±2.0 and 2.5±1.8 g/day in groups 1 , 2 and 3 , respectively . When compared with baseline values , only the fall induced by the combination of ARB and ACE-I attained statistical significance ( p<0.05 ) . Conclusion The antiproteinuric capacity of monotherapy at recommended doses with either an ACE-I or an ARB is lower than that obtained with the combination of the two drugs BACKGROUND The efficacy of ACE-inhibitor therapy is well documented in the treatment of chronic heart failure . As pharmacological mechanisms of ACE-inhibition and angiotensin II AT1-receptor-antagonists differ , an additional positive effect concerning left ventricular function can be expected in combining both classes of drugs . METHODS Twenty patients ( 64.9+/-8.5 years ) with advanced chronic heart failure ( NYHA class III ) receiving long-term medication with digitalis , diuretics and ACE-inhibitors  were  r and omized to either eprosartan ( 540+/-96 mg/day ) or placebo , according to a blinded protocol . Hemodynamic measurements by impedance cardiography were performed at baseline and after 8.85+/-1 . 5 days of study medication treatment . RESULTS Additional treatment with eprosartan result ed in a higher cardiac output than in the control group ( P<0.05 ) . While in the active treatment group cardiac output increased significantly from baseline ( 2.27 - 3.24 l/min , P=0 . 039 ) , there was no change in the control group . CONCLUSIONS The additional treatment with the AT1-receptor antagonist eprosartan , given to severe heart failure patients , who received digitalis , diuretics and ACE-inhibitors , result ed in a beneficial effect by increasing cardiac output . This effect may be due to eprosartan 's additional property of blocking the autocrine interaction of locally and not ACE-generated angiotensin II with their respective vascular and myocardial AT1-receptors as well as the influence on prejunctional AT1-receptors located on sympathetic nerve terminals BACKGROUND A number of animal studies and our own clinical trials point towards a possible influence of the renin-angiotensin-system ( RAS ) on erythropoietin ( EPO ) production . In this study we investigated the role of angiotensin II in the regulation of EPO production in humans . METHODS After a hemorrhage of 750 ml as a basic physiological stimulus 72 healthy male volunteers received in a parallel design either placebo ( physiologic electrolyte solution ) for 6 h , angiotensin II i.v . for 6 h ( 1 - 3 microgram min-1 , sufficient to increase systolic blood pressure by 20 mmHg ) , the selective AT1-receptor antagonist losartan , the ACE-inhibitor captopril , angiotensin II + losartan , or angiotensin II + captopril . RESULTS Administration of angiotensin II alone and in combination with captopril result ed in a significantly higher Cmax EPO ( 67 % higher vs. placebo , P < 0.05 ) and AUCEPO ( 0 - 24h ) ( 40 % higher vs. placebo , P < 0.05 ) . In the groups receiving losartan or captopril alone or the combination of angiotensin II + losartan no significant difference of Cmax EPO and AUCEPO(0 - 24h ) compared to placebo could be detected . CONCLUSIONS This study shows in a model of controlled , basic physiological stimulation of renal EPO production that angiotensin II is able to increase EPO levels in humans . This effect of angiotensin II can be blocked by the specific AT1-receptor antagonist losartan but not by the ACE-inhibitor captopril . The result may be interpreted as a hint that one signal for the control of EPO production in humans may be mediated by angiotensin II (AT1)-receptors BACKGROUND Chronic kidney diseases , particularly if presenting with significant proteinuria , are commonly associated with substantial alteration of serum lipid levels . Experimental evidence suggests that lipid abnormalities may contribute to the progression of kidney disease . However , studies in humans on the subject are scarce . METHODS In a prospect i ve , controlled open-label study , the authors have evaluated the effects of one-year treatment with atorvastatin , a 3-hydroxy-3-methyglutaryl coenzyme A ( HMG-CoA ) reductase inhibitor , versus no treatment on proteinuria and progression of kidney disease in 56 patients with chronic kidney disease . Before r and omization , all patients had already been treated for one year with angiotensin-converting enzyme ( ACE ) inhibitors or angiotensin AT1 receptor antagonists ( ARBs ) and other antihypertensive drugs .  RESULTS By the end of one-year treatment , urine protein excretion decreased from 2.2 + /- 0.1 to 1.2 + /- 1.0 g every 24 hours ( P < 0.01 ) in patients treated with atorvastatin in addition to ACE inhibitor and ARBs . By contrast , urinary protein excretion decreased only from 2.0 + /- 0.1 to 1.8 + /- 0.1 g every 24 hours ( P value not significant ) in patients who did not receive atorvastatin in addition to ACE inhibitor or ARBs . During this time , creatinine clearance decreased only slightly and not significantly ( from 51 + /- 1.8 to 49.8 + /- 1.7 ) in patients treated with atorvastatin . By contrast , during the same period of observation , creatinine clearance decreased from 50 + /- 1.9 to 44.2 + /- 1.6 mL/min ( P < 0.01 ) in patients who did not receive atorvastatin . CONCLUSIONS This study has shown that treatment with atorvastatin in addition to a regimen with ACE inhibitors or ARBs may reduce proteinuria and the rate of progression of kidney disease in patients with chronic kidney disease , proteinuria , and hypercholesterolemia . The benefits appear to occur in addition to those of treatment with ACE inhibitor and ARBs 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 Aims : In this study , we examined whether addition of an angiotensin II type 1 receptor blocker ( ARB ) , c and esartan or valsartan , to conventional antihypertensive treatment could improve blood pressure ( BP ) variability in hypertensive patients on peritoneal dialysis . Methods : 45 hypertensive patients on chronic peritoneal dialysis therapy were r and omly assigned to the ARB treatment groups either by c and esartan ( n = 15 ) or valsartan ( n = 15 ) , or the control group ( n = 15 ) . At baseline and 6 months after the treatment , 24-hour ambulatory BP monitoring , echocardiography  , and measurement of brachial-ankle pulse wave velocity ( baPWV ) were performed . Results : After the 6 months of treatment , 24-hour ambulatory BP values were similarly decreased in both the control group and ARB groups . However , short-term BP variability assessed on the basis of the st and ard deviation of 24-hour ambulatory BP was significantly decreased in the ARB groups , but remained unchanged in the control group . Furthermore , parameters of cardiovascular remodeling assessed by natriuretic peptides , echocardiography , and baPWV were significantly improved in the ARB groups but not in the control group . Conclusion : ARB treatment and control antihypertensive treatment similarly controlled 24-hour ambulatory BP values in hypertensive patients on peritoneal dialysis . However , ARB treatment is beneficial for the suppression of pathological cardiovascular remodeling with a decrease in BP variability Left ventricular hypertrophy ( LVH ) commonly occurs in patients with end-stage renal disease ( ESRD ) and is an independent risk factor for cardiovascular events . Angiotensin II type 1 receptor ( AT1-R ) antagonists may be able to reverse LVH independent to the hypotensive effect in the ESRD setting . Thirty chronically hemodialyzed uremic patients with hypertension were r and omly assigned to receive the AT1-R antagonist losartan ( n = 10 ) , the angiotensin-converting enzyme ( ACD ) inhibitor enalapril ( n = 10 ) , or calcium antagonist amlodipine ( n = 10 ) . Left ventricular mass ( LVM ) index was measured by echocardiography before and 6 months after treatment . The baseline demographic and clinical characteristics did not differ between the three groups . The mean baseline LVM index also did not differ in the three groups . After 6 months of treatment , losartan treatment significantly reduced the LVM index ( –24.7 ± 3.2 % ) than amlodipine ( –10.5 ± 5.2 % ) or enalapril ( –11.2 ± 4.1 % ) therapy . All three groups had a similar decrease in the mean blood pressure with treatment . The plasma angiotensin II concentration increased 5-fold with losartan treatment . In contrast , the plasma angiotension II concentration did not change with enalapril and only increased 2-fold with amlodipine . Thus , the present study indicates that losartan more effectively regresses LVH in patients with ESRD than do enalapril and amlodipine despite a comparable depressor effect between the three drugs The OSCAR study was a multicenter , prospect i ve r and omized open-label blinded end-point study of 1164 Japanese elderly hypertensive patients comparing the efficacy of angiotensin II receptor blocker ( ARB ) uptitration to an ARB plus calcium channel blocker ( CCB ) combination . In this prospect i ve study , we performed prespecified subgroup analysis according to baseline estimated glomerular filtration rate ( eGFR ) with chronic kidney disease ( CKD ) defined as an eGFR < 60 ml/min per 1.73 m2 .  Blood pressure was lower in the combined therapy than in the high-dose ARB cohort in both groups with and without CKD . In patients with CKD , significantly more primary events ( a composite of cardiovascular events and noncardiovascular death ) occurred in the high-dose ARB group than in the combination group ( 30 vs. 16 , respectively , hazard ratio 2.25 ) . Significantly more cerebrovascular and more heart failure events occurred in the high-dose ARB group than in the combination group . In patients without CKD , however , the incidence of primary events was similar between the two treatments . The treatment-by-subgroup interaction was significant . Allocation to the high-dose ARB was a significant independent prognostic factor for primary events in patients with CKD . Thus , the ARB plus CCB combination conferred greater benefit in prevention of cardiovascular events in patients with CKD compared with high-dose ARB alone . Our findings provide new insight into the antihypertensive strategy for elderly hypertensive patients with CKD To achieve the target blood pressure recommended by the latest guidelines , multiple antihypertensive drugs are needed in most patients . In this study , the efficacy of treatment using an angiotensin II receptor antagonist ( ARB ) combined with a calcium channel blocker ( CCB ) or a diuretic was compared from multiple perspectives in patients with hypertension . Twenty-nine patients with essential hypertension , who had failed to achieve their target blood pressure ( < 130/85 mm Hg for patients < 65 years old and < 140/90 mm Hg for those ⩾65 years ) when treated with the ARB olmesartan at 20 mg day−1 , were additionally given 8–16 mg day−1 of the CCB azelnidipine or 1–2 mg day−1 of trichlormethiazide ( a thiazide diuretic ) in a r and omized crossover manner for 4 months each . At the end of each combination therapy period , blood and urine sample s were collected and arterial stiffness was evaluated by measuring the cardio-ankle pulse wave velocity . Compared with monotherapy , the blood pressure was reduced similarly by adding azelnidipine ( −12/−10 mm Hg ) or trichlormethiazide ( −14/−9 mm Hg ) . The heart rate was decreased with the CCB by 4 b.p.m . ( P<0.05 ) , whereas it was unchanged with the thiazide . Serum K , lipids and blood glucose were not significantly changed with either combination , whereas serum uric acid was increased with the thiazide ( P<0.01 ) but was unchanged with azelnidipine  . Plasma levels of renin , angiotensin II and aldosterone were also increased with the thiazide period , whereas high-sensitivity C-reactive protein and oxidized low-density lipoprotein were decreased with azelnidipine . In addition , the cardio-ankle vascular index , a parameter of arterial stiffness , was decreased with the azelnidipine period but was unchanged with the thiazide period ( P<0.01 ) . It is suggested that the combination of olmesartan and azelnidipine has advantages over the combination of olmesartan and a thiazide with respect to avoiding hyperuricemia , sympathetic activation , renin – angiotensin-aldosterone system stimulation , inflammation , oxidative stress , and increased arterial stiffness in patients with moderate hypertension . These properties may provide cardiovascular protection in addition to the hypotensive effect The Hypertension Objective Treatment Based on Measurement by Electrical Devices of Blood Pressure ( HOMED-BP ) Study is the first large-scale intervention trial in Japan using a PROBE design to determine an optimal target blood pressure ( BP ) level on the basis of self-measured BP at home and optimal initial antihypertensive medication . The registered patients are r and omized to one of two different BP levels and to initial antihypertensive regimens ( i.e.  ,  calcium antagonist [ Ca-A ] , angiotensin-converting enzyme inhibitor [ ACE-I ] , or angiotensin II receptor antagonist [ ARB ] ) . At the end of February 2004 , 2729 , 1687 , and 971 patients were recruited , r and omized , and followed-up for 12 months or more . Among the 971 patients , mean systolic/diastolic BP levels at r and omization in the Ca-A , ACE-I , and ARB groups were 150/90 , 152/89 , and 151/89 mmHg , respectively . These values reduced after six months of Ca-A- , ACE-I- , and ARB-based treatment ( 133/81 mmHg , 135/80 mmHg , and 134/79 mmHg , respectively ) and further reduced after 12 months ( 131/80 mmHg , 134/79 mmHg , and 132/79 mmHg , respectively ) without any significant differences among groups . In more intensive and less intensive BP-lowering groups , mean systolic/diastolic BP levels at r and omization were 151/90 and 150/89 mmHg , respectively . Although BP levels reduced after 6-month ( 135/80 mmHg and 133/80 mmHg , respectively ) and 12-month treatment ( 133/79 mmHg and 132/80 mmHg , respectively ) in each target group , no significant difference in BP values was observed between groups . These results indicate the necessity of additional interventional strategies to improve the achievement of target BP levels , especially in the more intensive BP-lowering group Background The Swedish irbesartan left ventricular hypertrophy investigation versus atenolol ( SILVHIA ) . Objective Angiotensin II induces myocardial hypertrophy . We hypothesized that blockade of angiotensin II subtype 1 ( AT1 ) receptors by the AT1-receptor antagonist irbesartan would reduce left ventricular mass ( as measured by echocardiography ) more than conventional treatment with a beta blocker . Design and methods This double-blind study r and omized 115 hypertensive men and women with left ventricular hypertrophy to receive either irbesartan 150 mg q.d . or atenolol 50 mg q.d . for 48 weeks . If diastolic blood pressure remained above 90 mmHg , doses were doubled , and additional medications ( hydrochlorothiazide and felodipine ) were prescribed as needed . Echocardiography was performed at weeks 0 , 12 , 24 and 48 . Results Baseline mean blood pressure was 162/104 mmHg , and mean left ventricular mass index was 157 g/m2 for men and 133 g/m2 for women . Systolic and diastolic blood pressure reductions were similar in both treatment groups . Both irbesartan ( P < 0.001 ) and atenolol ( P < 0.001 ) progressively reduced left ventricular mass index , e.g. by 26 and 14 g/m2 ( 16 and 9 % ) , respectively , at week 48 , with a greater reduction in the irbesartan group ( P = 0.024 ) . The proportion of patients who attained a normalized left ventricular mass ( i.e. ⩽ 131 g/m2 for men and ⩽ 100 g/m2 for women ) tended to be greater with irbesartan ( 47 versus 32 % , P = 0.108 ) . Conclusions Left ventricular mass was reduced more in the irbesartan group than in the atenolol group . These results suggest that blocking the action of angiotensin II at AT1-receptors may be an important mechanism , beyond that of lowering blood pressure , in the regulation of left ventricular mass and geometry in patients with hypertension Higher doses of angiotensin II receptor blockers ( ARBs ) are expected to exert more protective effects against cardiovascular diseases . However , the significance of treatment of hypertension with high-dose ARB remains to be defined . The OlmeSartan and Calcium Antagonists R and omized ( OSCAR ) Study was design ed to determine whether high-dose ARB monotherapy is superior to the combination therapy of ARB plus calcium channel blocker ( CCB ) in the prevention of cardiovascular morbidity/mortality in Japanese elderly high-risk hypertensive patients . The OSCAR study is a multicenter , active-controlled , two-arm parallel group comparison , using the prospect i ve r and omized open-blinded end-point method . In the ‘ Step 1 ’ period , elderly hypertensive patients with diabetes or cardiovascular disease received monotherapy with ARB olmesartan medoxomil at a dose of 20 mg day−1 . If the target blood pressure control ( less than 140/90 mm Hg ) was not achieved by ARB monotherapy , the patients were r and omized to receive either ( 1 ) the increased dose of olmesartan at 40 mg day−1 ( high-dose ARB monotherapy ) or ( 2 ) the addition of a CCB ( amlodipine or azelnidipine ) to 20 mg day−1 olmesartan ( ARB plus CCB combination ) in the ‘ Step 2 ’ period . The follow-up duration will be 3 years . The primary end points will be the composite of fatal and non-fatal cardiovascular events , and death from any cause .  Recruitment for the OSCAR study ( around 1200 patients ) was completed by the end of May 2007 . The OSCAR study is the first large clinical trial comparing the efficacy of high-dose ARB monotherapy with that of an ARB plus CCB combination therapy in elderly high-risk hypertensive patients Objectives The physiological effects of polymorphisms of the renin – angiotensin — aldosterone system ( RAAS ) are poorly understood . Long-term effects of genetic variants can be studied in cross-sectional linkage studies . In this study , we examined the short-term effects of genetic polymorphisms of the angiotensin II AT1- and AT2-receptor subtypes in humans by means of angiotensin II infusion . Methods In 120 male , white , young ( 26 6 3 years ) subjects with normal or mildly elevated blood pressure , changes in mean arterial blood pressure , aldosterone levels , glomerular filtration rate ( GFR ) , and renal plasma flow ( RPF ) were measured in response to angiotensin II infusion ( 0.5 ng/kg per min and 3.0 ng/kg per min , each over 30 min ) . The −22228 G/A polymorphism of the AT1-receptor gene , and the + 1675 G/A polymorphism of the AT2-receptor gene were determined by restriction digestion and single str and conformation polymorphism analysis , respectively . Results Infusion of angiotensin II result ed in an increase in mean arterial pressure , serum aldosterone levels and GFR , and in a decrease in RPF ( all P < 0.001 ) . However , at similar baseline mean arterial pressure , aldosterone levels , and renal haemodynamics , the response to angiotensin II did not significantly differ across the AT1- and AT2-receptor genotypes with the sample size of our study being adequate to detect relevant differences accross the genotypes with a power of > 90 % for all parameters . Conclusions The response to angiotensin II infusion  does not differ across the the AT1- and AT2-receptor genotypes examined in our study . However , long-term effects of variants of angiotensin II receptor genes can not be ruled out with this approach We examined the effects of the addition of low-dose indapamide to antihypertensive drugs of other classes , as well as its duration of action , using blood pressure ( BP ) self-monitoring at home . Seventy-six patients undergoing monotherapy with a calcium channel blocker ( CCB ) , angiotensin converting-enzyme inhibitor ( ACEI ) , or angiotensin AT1-receptor blocker ( ARB ) , but had an average morning home systolic BP ( SBP ) ≥ 135 mmHg or diastolic BP ( DBP ) ≥ 85 mmHg , were studied .  Indapamide ( 1 mg ) was added to their existing treatment once daily for 4 weeks . The additional hypotensive effects  of indapamide were evaluated by casual and home BPs , and the results were compared among the three groups of subjects classified according to their initial drug treatment classes . The morning/evening ( M/E ) ratio of BP reduction was calculated to assess the duration of the effect . Overall , indapamide significantly ( P < 0.001 ) lowered morning home BP ( 147 ± 12/87 ± 9 mmHg to 135 ± 12/81 ± 9 mmHg ) , evening home BP ( 138 ± 15/79 ± 10 mmHg to 126 ± 12/73 ± 9 mmHg ) , and casual BP ( 145 ± 21/86 ± 14 mmHg to 136 ± 17/81 ± 13 mmHg ) . All groupsshowed significant indapamide-induced home SBP/DBP decreases , whereas only the ACEI and ARB groups , but not the CCB group , showed a home pulse pressure ( PP ) reduction . Evening SBP and PP decreases were significantly greater in the ARB group than in the CCB group . The mean M/E ratio with indapamide was 0.95 for SBP and 0.85 for DBP . Low-dose indapamide used in combination can provide additional anti-hypertensive efficacy lasting for 24 h. The added effect of indapamide may be more prominent on ARBs than on CCBs Background : The renin – angiotensin system ( RAS ) is thought to have a role in carcinogenesis , and RAS inhibition may prevent tumour growth . Methods : We retrospectively investigated the impact of angiotensin I-converting enzyme inhibitors ( ACEIs ) and angiotensin II type-1 receptor blockers ( ARBs ) in 155 patients with pancreatic cancer receiving gemcitabine monotherapy .  Patients were divided into three groups : the ACEI/ARB group ( 27 patients receiving an ACEI or ARB for hypertension ( HT ) ) , the non-ACEI/ARB with HT group ( 25 patients receiving antihypertensive drugs other than ACEIs or ARBs ) , and the non-HT group ( 103 patients receiving no antihypertensive drugs ) . Results : Patient characteristics were not different , except for age and HT medications . Progression-free survival ( PFS ) was 8.7 months in the ACEI/ARB group , 4.5 months in the non-ACEI/ARB with HT group , and 3.6 months in the non-HT group . Overall survival ( OS ) was 15.1 months in the ACEI/ARB group , 8.9 months in the non-ACEI/ARB with HT group , and 9.5 months in the non-HT group . The use of ACEIs/ARBs was a significant prognostic factor for both PFS ( P=0.032 ) and OS ( P=0.014 ) in the multivariate analysis . Conclusions : The ACEIs/ARBs in combination with gemcitabine might improve clinical outcomes in patients with advanced pancreatic cancer . Prospect i ve trials are needed to test this hypothesis 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 Hypertension Objective treatment based on Measurement by Electrical Devices of Blood Pressure Study ( HOMED BP Study ) is the first large‐scale intervention trial in Japan using a Prospect i ve R and omized Open Blinded Endpoint ( PROBE ) design to determine an optimal target blood pressure ( BP ) level on the basis of self‐measured BP at home , and an optimal initial course of antihypertensive medication . The registered patients are r and omized to either a more intensive BP‐lowering group ( home systolic BP < 125 mmHg and diastolic < 80 mmHg ) or a less intensive group ( home systolic/diastolic BP within the range 134–125/84–80 mmHg ) by host computer via the Internet . The differential effect of three classes of initial antihypertensive regimens on the prognosis , i.e. , calcium antagonist ( Ca‐A ) , angiotensin‐converting enzyme inhibitor ( ACE‐I ) or angiotensin II receptor antagonist ( ARB ) , which are used most frequently in Japan , are examined . Three regimens are also r and omly assigned to the host computer via the Internet . A pilot study was started in May 2001 . In March 2002 , the number of participating doctors was 461 . At the end of March 2002 , 546 patients were recruited . Of these , 412 ( 202 men and 210 women , aged 58.4 ± 10.2 y ) were r and omized . Patients will be recruited until February , 2006 and followed for 7 years Angiotensin II type 1 receptor ( AT1 ) mediates the vasoconstrictive and growth-promoting effect of angiotensin II in humans . It has been reported that a polymorphism of the AT1 gene ( an A/C transversion at position 1166 : A-C1166 ) occurs more frequently in resistant hypertensives taking two or more antihypertensive drugs . On the contrary , a recent study of the influence of the A-C1166 polymorphism on aortic stiffness demonstrated that the distribution of the genotypes did not differ between normotensive and hypertensive subjects . In addition , a recent population -based survey of Caucasian hypertensives reported lower blood pressure values in CC homozygotes than in heterozygotes and AA homozygotes . Because of these controversial results and the lack of a sufficient amount of data the present study was design ed to assess the contribution of the AT , gene A-C1166 polymorphism to resistant essential hypertension . Forty-eight subjects with resistant essential hypertension ( HT ) and 48 normotensive ( NT ) , age and sex-adjusted controls ( from a population of 300 healthy blood donors ) were selected . All subjects were genotyped for the A-C1166 polymorphism in the 3'-UTR of the AT1 gene using PCR-based techniques . The influence of genotype on blood pressure ( BP ) was investigated using ANOVA R and omized Complete Block ( ANOVA RCB ) design according to sex , age and BMI . There were no significant differences in allele or genotype frequencies between HT and NT subjects ( X2 = 0.61 ; P = NS ) . In HT subjects higher values of systolic blood pressure were associated with the C allele of the AT1 gene only in older and overweight patients ( P < 0.001 and P < 0.001 , respectively ) . Also in HT patients an association between the presence of the C allele of the AT1 gene and higher values of diastolic blood pressure was present in overweight patients ( P = 0.001 ) . These results suggest that in resistant hypertensive subjects the AT1 A-C1166 polymorphism is potentially involved in the regulation of blood pressure . As the effects of genotypes on blood pressure are pronounced in older and overweight subjects this polymorphism may amplify the effects of age and BMI on resistant essential hypertension OBJECTIVE Angiotensin II has been shown to increase hepatic glucose production and decrease insulin sensitivity . Patients who utilize either an ACE inhibitor ( ACEI ) or angiotensin receptor blocker ( ARB )  may experience a decreased incidence of new-onset type 2 diabetes . RESEARCH DESIGN AND METHODS Three review ers conducted a systematic literature search of Medline , EMBASE , CINAHL , and the Cochrane Library ( 1966 to present ) to extract a consensus of trial data involving an ACEI or ARB with an end point of new-onset type 2 diabetes . Studies were included if they were r and omized controlled trials verses placebo/routine therapy . A r and om-effects model was utilized . Subgroup and sensitivity analyses were conducted . RESULTS Eleven trials were identified , including 66,608 patients . An ACEI or ARB prevented new-onset type 2 diabetes ( odds ratio 0.78 [ 95 % CI 0.73 - 0.83 ] ) . The influence of either an ACEI ( six trials ) or an ARB ( five trials ) alone on new-onset type 2 diabetes was similar ( 0.79 [ 0.71 - 0.89 ] and 0.76 [ 0.70 - 0.82 ] , respectively ) . Regardless of indication for use , hypertension ( seven trials ) , coronary artery disease ( two trials ) , or heart failure ( two trials ) , reductions in new-onset type 2 diabetes were maintained ( 0.79 [ 0.72 - 0.85 ] , 0.76 [ 0.60 - 0.95 ] , and 0.70 [ 0.50 - 0.96 ] , respectively ) . No statistical heterogeneity was observed for any evaluation ( P > 0.1 for all comparisons ) . ACEIs and ARBs did not reduce the odds of mortality , cardiovascular , or cerebrovascular events versus control therapy among all of these studies combined or the hypertension trials . ACEIs and ARBs did reduce the odds of these outcomes among the coronary artery disease studies versus control therapy . CONCLUSIONS ACEIs or ARBs may decrease patients ' odds of developing new-onset type 2 diabetes but does not reduce the odds of mortality , cardiovascular , or cerebrovascular outcomes over the study follow-up periods among patients with hypertension Although the angiotensin receptor antagonist ( ARB ) shares the angiotensin-II-blocking activity with the angiotensin-converting enzyme inhibitor ( ACE-I ) , pharmacological mechanisms of action of these agents differ . We evaluated the temporal profiles of action of ACE-I and ARB on urinary protein excretion and nitrate/nitrate ( NOx ) excretion in hypertensive ( 140 and /or 90 mmHg ) patients with chronic renal disease ( serum creatinine<265 ( range , 44–265 ) μmol/l or creatinine clearance>30 ( range , 30–121 ) ml/min ) . Patients with mild ( < 1 g/day ; range , 0.4–1.0 ) and moderate proteinuria ( > 1 g/day ; range , 1.1–6.9 ) were r and omly assigned to ACE-I- and ARB-treated groups , and were treated with ACE-I ( tr and olapril or perindopril ) or ARB(losartan or c and esartan ) for 48 weeks . In all groups , treatment with ACE-I or ARB  decreased blood pressure to the same level , but had no effect on creatinine clearance . In patients with mild proteinuria  , neither ACE-I nor ARB altered urinary protein excretion . In patients with moderate proteinuria , ACE-I caused 44±6 % reduction in proteinuria ( from 2.7±0.5 to 1.5±0.4 g/day , n=14 ) at 12 weeks , and this beneficial effect persisted throughout the protocol ( 48 weeks , 1.2±0.2 g/day ) . In contrast , ARB did not produce a significant decrease in proteinuria at 12 weeks ( 23±8 % , n=13 ) , but a 41±6 % reduction in proteinuria was observed at 48 weeks . Similarly , although early ( 12 weeks ) increases in urinary NOx excretion were observed with ACE-I ( from 257±70 to 1111±160 μmol/day ) and ARB ( from 280±82 to 723±86 μmol/day ) , the ARB-induced increase in NOx excretion was smaller than that by ACE-I ( P<0.05 ) . In conclusion , although both ACE-I and ARB reduce blood pressure similarly , the effect of these agents on proteinuria differs in chronic renal disease with moderate proteinuria . Relatively early onset of the proteinuria-reducing effect was observed with ACE-I , which paralleled the increase in urinary NOx excretion .  Conversely , ARB decreased proteinuria and increased urinary NOx excretion gradually . These time course-dependent changes in proteinuria and urinary NOx may reflect the pharmacological property of ACE-I and ARB , with regard to the action on bradykinin BACKGROUND AND OBJECTIVES An AT1 receptor antagonist induces a counterregulatory renin release whose intensity and duration reflect the magnitude of the renin-angiotensin blockade . We investigated whether a renin inhibitor may neutralize this counterregulation and amplify the effects of AT1 receptor antagonists . DESIGN , SETTING , PARTICIPANTS , & MEASUREMENTS In 12 normotensive male individuals who were on a high-sodium diet , a double-blind , placebo-controlled , r and omized , crossover design was used to study the hormonal and BP effects of single oral administrations of 300 mg of the renin inhibitor aliskiren , 320 mg of valsartan , and a combination of these two drugs , each at half dosage ( 150 mg of aliskiren and 160 mg of valsartan ) . RESULTS Valsartan ( 320 mg ) increased plasma renin activity and angiotensin I and angiotensin II levels , but 300 mg of aliskiren decreased them for 48 h. Aliskiren ( 300 mg ) stimulated immunoreactive renin release more strongly than 320 mg of valsartan , decreased urinary aldosterone excretion for longer than 320 mg of valsartan , and had a similar BP-lowering effect as 320 mg of valsartan . In combination , 150 mg of aliskiren neutralized the valsartan ( 160 mg)-induced increase in plasma angiotensins for 48 h. The renin and aldosterone effects of the combination of 150 mg of aliskiren and 160 mg of valsartan were similar to those of 300 mg of aliskiren and greater than those of 320 mg of valsartan . When plasma drug concentrations were taken into account , the combination of 150 mg of aliskiren and 160 mg of valsartan had a synergistic effect on renin release . The BP-lowering effect of 150 mg of aliskiren and 160 mg of valsartan was similar to that of 300 mg of aliskiren and 320 mg of valsartan at peak but was more prolonged . CONCLUSION The stronger and longer lasting effects on plasma active renin and urinary aldosterone of aliskiren , alone or in combination , demonstrate a more effective blockade of the renin-angiotensin system than that obtained with 320 mg of valsartan alone BACKGROUND Addition of spironolactone ( SPR ) to angiotensin-converting enzyme ( ACE ) inhibitors or angiotensin II receptor blockers ( ARBs ) might provide antiproteinuric effects beyond what is gained by either medication alone . This study was design ed to assess the long-term efficacy of SPR/ARB combination in comparison with the st and ard ACE/ARB regimen in diabetic nephropathy . METHODS In an open-label , parallel-group , single-center , r and omized clinical trial ( NCT01667614 ) , 136 patients with diabetes and proteinuria , already treated with enalapril and losartan , were included . In 74 patients , ACE inhibitors  were discontinued . After a wash-out period of 2 weeks , 25 mg SPR daily was initiated . The remainder of the patients ( n = 62 ) received ACE inhibitors and ARBs as before . Patients were followed every 3 months for 18 months . During each visit , systolic and diastolic blood pressure ( BP ) , urinary albumin excretion ( UAE ) , serum creatinine , estimated glomerular filtration rate ( eGFR ) and serum potassium concentrations were determined . RESULTS After 18 months , three patients in the SPR/ARB group developed asymptomatic hyperkalemia .  SPR/ARB significantly reduced both systolic and diastolic BP ( P < 0.001 and 0.001 , respectively ) . SPR/ARB  decreased UAE by 46 , 72 and 59 % after 3 , 12 and 18 months , respectively . Compared with the continuation regimen , SPR/ARB was superior in UAE reduction ( P = 0.017 after 18 months ) , independent of BP change . In both groups , eGFR declined significantly over the trial course and the decline rate did not differ significantly between the two groups . CONCLUSIONS Addition of SPR to ARB provides added benefits with respect to BP control and proteinuria diminution . These antiproteinuric effects are not accompanied by prevention of eGFR loss compared with conventional therapy with ACE/ARB To compare the relative effectiveness of angiotensin-converting enzyme inhibitors ( ACEIs ) and angiotensin receptor blockers ( ARBs ) in reducing cardiovascular mortality in chronic hemodialysis patients , we conducted an observational analysis of all patients initiated on ACEI or ARB therapy undergoing chronic hemodialysis at a large dialysis provider .  Survival curves with mortality hazard ratios ( HRs ) were generated using the Kaplan-Meier method and Cox regression . Outcomes were compared using inverse probability of treatment weighting and propensity score matching . Over 6 years , 22,800 patients were newly initiated on an ACEI and 5828 on an ARB after at least 60 days of chronic hemodialysis . After adjustment for baseline cardiovascular risk factors , there was no significant difference in the risk of cardiovascular , all-cause , or cerebrovascular mortality in patients initiated on an ARB compared with an ACEI ( HR of 0.96 ) . A third of 28,628 patients , newly started on an ACEI or ARB , went on to another  antihypertensive medication  in succession . After adjustment for risk factors , 701 patients initiated on combined ACEI and ARB therapy ( HR of 1.45 ) or 6866 patients on ACEI and non-ARB antihypertensive agent ( HR of 1.27 ) were at increased risk of cardiovascular death compared with 1758 patients initiated on an ARB and non-ACEI antihypertensive therapy . Thus , an ARB , in combination with another antihypertensive medication ( but not an ACEI ) , may have a beneficial effect on cardiovascular mortality . As observational studies may be confounded by indication , even when adjusted , r and omized clinical trials are needed to confirm these findings It has long been proposed that the renin-angiotensin system exerts a stimulatory influence on the sympathetic nervous system , including augmentation of central sympathetic outflow and presynaptic facilitation of norepinephrine release from sympathetic nerves . We tested this proposition in 19 patients with essential hypertension , evaluating whether the angiotensin receptor blockers ( ARBs ) eprosartan and losartan had identifiable antiadrenergic properties . This was done in a prospect i ve , r and omized , three-way placebo-controlled study of crossover design . Patients were r and omized to 600 mg of eprosartan daily , 50 mg of losartan daily , or placebo . The treatment period was 4 wk , with 2-wk washout periods . Multiunit firing rates in efferent sympathetic nerves distributed to skeletal muscle vasculature ( muscle sympathetic nerve activity , MSNA ) were measured with microneurography , testing whether ARBs inhibit central sympathetic outflow . In parallel , isotope dilution methodology was used to measure whole body norepinephrine spillover to plasma . Mean blood pressure on placebo was 151/98 mmHg , with both ARBs causing reductions of approximately 11 mmHg systolic and 6 mmHg diastolic pressure , placebo corrected . Both MSNA [ 35 + /- 12 bursts/min ( mean + /- SD ) on placebo ] and whole body norepinephrine spillover [ 366 + /- 247 ng/min ] were unchanged by ARB administration , indicating that the ARBs did not material ly inhibit central sympathetic outflow or act presynaptically to reduce norepinephrine release at existing rates of nerve firing . These findings contrast with the easily demonstrable reduction in sympathetic nervous activity produced by antihypertensive drugs of the imidazoline-binding class , which are known to act within the brain to inhibit sympathetic nervous outflow . We conclude that sympathetic nervous inhibition is not a major component of the blood pressure-lowering action of ARBs in essential hypertension When observed in elderly hypertensive patients , increased pulse pressure ( PP ) and arterial stiffness are known to be independent risk factors for cardiovascular diseases . Increased systolic blood pressure ( SBP ) leads to left ventricular hypertrophy , while decreased diastolic blood pressure ( DBP ) results in decreased coronary circulation . It is known that increased arterial stiffness is the major cause of increased PP . Thus basic morbid states of cardiac failure or ischemic heart diseases are more likely to develop in elderly hypertensive patients with increased PP and arterial stiffness , and there is need of antihypertensive drugs that decrease these effects in elderly hypertensives . In this study , we compared the effects of an angiotensin-receptor blocker ( ARB : valsartan ) , an angiotensin-converting enzyme inhibitor ( ACE-I : temocapril ) , and long-acting Ca antagonists ( L- and N-type Ca channel blocker : cilnidipine ; and L-type Ca channel blocker : nifedipine CR ) on PP and arterial stiffness measured by pulse wave velocity in elderly hypertensive patients for 3 months . The ARB yielded the largest reductions in PP and brachial-ankle pulse wave velocity ( baPWV ) , followed by the ACE-I and L- and N-type Ca channel blocker , while the L-type Ca channel blocker yielded no improvement . The effects on arterial stiffness and PP thus varied among the drug characteristics . Although ARB achieved the largest reduction in baPWV , this decrease was not associated with any reductions in PP , SBP , DBP , or mean blood pressure , as were the baPWV-decreases achieved by the other drugs , suggesting that ARB may further reduce the risk of arteriosclerosis in elderly hypertensive patients by decreasing arterial stiffness in addition to its antihypertensive effect BACKGROUND Recent studies have shown that the renin-angiotensin system is implicated in hepatic fibrogenesis in vitro and in vivo . However , no study was done in humans with alcoholic liver disease . AIM To investigate the antifibrotic effect of angiotensin II type 1 receptor ( AT1-R ) blocking agents ( ARB ) in patients with alcoholic liver disease . METHODS The primary outcome was improvement in patients ' histological features . Eighty-five patients with compensated alcoholic liver fibrosis ( ≥ F2 ) which was confirmed by baseline liver biopsy were r and omized ( intention-to-treat ( ITT ) ) to receive either ARB , c and esartan ( 8 mg/day ) with ursodeoxycholic acid ( UDCA ) ( 600 mg/day ) ( n = 42 ) or UDCA alone ( n = 43 ) as control for 6 months and follow-up liver biopsies were conducted . RESULTS According to the Laennec fibrosis system , c and esartan showed significantly higher rates of histological improvements ( ITT , 33.3 % vs. 11.6 % , P = 0.020 ) . In addition , the fibrosis score was significantly reduced from 3.4 ± 1.4 to 3.1 ± 1.5 ( P = 0.005 ) in the c and esartan group . C and esartan also reduced the area of fibrosis and α-smooth muscle actin positive from 11.3 ± 6.0 to 8.3 ± 4.7 and 28.7 ± 10.5 to 23.9 ± 10.3 ( % ) , and the hydroxyproline levels ( μg/g liver tissue ) from 7.8 ± 2.4 to 6.3 ± 1.7 respectively ( P < 0.05 ) . In addition , the relative expression of transforming growth factor-β1(TGF-β1 ) , collagen-1 , AT1-R , tissue inhibitor of metalloproteinase 1 ( TIMP-1 ) , metalloproteinases2 ( MMP2 ) , Rac1 and p22phox by real-time RT-PCR decreased in the c and esartan group ( P < 0.05 ) . Mean arterial blood pressure in the c and esartan group decreased mildly but significantly ( P < 0.001 ) . No significant complications and side effects were observed during the present study . CONCLUSIONS Administration of ARB in compensated alcoholic liver disease induces improvement of fibrosis in histological and quantitative measurements BACKGROUND The effects of different antihypertensive medication classes on C-reactive protein ( CRP ) levels are still not well characterized , and might be of relevance to treatment choices . METHODS We studied the association between antihypertensive medication class and CRP levels among participants with treated hypertension in the Multi-Ethnic Study of Atherosclerosis . We performed a cross-sectional study of hypertensive participants free of clinical cardiovascular disease who were taking one or more of the following medication classes : beta-blockers , calcium channel blockers , diuretics , and angiotensin-converting enzyme ( ACE ) inhibitors , or angiotensin II type I receptor blockers ( ARB ) .  RESULTS Among 2340 participants taking one or more antihypertensive medications , the mean serum CRP level was lower among participants taking a beta-blocker than among those not taking a beta-blocker ( 2.13 v 2.54 mg/L , P = .002 ) . This difference persisted after multivariate adjustment ( P = .021 ) . There were no other statistically significant differences in multivariate models . Among 1314 participants receiving monotherapy , the multivariate adjusted mean CRP level among participants taking a beta-blocker was lower ( 1.97 mg/L ) than those taking a diuretic ( 2.72 mg/L , P < .001 ) . In this monotherapy group , participants taking an ACE inhibitor or ARB also had a lower adjusted mean CRP ( 2.25 mg/L ) than those taking a diuretic ( P = .046 ) . African-American race/ethnicity did not modify any of those relationships . CONCLUSIONS The beta-blocker use was associated with lower CRP levels overall and among participants on monotherapy , whereas ACE inhibitor and ARB use was associated with lower CRP levels among participants on monotherapy . These findings warrant further evaluation in r and omized trials The angiotensin II type 1 ( AT1 ) receptor has a key role in mediating the vasoconstrictor and growth-promoting effects of angiotensin II . It has been reported that a polymorphism of the AT1 receptor gene ( an A/C transversion at position 1166 ) may be associated with cardiovascular phenotypes , such as arterial blood pressure and aortic stiffness , that underlie a condition of increased cardiovascular risk . We examined a sample of 212 subjects r and omly selected from a general population in northern Italy to investigate the role of  AT1 receptor gene polymorphism , in the regulation of blood pressure and cardiovascular growth . We measured  blood pressure ( both clinic and 24-hour ambulatory recording ) ,  left ventricular mass ( echocardiography )  , and  carotid artery wall thickness ( B-mode ultrasound )  ; we assessed the AT1 receptor genotype by polymerase chain reaction and allele-specific oligonucleotide hybridization .  Blood pressure values were lower in CC homozygotes than in heterozygotes and AA homozygotes ; the difference was statistically significant for clinic measurements ( mean difference for mean blood pressure , -6.6 mm Hg , P = .01 ; 95 % confidence interval , -1.6 to -11.7 mm Hg ) but not for ambulatory blood pressure measurements . CC homozygotes also presented a lower incidence of a positive family history of hypertension ( P = .027 ) . No statistically significant differences among AT1 receptor A/C1166 genotypes were observed for left ventricular mass or carotid artery wall thickness . We conclude that the present study does not support a major role of the AT1 receptor gene A/C1166 polymorphism as a marker of conditions associated with increased cardiovascular risk It has becoming clear that angiotensin receptor blockers ( ARBs ) show varying levels of angiotensin II type 1 ( AT1 ) receptor blocking activity . Although the duration of activity and the efficacy on blood pressure of ARB are reported to vary , depending on the agents used , it has not been examined whether the effects on proteinuria and urinary nitrite/nitrate ( NOx ) excretion differ in hypertensive patients with chronic renal disease . In the present study , patients with hypertension ( > 140 and /or 90 mmHg ) and chronic renal disease ( proteinuria > 0.5g/day ; serum creatinine < 265 micromol/l or creatinine clearance > 30 ml/min/1.72 m2 ) were r and omly assigned to perindopril- ( n = 15 ) , tr and olapril- ( n = 15 ) , c and esartan- ( n = 17 ) , and losartan-treated groups ( n = 15 ) , and were followed up for 96 weeks . All agents decreased blood pressure to the same level , and none of them had any effect on creatinine clearance .  C and esartan , perindopril , and tr and olapril reduced proteinuria markedly ( from 3.0 + /- 0.6 to 1.8 + /- 0.5 g/day , 2.7 + /- 0.5 to 1.6 + /- 0.4 g/day , and 2.7 + /- 0.5 to 1.7 + /- 0.4 g/day , respectively ) at 12 weeks , and the beneficial effect persisted throughout the study . The effect of losartan , however , diminished over the study period . Whereas perindopril , tr and olapril , and c and esartan markedly increased urinary NOx excretion ( from 257 + /- 23 to 1,011 + /- 150 micromol/day , 265 + /- 70 to 986 + /- 130 micromol/day , and 260 + /- 62 to 967 + /- 67 micromol/day at 12 weeks , respectively ) , a relatively blunted increase was observed with losartan ( from 309 + /- 42 to 596 + /- 64 micromol/day ) . In conclusion , renal action of ARB varies , with relatively less proteinuria-sparing , as well as NOx-enhancing , effects observed with c and esartan showing the greatest reduction of proteinuria and greatest enhancement of NOx . Furthermore , renal nitric oxide may contribute to the renal protective action of these agents when administered to patients with chronic renal disease Background Therapies that can slow the progression of liver fibrosis in chronic liver disease are needed . Evidence suggests that the renin-angiotensin system ( RAS ) contributes to inflammation and fibrosis in chronic liver disease . Both animal and limited human studies have shown that RAS inhibition with angiotensin-converting enzyme inhibitors ( ACEi ) and angiotensin receptor-1 [ AT-1 ] blockers ( ARBs ) has antifibrogenic properties . Aims In this study , we evaluated the effects of continuous ACEi/ARB use for 3.5 years on histological liver fibrosis progression in the HALT-C Trial cohort . Methods In the HALT-C Trial , subjects with chronic hepatitis C and advanced hepatic fibrosis ( Ishak stage ≥3 ) underwent serial liver biopsies at baseline , 1.5 years , and 3.5 years after r and omization . The primary outcome was a ≥2-point increase in Ishak fibrosis score in at least one of the two serial biopsies . Sixty-six subjects were continuously taking ACEi/ARBs over the observation period , 126 were taking other antihypertensive medications , and 343 subjects took no antihypertensive medications . Results The three groups were similar in baseline fibrosis scores , and the two groups being treated with antihypertensives were taking a similar number of antihypertensive medications . Fibrosis progression occurred in 33.3 % of the ACEi/ARB group , 32.5 % of the other antihypertensive medications group , and in 25.7 % of subjects taking no antihypertensive medications . No significant associations between ≥2-point increases in fibrosis scores and continuous ACEi/ARB use were apparent at either 1.5 or 3.5 years in diabetes-adjusted and unadjusted odds ratios . Conclusions ACEi/ARB therapy did not retard the progression of hepatic fibrosis BACKGROUND Patients with mild-to-moderate essential hypertension in the HOMED-BP trial were r and omly allocated to first-line treatment with a calcium channel blocker ( CCB ) , angiotensin-converting enzyme inhibitor ( ACEI ) or angiotensin II receptor blocker ( ARB ) . METHODS We recruited 265 ( 93 for CCB , 71 for ACEI and 101 for ARB ) patients who completed the genomic study .  Home blood pressure was measured for 5 days off-treatment before r and omization and for 5 days after 2 - 4 weeks of r and omized drug treatment . Genotyping was performed by 500 K DNA microarray chips . The blood pressure responses to the three drugs were analyzed separately as a quantitative trait . For replication of SNPs with p < 10(-4 ) , we used the multicenter GEANE study , in which patients were r and omized to valsartan or amlodipine . RESULTS SNPs in PICALM , TANC2 , NUMA1 and APCDD1 were found to be associated with CCB responses and those in ABCC9 and YIPF1 were found to be associated with ARB response with replication . CONCLUSION Our approach , the first based on high-fidelity phenotyping by home blood pressure measurement , might be a step in moving towards the personalized treatment of hypertension BACKGROUND / AIMS The renin-angiotensin system plays an important role in hepatic fibrogenesis and in portal hypertension . To examine the long-term effects of C and esartan cilexetil , an angiotensin type 1 ( AT1 ) receptor blocker , on portal-systemic haemodynamics and on liver fibrosis . METHODS Forty-seven compensated Child A and Child B ( 8) cirrhotic patients were r and omly assigned to receive C and esartan cilexetil , 8 mg/d ( N.24 ) and no treatment ( N.23 ) for 1 year . Portal-systemic haemodynamic parameters , serological levels of procollagen ( PIIINP ) , hyaluronic acid ( HA ) and transforming growth factor beta 1 ( TGFbeta1 ) were assessed at baseline and after 12 months . RESULTS No patients discontinued or decreased the drug . The hepatic venous pressure gradient ( HVPG ) decreased significantly in treated patients ( -8.4%+/-2.4 ) with a reduction > 20 % in 25 % of cases vs+5.6%+/-2.9 in the untreated group . HA plasma levels decreased significantly in C and esartan treated patients in whom HVPG diminished and rose in untreated patients in whom HVPG increased . CONCLUSIONS In selected cirrhotic patients , pharmacological inhibition of the AT1 receptor is well tolerated and induced a mild reduction of portal pressure . This haemodynamic effect might be related to liver fibrogenesis activity Persistence on treatment affects the efficacy of antihypertensive treatment . We prospect ively investigated the persistence on therapy and the extent of  blood pressure ( BP ) control  in 347 hypertensive patients ( age 59.4 ± 6 years ) r and omly allocated to a first-line treatment with : angiotensin-converting enzyme ( ACE ) inhibitors , calcium-channel blockers ( CCBs ) , ß-blockers , angiotensin-II receptor blockers ( ARBs ) , or diuretics and followed-up for 24-months . Persistence on treatment was higher in patients treated with ARBs ( 68.5 % ) and ACE inhibitors ( 64.5 % ) vs CCBs ( 51.6 % ; p < 0.05 ) , β-blockers ( 44.8 % , p < 0.05 ) , and diuretics ( 34.4 % , p < 0.01 ) . No ARB , ACE inhibitor , β-blocker , or diuretic was associated with a higher persistence in therapy compared with the other molecules used in each therapeutic class . The rate of persistence was significantly higher in patients treated with lercanidipine vs others CCBs ( 59.3 % vs 46.6 % , p < 0.05 ) . Systolic and diastolic BP was decreased more successfully in patients treated with ARBs ( −11.2/−5.8 mmHg ) , ACE inhibitors ( −10.5/−5.1 mmHg ) , and CCBs ( −8.5/−4.6 mmHg ) compared with ß-blockers ( −4.0/−2.3 mmHg p < 0.05 ) and diuretics ( −2.3/−2.1 mmHg , p < 0.05 ) . No ARB , ACE inhibitor , β-blocker , or diuretic was associated with a higher BP control compared with the other molecules used in each therapeutic class . A trend toward a better BP control was observed in response to lercanidipine vs other CCBs ( p = 0.059 ) . The present results confirm the importance of persistence on treatment for the management of hypertension in clinical practice Combined antihypertensive therapy plays a crucial role in achieving targeted blood pressure reductions and renoprotection . We therefore compared the antihypertensive and antiproteinuric effects of combined therapy with either a calcium channel blocker ( CCB ) plus an angiotensin II receptor blocker ( ARB ) or an angiotensin converting enzyme inhibitor ( ACE-I ) plus an ARB in patients with type 2 diabetes mellitus complicated by overt nephropathy and mild to moderate hypertension . After a 12-week dietary control period , diabetic patients with mildly to moderately impaired renal function were r and omly assigned to either a CCB ( amlodipine 5 mg once daily ) or an ACE-I ( temocapril 2 mg once daily ) for 12 weeks ( monotherapy period ) . Both groups then received add-on therapy with an ARB ( c and esartan 4 mg once daily ) for an additional 12 weeks . During the monotherapy period , blood pressure was decreased equally well in both groups . Daily urinary protein excretion remained unchanged in the CCB-treated group ( control period , 4.0 + /- 1.8 g/day vs. CCB period , 4.1 + /- 1.9 g/day ; ns ; n = 8) , but decreased in the ACE-I-treated group ( control period , 4.3 + /- 1.8 g/day vs. ACE-I period , 3.5 + /- 1.7 g/day ; p < 0.05 ; n = 9 ) . After the combined therapy period , blood pressure was decreased to the same degree in both groups . Although ARB plus CCB significantly reduced urinary protein excretion ( to 3.5 + /- 1.5 g/day ; p < 0.05 vs. control period ; n = 8) , a more profound reduction was achieved with ARB plus ACE-I ( to 2.6 + /- 1.3 g/day ; p < 0.01 vs. control period ; n = 9 ) . Monotherapy with the ACE-I increased the serum potassium concentration , and this elevation was sustained after addition of the ARB . In contrast , the serum potassium concentration was not influenced by monotherapy with the CCB , but was significantly increased after addition of the ARB . A decreased hematocrit was observed in the ARB plus ACE-I group . The present study suggests that combined antihypertensive therapy with either a CCB plus an ARB or an ACE-I plus an ARB exerts an antiproteinuric effect in patients with type 2 diabetic nephropathy with mildly impaired renal function . Although the latter combination had a more profound effect , it was associated with an increased serum potassium concentration and worsening of renal anemia . Thus , the combination of a CCB and an ARB should be the first line antihypertensive therapy in those with overt diabetic nephropathy . The long-term efficacy of these combined antihypertensive therapies will need to be further addressed in a future study Introduction The number of patients with both hypertension and obesity has been increasing in Japan . Many of these patients may also have insulin resistance . Telmisartan , an angiotensin II receptor blocker ( ARB ) , selectively activates peroxisome proliferatoractivated receptor (PPAR)-gamma , and this effect is considered to markedly improve insulin resistance in obese patients with hypertension . We compared the antihypertensive and insulin resistance-improving effects of telmisartan with those of c and esartan and valsartan in this patient population . Methods Twenty-eight elderly patients with an average body mass index ( BMI ) of 27.1 kg/m2 were enrolled in this 6-month study . Patients were r and omly selected to either switch from c and esartan or valsartan to telmisartan or to continue with their current ARB . A 75 g oral glucose tolerance test ( OGTT ) was performed before and after switching , and the effect of telmisartan on the insulin response to glucose loading was investigated . Results There was no significant difference in blood pressure between the two groups after drug administration , but glucose tolerance significantly improved in the telmisartan group . The hyperinsulin response to glucose loading also significantly improved in those taking telmisartan , as well as homeostasis model assessment of insulin resistance ( HOMA-IR ) . These changes were not observed in the control group . Conclusion In patients with hypertension and obesity showing insulin resistance , treatment with telmisartan significantly improved the hyperinsulin response to glucose loading .  Telmisartan may therefore be beneficial in these patients Abstract : Qian Yang He Ji ( QYHJ ) is a traditional Chinese medicine composed of Digitalis purpurea , Uncaria gambir , Fructus tribuli terrestris , and Ligustrum lucidum . Here , we explored whether combining an antihypertensive angiotensin II receptor blocker ( ARB ) therapy with QYHJ can improve the arterial functionality of hypertensive patients . One hundred and eight hypertensive patients were r and omized into 2 groups ; 1 group ( n = 53 ) was treated with ARB and the other group ( n = 55 ) was treated with ARB combined with QYHJ . Each of the 2 groups included 3 subgroups ( pure hypertension , hypertension with diabetes , and hypertension with coronary heart disease ) and was further divided into patients with and without complications . The cardioankle vascular index and intima-media thickness and pulse pressure were the outcome evaluation parameter . Combined QYHJ and ARB treatment reduced the values of cardioankle vascular index , systolic blood pressure , diastolic blood pressure , and pulse pressure to significantly lower levels than ARB treatment alone did in hypertension patients after 6 months of treatment . ARB improves hypertension , but a combined QYHJ treatment can additionally ameliorate the arterial functionality not only in solely hypertensive patients but also in hypertensive patients with diabetes and coronary heart disease complications . QYHJ coapplication might be a choice to further improve the arterial functionality during an ARB hypertension treatment Background / Aims : Pharmacological inhibition of renin-angiotensin-aldosteron system ( RAAS ) may reduce proteinuria and the rate of chronic kidney disease progression . The aim was to compare the effects on albuminuria of the therapy with either : i ) telmisartan 80 mg and aliskiren 300 mg , ii ) telmisartan 80 mg and eplerenone 50 mg , iii ) telmisartan 160 mg as monotherapy . Design and patients : R and omized , double-center , double-blind , cross-over , three treatments-three periods of 8 weeks each study . 18 patients with non-diabetic proteinuric CKD stage 1 - 3 completed the protocol . Results : There was significant difference in albuminuria between studied therapies ( ANOVA ; p<0.01 ) . The combination therapy with telmisartan plus aliskiren decreased albuminuria more effectively than the treatment with telmisartan plus eplerenone and monotherapy with telmisartan 160 mg OD [ 376 mg/g creatinine ( 286 - 686 ) vs. 707 ( 502 - 1204 ) vs. 525 ( 318 - 763 ) ; post-hoc p<0.01 and p<0.05 , respectively ] . Conclusions : The study demonstrated that the combination therapy with angiotensin receptor blocker ( ARB ) and renin inhibitor was more effective in albuminuria lowering than the concomitant usage of ARB and mineralocorticoid receptor antagonist as well as than ARB in doses two-fold higher than usually used in treatment of hypertension in patients with non-diabetic CKD and that this higher antiproteinuric efficacy was independent on changes in blood pressure
RESULTS The global antihypertensive activity of ARB differs from that observed with amlodipine in the sense that the magnitude of the reduction in the BP values does not essentially depend on the initial BP values nor on the dose used .
When only ARB were considered , the drug used was a determinant for systolic BP reduction , whereas for diastolic BP the influence was on the BP reduction and the duration of the antihypertensive activity .
The dose used had a particular influence on the duration of the antihypertensive activity for both systolic and diastolic BP .
CONCLUSION Among the ARB , the influence is on duration more than on the magnitude of BP reduction .
Dose , therefore , is an important factor in the duration of antihypertensive activity
OBJECTIVE To perform a systematic review of the antihypertensive activity of the angiotensin II AT1 receptor antagonists ( ARB ) .