Effects Of Angiotensin Receptor Blockers Research Articles

Abstract 9472: Pretreatment with Novel Angiotensin type I Receptor Antagonist, Fimasartan, Prevents Doxorubicin-Induced Cardiac Toxicity and Improves Survival

Background: Cardiac toxicity are important complications of Doxorubicin-based chemotherapy. Protective effect of angiotensin receptor blockers (ARBs) in heart failure been established; however efficacy of ARB on prevention of doxorubicin induced cardiomyopathy and the survivals were not been investigated. We performed a preclinical study to evaluate the preventive effect of a novel ARB, fimasartan, in doxorubicin-induced cardiomyopathy. Method: All animals (n=63) were randomly assigned into 3 groups; daily treated with vehicle (Dox-only), 5mg/Kg (Low-fima), and 10mg/Kg of fimasartan (High-fima). Doxorubicin (3mg/kg) was injected intravenously once a week for 6 weeks. Fimasartan were administered daily for 8 weeks via gastric gavage. Echocardiography was performed in baseline, 6th and 8th week. Hemodynamic assessment was performed at 9th week using the miniaturized conductance catheter system. Result: 8-wk survival rate in High-Fima was higher (100%), than those in Low-fima (75%), and in Dox-only group (50%, p<0.05). Echocardiography showed preserved LV systolic function in in High-Fima after 8weeks of treatment (LV EF=72±7%), but not in Dox-only group (54.6±8.4%, p=0.002). LV end-systolic and end-diastolic dimension increased progressively in Dox-only group; however remodeling was attenuated in Low-fima and High-fima group. Hemodynamic study showed higher positive (5931±1354 mmHg/sec) and negative dP/dt (-5410.3±1338.2) in High-fima group, than Dox-only group. (3425±947, -3123±1127 mmHg/sec, p<0.001). Animals in Dox-only group looked very sick and showed severe anorexia, rat shedding, eye discharge and ascites compared to Low- and High-fima group. Conclusion: A novel ARB, fimasartan, prevents doxorubicin-induced cardiomyopathy and improves survivals in dose-dependent manner in doxorubin-induced cardiomyopathy. It shows possibility of fimasartan as a treatment option to prevent doxorubicin-induced cardiomyopathy.

Abstract 9641: Effects of Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers on Mortality and Cardiovascular Events in Patients Without Heart Failure. A Meta-Analysis of Randomized Clinical Trials in 108,233 patients

Objective: To verify whether Angiotensin-Converting-Enzyme inhibitors (ACE-Is) and Angiotensin Receptor Blockers (ARBs) reduce cardiovascular (CV) events in patients without left ventricular systolic dysfunction (LVSD). Methods and Results: MEDLINE, Cochrane, ISI Web of Science and SCOPUS were searched for randomized trials comparing ARBs or ACE-Is versus placebo in patients without LVSD. Twenty-six trials enrolling 108,233 participants were included. The effects of ACE-Is and ARBs were analyzed for the occurrence of a composite outcome including CV death, myocardial infarction (MI) and stroke as well for all-cause death, new onset diabetes mellitus and heart failure. Compared to placebo, ACE-Is significantly reduce the risk of the composite outcome (Odds Ratio [OR]:0.831, 95% Confidence Interval [C]I:0.748 to 0.922, p=0.001)(Figure), MI (OR:0.835, CI:0.781 to 0.894, p<0.001), stroke (OR:0.796, CI:0.685 to 0.924, p<0.003), all-cause death (OR:0.908, 95% CI:0.845 to 0.975, p=0.008), new onset heart failure (OR:0.753, CI:0.679 to 0.834, p<0.001) and diabetes mellitus (OR:0.812, CI:0.706 to 0.932, p<0.001), whereas reduction of CV death approximated statistical significance (OR:0.892, CI:0.783 to 1.017, p=0.087). ARBs significantly reduce the risk of the composite outcome (OR:0.936, CI:0.888 to 0.987, p=0.014)(Figure), stroke (OR:0.909, CI:0.840 to 0.983, p=0.017) and new onset diabetes mellitus (OR:0.854, CI:0.797 to 0.915, p<0.001), but not MI, CV death, new onset heart failure and all-cause death. Conclusions: In patients at high CV risk but without LVSD, ACE-Is and ARBs reduce the risk of the composite outcome including CV death, MI and stroke, and of new onset diabetes mellitus. At variance with ACE-Is, no significant effects on all-cause death, MI and new onset heart failure are observed for ARBs. Thus, ACE-Is should represent the first choice to reduce CV mortality/morbidity in high-risk patients.

Angiotensin receptor blockers and outcomes in real‐world older patients with heart failure and preserved ejection fraction: a propensity‐matched inception cohort clinical effectiveness study

To examine the clinical effectiveness of angiotensin receptor blockers (ARBs) in older patients with heart failure and preserved ejection fraction (HF-PEF). Of the 10 570 hospitalized HF-PEF patients, aged ≥ 65 years, EF ≥ 40%, in OPTIMIZE-HF (2003-2004), linked to Medicare data (up to 31 December 2008), 3806 were not receiving angiotensin-converting enzyme inhibitors or prior ARB therapy. Of these, 303 (8%) patients received new discharge prescriptions for ARBs. Propensity scores for the receipt of ARBs, estimated for each of the 3806 patients, were used to assemble a cohort of 296 pairs of patients receiving and not receiving ARBs, who were balanced on 114 baseline characteristics. Patients had a mean age of 80 years, mean EF of 55%, 69% were women, and 12% were African American. During 6 years of follow-up, the primary composite endpoint of all-cause mortality or HF hospitalization occurred in 79% (235/296) and 81% (241/296) of patients receiving and not receiving ARBs, respectively [hazard ratio (HR) associated with ARB use 0.88, 95% confidence interval (CI) 0.74-1.06; P = 0.179]. ARB use had no association with individual endpoints of all-cause mortality (HR 0.93, 95% CI 0.76-1.14; P = 0.509), HF hospitalization (HR 0.90, 95% CI, 0.72-1.14; P = 0.389), or all-cause hospitalization (HR 0.91, 95% CI 0.77-1.08; P = 0.265). These associations remained unchanged when we compared any (prevalent and new prescriptions) ARB use vs. non-use in a separately assembled propensity-matched cohort of 1137 pairs of HF-PEF patients. In real-world older HF-PEF patients, ARB use was not associated with improved clinical outcomes.

The effects of angiotensin receptor blockers vs. calcium channel blockers on the acute exercise-induced inflammatory and thrombotic response

Arterial hypertension is an established risk factor for acute coronary syndromes, and physical exertion may trigger the onset of such an event. The mechanisms involved include the rupture of a small, inflamed, coronary plaque and the activation of thrombogenic factors. Blood pressure (BP)-lowering treatment has been associated with beneficial effects on subclinical inflammation and thrombosis at rest and during exercise. This prospective study sought to compare the effect of different antihypertensive drugs on the inflammatory and thrombotic response during exercise. A total of 60 never-treated hypertensive patients were randomized to an angiotensin receptor blocker (ARB)- or non-dihydropyridine calcium channel blocker (CCB)-based regimen. Patients with inflammatory or coronary artery disease were excluded. Six months after pharmaceutical BP normalization, the patients underwent a maximal treadmill exercise testing. High-sensitivity C-reactive protein (hsCRP), serum amyloid A (SAA), white blood cells (WBC), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), total fibrinogen (TF) and von Willebrand factor (vWF) levels, as well as plasminogen activator inhibitor-1 (PAI-1) activity were measured in blood samples taken while the patients were at rest and during peak exercise. All of these biomarkers increased with exercise, except PAI-1, which decreased (P<0.05 for the difference between resting and peak exercise for all biomarkers). The ARB group had less marked (P<0.05) exercise-induced changes than the CCB group in hsCRP (5.8% vs. 7.7%), SAA (4.2% vs. 7.2%), WBC (46.8% vs. 52.6%), TNF-α (16.3% vs. 24.3%), TF (9.5% vs. 16.9%) and PAI-1 (-9.5% vs. -12.3%) but a similar (P=NS) change in IL-6 (39.4% vs. 38.6%) and vWF (29.2% vs. 28.6%). In conclusion, ARBs are most likely more effective than CCBs at suppressing the exercise-induced acute phase response. Potential protection against exercise-related coronary events remains to be elucidated.

Abstract 502: Salt-Excess Induced Exacerbated Hypertension Prevention by Telmisartan in Spontaneously Hypertensive Rats

The effects of angiotensin receptor blocker (AGA), diuretic, a calcium antagonist (CA), and their combination were evaluated on the progression of cardiovascular damage in spontaneously hypertensive rats (SHR) given salt-excess. To this end, 8-week male SHR rats were divided into 7 groups. The control group (C) received regular NaCl (0.6%) diet. All other groups were given 8% NaCl rat chow. In addition, Group 2 (HS) was given placebo, Group 3 (T) the AGA telmisartan (10 mg/kg/day), Group 4 (D) received the chlorothiazide (80 mg/kg/day), Group 5 (T+D) telmisartan plus diuretic, Group 6 (A) was given the CA amlodipine (10 mg/kg/day), and Group 7 (T+A) telmisartan plus amlodipine. All treatments lasted 8 weeks. Compared with controls, mean arterial pressure (MAP), renal blood flow, coronary flow reserve (CFR), minimal coronary vascular resistance, diastolic time constant, and maximal rate of ventricular pressure fall (-dP/dT) were all adversely affected by salt-loading (Table). Increased left ventricular weight (LVWI) with marked cardiac fibrosis was also found with salt overload. Telmisartan normalized all indices except MAP, whereas diuretic and amlodipine only partially restored cardiac function and mass. Combination therapy with telmisartan and either diuretic or amlodipine also normalized all indices including arterial pressure (Table). These data show that: (1) cardiovascular and renal damage induced by salt-excess in SHR were not pressure dependent; and (2) compared with the CA and diuretic, AGA was more effective in this model suggesting that local renin in target organs participated in salt-induced hypertension.

352 EFFECTS OF CANDESARTAN IN ACUTE STROKE ON COGNITIVE FUNCTION AT 6 MONTHS

Background: There has been considerable interest in the effect of angiotensin receptor blockers on cognitive function after stroke. We wanted to assess the effect of candesartan in the acute phase of stroke on long-term cognitive function, in the Scandinavian Candesartan Acute Stroke Trial. Methods: SCAST was a randomised, placebo-controlled trial of candesartan in 2,029 patients with acute stroke and systolic BP >140 mm Hg. Treatment was administered for 7 days. Cognitive function was assessed at 6 months by the Mini Mental State Examination (MMSE). MMSE scores (range 0 – 30) was divided into three groups: no cognitive impairment (scores 27 – 30), possible (24 – 26), and definite cognitive impairment (0 – 23). We used ordinal logistic regression, adjusting for age, gender, cause of stroke (ischaemic vs. all other), systolic blood pressure, and SSS score at baseline. Results: Data on MMSE score were available on 1642 patients (81%). Median score was 28 in both groups. There was no difference in risk of cognitive impairment in the two groups (common OR 0.98, 95% CI 0.82 – 1.22, p = 0.99).Conclusion: Candesartan showed no effect on cognitive function. This result is in accordance with the SCAST main result, and supports the conclusion that there is no indication for routine blood pressure lowering treatment with candesartan in the acute phase of stroke.

Effect of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers on Risk of Atrial Fibrillation before Coronary Artery Bypass Grafting

To review the primary literature evaluating the effect preoperative use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) has on the risk of postoperative atrial fibrillation following coronary artery bypass grafting (CABG). PubMed was searched from January 1, 2000, to May 17, 2012, using the MeSH terms coronary artery bypass, angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, and atrial fibrillation. Additional articles were identified from the reference lists of the articles identified in the PubMed search. Abstracts from the PubMed search were screened for relevance to the topic. Articles including information on the effect of ACE inhibitors or ARBs on postoperative atrial fibrillation following CABG were indentified for further review. Data extracted from these studies included patient baseline characteristics, outcome definitions, incidence of atrial fibrillation after CABG, and preoperative use of ACE inhibitors or ARBs. The PubMed search resulted in 6 articles, 4 of which were applicable to the clinical question. Four other articles were identified from the reference lists of the applicable studies, resulting in a literature review of 8 studies. These studies included patients undergoing CABG with or without valve procedures. Four studies included patients undergoing isolated CABG procedures; the remaining 4 included patients undergoing CABG with a valve procedure. Information on preoperative ACE inhibitor or ARB use was included in all studies. Two studies suggested a decreased risk of postoperative atrial fibrillation following CABG with preoperative ACE inhibitor or ARB therapy, 3 suggested an increased risk, and 3 found no effect on risk. The studies reviewed here had conflicting results. Randomized placebo-controlled trials are necessary to determine the risk for atrial fibrillation after CABG associated with preoperative use of ACE inhibitors and ARBs. The decision to continue or withhold the drugs is not evidence-based and should be based on a patient's other clinical characteristics.

1027 ANGIOTENSIN RECEPTOR BLOCKERS INHIBIT DE NOVO ONSET OF MALIGNANT TUMORS

Objective: Angiotensin receptor blockers (ARBs) are commonly used anti-hypertensives. We previously reported that high dose of ARB inhibited growth of malignant tumors in mice. While recent meta-analysis of randomized clinical trials indicated no relation between cancer risk and ARBs, some data suggested potential anti-tumor efficacies of ARBs. We performed a retrospective-cohort for the de novo onset of malignant tumors in Japanese hypertensive patients. Methods: Study population consisted of patients without cancer treated for hypertension for >1year, enrolled from January 2003 to December 2008, grouped based on with or without ARB treatment. Kaplan-Meier time event curve was used to predict time to onset, and log-rank test was performed. In each anti-hypertensive agent (ARB, ACEI, CCB, β-blocker and diuretic drug), incidence rate was calculated using Cox hazard model with 95% confidence interval (CI). Results: Among 3688 patients (2510 in ARB and 1178 in non-ARB group, mean age 60.9), 63 in the ARBs (2.51%) and 47 in the non-ARB group (3.99%) developed de novo tumor (log-rank test p = 0.02). Cox hazard model revealed statistical significance in the inhibition of de novo occurrence of tumors in the ARB group (incidence rate ratio: 0.65, 95% CI 0.45-0.95). Univariate analysis didn’t show any significant inhibiting effects on the de novo tumor by other anti-hypertensive agents. Conclusion: Development of de novo malignant tumors was significantly lower in hypertensive patients receiving ARBs. This phenomenon wasn’t confirmed in other anti-hypertensive regimens. Further prospective study should be needed to examine the effects of ARBs on cancer incidence in Japanese hypertensive patients.

Telmisartan Prevents Excess-Salt-Induced Exacerbated (Malignant) Hypertension in Spontaneously Hypertensive Rats

The effects of angiotensin receptor blocker, diuretic, a calcium antagonist, and their combination were evaluated on the progression of cardiovascular and renal damage in spontaneously hypertensive rats (SHRs) given excess salt. To this end, 8-week male SHRs were divided into 7 groups. The control group (C) received normal NaCl (0.6%) diet. All other groups were given 8% NaCl rat chow. In addition, group 2 was given placebo (tap water alone), group 3 the angiotensin receptor antagonist telmisartan (10 mg/kg per d), group 4 received the diuretic chlorothiazide (80 mg/kg per d), group 5 was given telmisartan plus the diuretic, group 6 was given the calcium antagonist amlodipine (10 mg/kg per d), and group 7 was given telmisartan plus amlodipine. All treatments lasted for 8 weeks. Compared with controls, mean arterial pressure (MAP), renal blood flow, coronary flow reserve, minimal coronary vascular resistance, diastolic time constant, and maximal rate of ventricular pressure fall were all adversely affected by salt loading. Increased left ventricular mass with marked cardiac fibrosis was also found in the salt-overloaded SHR group. Telmisartan normalized all indices except MAP, whereas diuretic and amlodipine only partially restored cardiac functional and mass indexes. Combination therapy with telmisartan and either diuretic or amlodipine also normalized all indices including arterial pressure. These data suggest that (1) cardiovascular damage induced by excess salt in the SHRs was not pressure dependent; (2) compared with the calcium antagonist and diuretic, blockade of angiotensin receptors was extremely effective in this model.

You are what you eat: dietary salt intake and renin–angiotensin blockade in diabetic nephropathy

Interactions between sodium intake, the renin angiotensin system and renal and cardiovascular outcomes are incompletely understood. Lambers Heerspink et al's analysis shows that angiotensin receptor blockade (ARB) improves diabetic nephropathy and cardiovascular disease more when dietary sodium intake is low and suggests possible harm when sodium intake is high. These findings highlight dietary salt as a modifiable cardiovascular and renal risk factor and emphasize the need for need for detailed mechanistic studies.

Moderation of dietary sodium potentiates the renal and cardiovascular protective effects of angiotensin receptor blockers

Dietary sodium restriction has been shown to enhance the short-term response of blood pressure and albuminuria to angiotensin receptor blockers (ARBs). Whether this also enhances the long-term renal and cardiovascular protective effects of ARBs is unknown. Here we conducted a post-hoc analysis of the RENAAL and IDNT trials to test this in patients with type 2 diabetic nephropathy randomized to ARB or non-renin-angiotensin-aldosterone system (non-RAASi)-based antihypertensive therapy. Treatment effects on renal and cardiovascular outcomes were compared in subgroups based on dietary sodium intake during treatment, measured as the 24-h urinary sodium/creatinine ratio of 1177 patients with available 24-h urinary sodium measurements. ARB compared to non-RAASi-based therapy produced the greatest long-term effects on renal and cardiovascular events in the lowest tertile of sodium intake. Compared to non-RAASi, the trend in risk for renal events was significantly reduced by 43%, not changed, or increased by 37% for each tertile of increased sodium intake, respectively. The trend for cardiovascular events was significantly reduced by 37%, increased by 2% and 25%, respectively. Thus, treatment effects of ARB compared with non-RAASi-based therapy on renal and cardiovascular outcomes were greater in patients with type 2 diabetic nephropathy with lower than higher dietary sodium intake. This underscores the avoidance of excessive sodium intake, particularly in type 2 diabetic patients receiving ARB therapy.

Is there an embryopathy associated with first‐trimester exposure to angiotensin‐converting enzyme inhibitors and angiotensin receptor antagonists? A critical review of the evidence

Drugs that interfere with the renin-angiotensin system, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), are widely used to manage hypertension and heart failure. Adequate functioning of the RAS is essential for normal fetal kidney development. The potential for ACEIs and ARBs to impair fetal and neonatal renal function if taken after the first trimester of pregnancy has been well documented. Although these drugs were not found to be teratogenic in animals, until recently little was known about the teratogenic effects of ACEIs and ARBs in humans when exposure was limited to the first trimester of pregnancy. New evidence from epidemiologic studies indicates that there may be an elevated teratogenic risk when these drugs are taken during the first trimester of pregnancy. However, this elevated risk does not appear to be specific to ACEIs and ARBs, but is instead related to maternal factors and diseases that typically coexist with hypertension in pregnancy, such as diabetes, advanced maternal age, and obesity. Women who become pregnant while being treated with an ACEI or ARB should be advised to avoid exposure to these drugs during the second and third trimesters of pregnancy by switching to a different class of antihypertensive drugs between weeks 8 and 10 after conception.

Effects of angiotensin receptor blockers on endothelial nitric oxide release: the role of eNOS variants

• Angiotensin II receptor blockers improve endothelial cell-dependent vasodilation in patients with hypertension through suppression of angiotensin II type 1 receptors but may have additional and differential effects on endothelial nitric oxide synthase (eNOS) function. • The key finding from this study is that angiotensin II receptor blockers (ARBs) differentially enhanced nitric oxide (NO) release in a manner influenced by certain genetic variants of eNOS. This finding provides new insights into the effects of ARBs on endothelial cell-dependent vasodilation and eNOS function that are of high importance in vascular medicine and clinical pharmacology. AIM Angiotensin II receptor blockers (ARBs) improve endothelial cell (EC)-dependent vasodilation in patients with hypertension through suppression of angiotensin II type 1 receptors but may have additional and differential effects on endothelial nitric oxide (NO) synthase (eNOS) function. To investigate this question, we tested the effects of various ARBs on NO release in ECs from multiple donors, including those with eNOS genetic variants linked to higher cardiovascular risk. The effects of ARBs (losartan, olmesartan, telmisartan, valsartan), at 1 µm, on NO release were measured with nanosensors in human umbilical vein ECs obtained from 18 donors. NO release was stimulated with calcium ionophore (1 µm) and its maximal concentration was correlated with eNOS variants. The eNOS variants were determined by a single nucleotide polymorphism in the promoter region (T-786C) and in the exon 7 (G894T), linked to changes in NO metabolism. RESULTS All of the ARBs caused an increase in NO release as compared with untreated samples (P < 0.01, n= 4-5 in all eNOS variants). However, maximal NO production was differentially influenced by eNOS genotype. Olmesartan increased maximal NO release by 30%, which was significantly greater (P < 0.01, n= 4-5 in all eNOS variants) than increases observed with other ARBs. The ARBs differentially enhanced NO release in ECs in a manner influenced by eNOS single nucleotide polymorphisms. These findings provide new insights into the effects of ARBs on EC-dependent vasodilation and eNOS function.

Angiotensin receptor blockers for heart failure

Chronic heart failure (HF) is a prevalent world-wide. Angiotensin receptor blockers (ARBs) are widely prescribed for chronic HF although their role is controversial. To assess the benefit and harm of ARBs compared with ACE inhibitors (ACEIs) or placebo on mortality, morbidity and withdrawals due to adverse effects in patients with symptomatic HF and left ventricular systolic dysfunction or preserved systolic function. Clinical trials were identified by searching CENTRAL, HTA, and DARE , (The Cochrane Library 2010 Issue 3), as well as MEDLINE (2002 to July 2010), and EMBASE (2002 to July 2010). Reference lists of retrieved articles and systematic reviews were checked for additional studies not identified by the electronic searches. Double blind randomised controlled trials in men and women of all ages who have symptomatic (NYHA Class II to IV) HF and: 1) left ventricular systolic dysfunction, defined as left ventricular ejection fraction (LVEF) ≤40%; or 2) preserved ejection fraction, defined as LVEF >40%. Two authors independently assessed risk of bias and extracted data from included studies. Twenty two studies evaluated the effects of ARBs in 17,900 patients with a LVEF ≤40% (mean 2.2 years). ARBs did not reduce total mortality (RR 0.87 [95% CI 0.76, 1.00]) or total morbidity as measured by total hospitalisations (RR 0.94 [95% CI 0.88, 1.01]) compared with placebo.Total mortality (RR 1.05 [95% CI 0.91, 1.22]), total hospitalisations (RR 1.00 [95% CI 0.92, 1.08]), MI (RR 1.00 [95% CI 0.62, 1.63]), and stroke (RR 1.63 [0.77, 3.44]) did not differ between ARBs and ACEIs but withdrawals due to adverse effects were lower with ARBs (RR 0.63 [95% CI 0.52, 0.76]). Combinations of ARBs plus ACEIs increased the risk of withdrawals due to adverse effects (RR 1.34 [95% CI 1.19, 1.51]) but did not reduce total mortality or total hospital admissions versus ACEI alone.Two placebo-controlled studies evaluated ARBs in 7151 patients with a LVEF >40% (mean 3.7 years). ARBs did not reduce total mortality (RR 1.02 [95% CI 0.93, 1.12]) or total morbidity as measured by total hospitalisations (RR 1.00 [95% CI 0.97, 1.05]) compared with placebo. Withdrawals due to adverse effects were higher with ARBs versus placebo when all patients were pooled irrespective of LVEF (RR 1.06 [95% CI 1.01, 1.12]). In patients with symptomatic HF and systolic dysfunction or with preserved ejection fraction, ARBs compared to placebo or ACEIs do not reduce total mortality or morbidity. ARBs are better tolerated than ACEIs but do not appear to be as safe and well tolerated as placebo in terms of withdrawals due to adverse effects. Adding an ARB in combination with an ACEI does not reduce total mortality or total hospital admission but increases withdrawals due to adverse effects compared with ACEI alone.

The Role of Apelin on the Alleviative Effect of Angiotensin Receptor Blocker in Unilateral Ureteral Obstruction-Induced Renal Fibrosis

Background: Apelin is a selective endogenous ligand of the APJ receptor, which genetically has closest identity to the angiotensin II type 1 receptor (AT-1). The effects of the apelin/APJ system on renal fibrosis still remain unclear. Methods: We examined the effects of the apelin/APJ system on renal fibrosis during AT-1 blockade in a mouse unilateral ureteral obstruction (UUO) model. Results: We obtained the following results: (1) At UUO day 7, mRNA expressions of apelin/APJ and phosphorylations of Akt/endothelial nitric oxide synthase (eNOS) in the UUO kidney were increased compared to those in the nonobstructed kidney. (2) AT-1 blockade by the treatment with losartan resulted in a further increase of apelin mRNA as well as phosphorylations of Akt/eNOS proteins, and this was accompanied by alleviated renal interstitial fibrosis, decreased myofibroblast accumulation, and a decreased number of interstitial macrophages. (3) Blockade of the APJ receptor by the treatment with F13A during losartan administration completely abrogated the effects of losartan in the activation of the Akt/eNOS pathway and the amelioration of renal fibrosis. (4) Inhibition of NOS by the treatment with L-NAME also resulted in a further increase in renal fibrosis compared to the control group. Conclusion: These results suggest that increased nitric oxide production through the apelin/APJ/Akt/eNOS pathway may, at least in part, contribute to the alleviative effect of losartan in UUO-induced renal fibrosis.

EFFECT OF LOSARTAN/HYDROCHLOROTHIAZIDE ON DIASTOLIC FUNCTION IN PATIENTS WITH HYPERTENSION AND CHRONIC STABLE CORONARY ARTERY DISEASE

Hypertension and coronary artery disease (CAD) is associated with an increased risk of heart failure with preserved ejection fraction (HFpEF). This subgroup analysis of the Effect of angiotensin receptor blocker (ARB)/Diuretics on diastolic function in patients with hypertension (EDEN) trial

Comparative effectiveness of renin–angiotensin system inhibitors in hypertension

Hypertension is a chronic problem in the USA and there are three main ways to block the renin-angiotensin system: direct renin inhibitors, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). This article is a summary of a direct comparative effectiveness review of direct comparative trials in patients with hypertension. In patients with hypertension, ACEIs and ARBs provide similar blood pressure effects and no differences were seen in final health outcomes. ARBs have less ACE-induced cough and fewer withdrawals due to adverse events. Direct renin inhibitors versus ACE inhibitors or ARBs have not been extensively studied and their role is less clear.

Potential role of urinary angiotensinogen in predicting antiproteinuric effects of angiotensin receptor blocker in non-diabetic chronic kidney disease patients: a preliminary report

ObjectivesMany chronic kidney disease (CKD) patients have persistent overt proteinuria despite angiotensin receptor blocker (ARB) treatment. This study investigated whether the initial difference in intrarenal renin–angiotensin system activity measured with...

Predictors of proteinuria reduction by monotherapy with an angiotensin receptor blocker, olmesartan

It is known that reduced glomerular filtration rate (GFR) is a crucial factor to limit the blood pressure lowering effect of antihypertensives. In the present study, we tested whether the effects of monotherapy with an angiotensin receptor blocker (ARB) to lower proteinuria could be restricted by reduced GFR. Thirty-five renal patients who had albuminuria more than 30 mg/day, but did not have diabetic nephropathy or nephrotic syndrome, were studied before and during eight weeks of monotherapy with ARB, olmesartan. Blood pressure was lowered from 129 ± 18/79 ± 12 to 116 ± 18/72 ± 12 mmHg (p < 0.0001), while albuminuria was reduced from 614±630 to 343±472 mg/day (p < 0.0001). Albuminuria was inversely correlated with GFR both before and during treatment. Albuminuria reduction was enhanced as plasma renin activity (p = 0.047) and dose of olmesartan were increased (p = 0.04). Although the absolute reduction in proteinuria was not correlated with GFR (p = 0.56), the % reduction was significantly proportional with GFR (p = 0.027). Multiple regression analysis demonstrated that 64% of proteinuria reduction could be explained by baseline levels of albuminuria, GFR and renin activity. The reduction in proteinuria by olmesartan may be roughly predicted using baseline GFR and other parameters. These findings clarify that the effect of ARB on proteinuria reduction is restricted by reduced GFR.

Abstract 2559: Subgroup analysis of the Cilostazol Stroke Prevention Study 2 (CSPS 2)

Background: Cilostazol has been suggested to be superior to aspirin in secondary stroke prevention in patients with non-cardioembolic ischemic stroke from the results of the CSPS 2 and meta-analysis of the Cochrane Collaboration. The purpose of this study was to investigate the efficacy and safety of cilostazol and aspirin in the various subgroups of the study population. Methods: Recurrence of stroke was studied in the subgroup analysis according to patient's characteristics, concomitant use of drugs, and ischemic stroke subtypes. Heterogeneity of stroke risk between subgroups classified by each variable was analyzed using Log-rank test. Results: A total of 2672 Japanese patients enrolled in the CSPS 2 (Lancet Neurol 2010;9:959-68) were analyzed. A tendency of interaction was observed in alcohol drinking (p=0.0782) and dyslipidemia (p=0.0873). Stroke rates in alcohol drinkers (HR 0.574, 95% CI 0.386-0.855) and non-dyslipidemic patients (HR 0.608, 95% CI 0.426-0.869) were lower in the cilostazol group than in the aspirin group. A significant interaction was demonstrated in the use of angiotensin receptor blocker (ARB) (p=0.0267). Stroke rate in non-users of ARB was lower in the cilostazol group than in the aspirin group (HR 0.542, 95% CI 0.370-0.793), while it was not different between both groups in users of ARB (HR 1.016, 95% CI 0.677-1.524). There was no significant difference in the rate of ischemic stroke between both treatment groups in patients with atherothrombotic stroke (cilostazol 1.77%/year, aspirin 2.45%/year, p=0.2808) and lacunar stroke (cilostazol 2.68%, aspirin 2.88%/year, p=0.7198). The rate of hemorrhagic stroke was not different between both groupsin patients with atherothrombotic stroke (cilostazol 0.31%/year, aspirin 0.59%/year, p=0.3444), while it was significantly much lower in the cilostazol group (0.36%/year) than in the aspirin group (1.20%/year) (RRR 65.0%, p=0.0030) among patients with lacunar stroke. Conclusion: Superiority of cilostazol over aspirin in secondary stroke prevention tended to be more obvious in alcohol drinkers and non-dyslipidemics. A significant interaction was observed in the concomitant use of ARB, which might be related to pleiotropic effects of cilostazol and ARB. Cilostazol has an advantage over aspirin in lower risk of cerebral hemorrhage especially in Japanese patients with lacunar stroke.