Effects Of Angiotensin Receptor Blockers Research Articles

Effect of valsartan on atrial fibrillation recurrence following pulmonary vein isolation in patients.

Pulmonary venous isolation has emerged as an effective therapy for atrial fibrillation (AF); however, AF recurrence is common. The aim of the present study was to investigate the effect of angiotensin receptor blockers (ARBs) on the recurrence rate of AF following ablation therapy. In total, 120 patients, who were scheduled for ablation, were randomly selected. The patients were randomly divided into three groups, which received treatment with a placebo (n=40), 80 mg valsartan daily (n=40) or with 160 mg valsartan daily (n=40). The demographic characteristics, comorbidities, AF type and information regarding treatment with ARBs were recorded and analyzed. Following a mean follow-up period of 13.8±8.6 months, 66.7% of patients were found to be free of AF. Kaplan-Meier analysis of the time until the first recurrence during the follow-up period revealed that patients treated with 160 mg/day valsartan presented a higher probability of remaining free of AF (88%, vs. 47% for the control and 65% for the 80 mg/day valsartan groups). In addition, multivariate analysis demonstrated that treatment with ARB was associated with lower AF recurrence rates (hazard ratio, 0.46; 95% confidence interval, 0.20–0.93] P=0.01). In conclusion, treatment with 160 mg/day valsartan markedly reduced the risk of recurrence of AF in a dose-dependent manner in AF patients following ablation.

Effectiveness of olmesartan-based treatment on home and clinic blood pressure in elderly patients with masked and white coat hypertension

Few large-scale studies have evaluated the effectiveness of angiotensin receptor blockers in patients with masked hypertension (MH) and white coat hypertension (WCH) based on age using real-world blood pressure (BP) data. We used data from the Home BP measurement with Olmesartan Naive patients to Establish Standard Target BP (HONEST) study to investigate the effectiveness of olmesartan-based treatment by patient age (<65 years of age, n=9817; 65–74 years of age, n=6792; ⩾75 years of age, n=4732), focusing on morning home BP (strongly associated with cardiovascular disease and useful for MH and WCH diagnosis). Sixteen weeks of treatment changed morning home BP (mean systolic/diastolic) by −18.1/−9.7, −15.9/−7.4 and −14.2/−6.4 mm Hg and clinic BP by −20.1/−11.3, −17.3/−8.7 and −15.4/−7.2 mm Hg, in these age groups, respectively (P<0.0001). Pulse pressure decreased (−7.8 to −8.8 mm Hg, P<0.0001). Patients aged ⩾80 years experienced similar BP and pulse pressure changes. In patients aged ⩾75 years, mean morning and clinic BP after 16 weeks was 137.5/74.8 and 129.7/70.4 mm Hg, respectively, in MH patients and 132.3/72.2 and 139.7/72.7 mm Hg, respectively, in WCH patients. Regardless of age, only elevated clinic or home BP values decreased to target ranges. The incidence of adverse effects associated with excessive BP lowering was low in all of the age groups. In conclusion, our study suggests that olmesartan-based treatment was safe and useful for managing MH, WCH and sustained hypertension in elderly patients. The lack of a placebo group was a limitation of the study.

Angiotensin converting enzyme (ACE) inhibitors versus angiotensin receptor blockers for primary hypertension.

Angiotensin converting enzyme inhibitors (ACE inhibitors) and angiotensin receptor blockers (ARBs) are widely prescribed for primary hypertension (systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg). However, while ACE inhibitors have been shown to reduce mortality and morbidity in placebo-controlled trials, ARBs have not. Therefore, a comparison of the efficacies of these two drug classes in primary hypertension for preventing total mortality and cardiovascular events is important. To compare the effects of ACE inhibitors and ARBs on total mortality and cardiovascular events, and their rates of withdrawals due to adverse effects (WDAEs), in people with primary hypertension. We searched the Cochrane Hypertension Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the World Health Organization (WHO) International Clinical Trials Registry Platform, and the ISI Web of Science up to July 2014. We contacted study authors for missing and unpublished information, and also searched the reference lists of relevant reviews for eligible studies. We included randomized controlled trials enrolling people with uncontrolled or controlled primary hypertension with or without other risk factors. Included trials must have compared an ACE inhibitor and an ARB in a head-to-head manner, and lasted for a duration of at least one year. If background blood pressure lowering agents were continued or added during the study, the protocol to do so must have been the same in both study arms. We used standard methodological procedures expected by The Cochrane Collaboration. Nine studies with 11,007 participants were included. Of the included studies, five reported data on total mortality, three reported data on total cardiovascular events, and four reported data on cardiovascular mortality. No study separately reported cardiovascular morbidity. In contrast, eight studies contributed data on WDAE. Included studies were of good to moderate quality. There was no evidence of a difference between ACE inhibitors and ARBs for total mortality (risk ratio (RR) 0.98; 95% confidence interval (CI) 0.88 to 1.10), total cardiovascular events (RR 1.07; 95% CI 0.96 to 1.19), or cardiovascular mortality (RR 0.98; 95% CI 0.85 to 1.13). Conversely, a high level of evidence indicated a slightly lower incidence of WDAE for ARBs as compared with ACE inhibitors (RR 0.83; 95% CI 0.74 to 0.93; absolute risk reduction (ARR) 1.8%, number needed to treat for an additional beneficial outcome (NNTB) 55 over 4.1 years), mainly attributable to a higher incidence of dry cough with ACE inhibitors. The quality of the evidence for mortality and cardiovascular outcomes was limited by possible publication bias, in that several studies were initially eligible for inclusion in this review, but had no extractable data available for the hypertension subgroup. To this end, the evidence for total mortality was judged to be moderate, while the evidence for total cardiovascular events was judged to be low by the GRADE approach. Our analyses found no evidence of a difference in total mortality or cardiovascular outcomes for ARBs as compared with ACE inhibitors, while ARBs caused slightly fewer WDAEs than ACE inhibitors. Although ACE inhibitors have shown efficacy in these outcomes over placebo, our results cannot be used to extrapolate the same conclusion for ARBs directly, which have not been studied in placebo-controlled trials for hypertension. Thus, the substitution of an ARB for an ACE inhibitor, while supported by evidence on grounds of tolerability, must be made in consideration of the weaker evidence for the efficacy of ARBs regarding mortality and morbidity outcomes compared with ACE inhibitors. Additionally, our data mostly derives from participants with existing clinical sequelae of hypertension, and it would be useful to have data from asymptomatic people to increase the generalizability of this review. Unpublished subgroup data of hypertensive participants in existing trials comparing ACE inhibitors and ARBs needs to be made available for this purpose.

Angioedema Related to Angiotensin Inhibitors

Angiotensin inhibitors have been extensively evaluated in clinical trials and have demonstrated significant reductions in morbidity and mortality following myocardial infarction and stroke, as well as in patients with heart failure or who are at risk of cardiovascular disease. Further, both angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are frequently prescribed for the treatment of hypertension and to preserve renal function in patients with diabetes mellitus and chronic kidney disease. Angioedema is a known, but rare, adverse effect of ACEIs and ARBs. Therefore, it is important for clinicians to have a thorough understanding of risks and benefits of prescribing these medications, particularly in patients with a history of angioedema. This review describes the literature evaluating the incidence and cross-reactivity of angioedema with ACEIs and ARBs in order to provide guidance for clinical decision making.

Abstract 227: Activation of Angiotensin II Type 2 Receptor Suppresses TNFα-induced ICAM-1 via NF-κB: Possible Role of ACE2

Activation of the renin-angiotensin system (RAS) is a major factor contributing to the pathophysiology of cardiovascular disease (CVD). Blockade of the RAS with angiotensin receptor blockers (ARBs) has been a standard treatment for CVD. Activation of angiotensin II type 2 receptor (AT2) and angiotensin I-converting enzyme 2 (ACE2) contribute to the cardioprotective effects of ARBs. Both AT2 and ACE2 counteract the vasoconstrictor and pro-inflammatory effects of angiotensin II. However, the possible interaction between AT2 and ACE2 has never been established. Tumor necrosis factor (TNFα) is a cytokine involved in angiotensin II signaling and promotes the inflammatory response via NF-κB. We hypothesized that activation of AT2 increases ACE2, thereby preventing TNFα-stimulated intercellular adhesion molecule-1 (ICAM-1) expression via inhibition of NF-κB. Human coronary artery endothelial cells were pretreated with AT2 antagonist PD123319 or ACE2 inhibitor DX-600, and then stimulated with TNFα in the presence or absence of AT2 agonist CGP42112A. ACE2 mRNA was measured by real-time RT-PCR. ACE2 activity was measured using a Fluorimetric Kit. ICAM-1 and phospho-inhibitory κB (p-IκB) were measured by Western Blot. Activation of AT2 with CGP42112A increased ACE2 mRNA by 1.82 ± 0.09 fold (p&lt;0.01) and ACE2 activity from 0.61 ± 0.05 to 0.95 ± 0.03 (pg/μl/h/μg protein) (p&lt;0.01). This effect was diminished by inhibition of AT2 or ACE2. ICAM-1 expression was almost undetectable in untreated cells but greatly increased by TNFα. Activation of AT2 reduced TNFα-induced ICAM-1 expression by 47% (from control value of 1 to 0.53 units) ± 5% (p&lt;0.01), which was diminished by AT2 antagonist or ACE2 inhibitor. We also found that TNFα increased p-IκB by 7.46 ± 0.51 fold (p&lt;0.01) compared to untreated cells and this effect was diminished by AT2 activation. Furthermore, ACE2 inhibitor blunted the effects of AT2 on TNFα-induced p-IκB expression. Our findings suggest that stimulation of AT2 reduces TNFα-induced ICAM-1 expression, which is partly through ACE2-mediated inhibition of NF-κB. Perspective: understanding the mechanisms underlying AT2-mediated anti-inflammatory effects could lead to new therapeutic strategies such as specific activation of AT2 and/or ACE2.

Blood pressure variability, impaired autonomic function and vascular senescence in aged spontaneously hypertensive rats are ameliorated by angiotensin blockade

ObjectiveElderly hypertensive patients are characterized by blood pressure (BP) variability, impaired autonomic function, and vascular endothelial dysfunction and stiffness. However, the mechanisms causing these conditions are unclear. The present study examined the effect of angiotensin receptor blockers (ARBs) on aged spontaneously hypertensive rats (SHR). MethodsWe surgically implanted telemetry devices in SHR and WKY at the age of 15 weeks (Young) and 80 weeks (Aged). Aged SHR were orally administered either olmesartan or valsartan once daily at 19:00 h (at the beginning of the dark period (active phase)) for 4 weeks to examine the effects on BP variability, impaired autonomic function, and vascular senescence. ResultsAging and hypertension in SHR additively caused the following: increased low frequency (LF) power of systolic BP, a decreased spontaneous baroreceptor reflex gain (sBRG), increased BP variability, increased urinary norepinephrine excretion, increased vascular senescence-related beta-galactosidase positive cells and oxidative stress. Treatment with olmesartan or valsartan significantly ameliorated these changes in aged SHR. However, olmesartan ameliorated these changes in aged SHR better than valsartan. The reductions in BP caused by olmesartan in aged SHR were sustained longer than reductions by valsartan. This result indicates longer-lasting inhibition of the AT1 receptor by olmesartan than by valsartan. ConclusionARBs ameliorated autonomic dysfunction, BP variability, and vascular senescence in aged SHR. Olmesartan ameliorated the aging-related disorders better than valsartan and was associated with longer-lasting AT1 receptor inhibition by olmesartan. Thus, the magnitude of improvement of these aging-related abnormalities differs for ARBs.

To compare the effect of Telmisartan with Metoprolol on arterial stiffness in hypertension: Prospective randomized parallel group trial

BackgroundHypertension is often complicated by increased arterial stiffness and is an independent predictor of adverse cardiovascular (CV) outcome. Beta blockers and angiotensin receptor blockers (ARBs) are commonly used antihypertensive agents. The effect of beta blockers and ARBs on arterial stiffness has not been compared adequately. The aim of the present study is to compare the effect of telmisartan with metoprolol on arterial stiffness in hypertensive patients in prospective open label randomized parallel group intervention study. Methods100 patients of hypertension, not on any antihypertensive agents, were enrolled after obtaining informed consent. Baseline recording of data related to demographics, CV risk factors, anthropometry and BP were made. Arterial stiffness was measured noninvasively by recording pulse wave velocity (PWV) using periscope (Genesis medical system). Left ventricular (LV) mass was measured using 2D guided M-mode echocardiography. Blood sugar, renal function, lipids and uric acid estimations were done in fasting state. Patients were randomized to receive metoprolol and telmisartan using stratified randomization technique. Dose of the study drugs were titrated to achieve target BP of <140/90 mmHg. Data related to PWV, BP, anthropometry and blood biochemistry was repeated after 6 months of treatment with study drugs. ResultsTelmisartan resulted in significantly greater reduction in arterial stiffness index (ASI) in left and right lower limb arterial bed (39.9 ± 11.7 vs. 46.8 ± 17.0 m/s, p < 0.02) and (36.4 ± 9.6 vs. 44.86 ± 15.1 m/s, p < 0.002) respectively and systolic blood pressure (SBP) (−4.9 mmHg with 95% C.I. of −8.0–1.7 mmHg, p < 0.003) compared to metoprolol. Reduction in diastolic blood pressure (DBP) in telmisartan and metoprolol groups was not different statistically (−1.0 mmHg with 95% C.I. of −3.3–1.2 mmHg, p < 0.3). The change in LV mass was not significantly different between the study groups (135.5 ± 37.6 vs. 143.2 ± 41.5, p < 0.3).

Angiotensin Type 1 Receptor Antagonists—A Novel Approach to Augmenting Posttraumatic Stress Disorder and Phobia Therapies?

The renin-angiotensin system system, which includes the renin and angiotensin-converting enzyme pathways, and its primary effector peptide angiotensin II (AII) acting through its two cognate receptors, AT1 and AT2 receptors, has been known for 70 years as a major regulator of vascular tone and fluid metabolism (1). Angiotensin receptor blockers (ARBs), consisting of a group of orally active drugs such as losartan (the group is often referred to as the “sartans”), and angiotensinconverting enzyme inhibitors are currently mainstream treatments for essential hypertension and some aspects of diabetes. In addition to these peripheral effects, AII and AT1 receptors are widely distributed in the brain and are being implicated in the regulation of many brain functions, including cerebral circulation, inflammation, neuroendocrine responses, learning, and memory (2). Because many ARBs are already on the market and have a good safety record with long-term use, they would be particularly attractive candidates to be used as novel treatments for central nervous system disorders where current therapies are inadequate. The article by Marvar et al. (3) in this issue of Biological Psychiatry may provide a strong impetus to consider testing ARBs, particularly as an adjunct therapy to augment cognitive-behavioral therapy, in posttraumatic stress disorder (PTSD) and phobias. The idea that ARBs may have some beneficial effects for patients with PTSD first arose from a correlational finding in an epidemiologic study, where veterans treated with ARBs for their medical conditions appeared to develop a less severe form of PTSD compared with veterans who were not taking ARBs (4). Although such correlations may turn out to be spurious, Marvar et al. decided to test whether the beneficial effect of ARBs is mechanistically demonstrable using preclinical models. There are robust animal models that can be used to study the basic circuits and phenotypes involved in PTSD symptoms. Using a standard auditory-cue paired conditioned fear model in mice, Marvar et al. tested the effects of single and multiple doses of selective AT1 antagonist losartan on fear extinction behavior, gene expression changes in the brain, and neuroendocrine and cardiovascular responses. They found that losartan treatment enhanced the consolidation of fear extinction without affecting acquisition, baseline anxiety, blood pressure, and neuroendocrine stress measures. Mice treated with losartan for 2 weeks also demonstrated reduced amygdala AT1 receptor messenger RNA (mRNA) levels. The authors concluded that AT1 receptor antagonism does have potential beneficial effects in a preclinical model of PTSD symptoms and could enhance the extinction of fear memories in PTSD.

Effect of angiotensin receptor blockers on glycaemic control in type 2 diabetic patients? A retrospective analysis

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Erectile dysfunction in arterial hypertension

Erectile dysfunction, the inability to attain, respec-tively maintain a penile erection sufficient for sexual intercourse, is a frequent finding in the general popu-lation. It is a multi-factorial syndrome that may arise from chronic disease such as arterial hypertension, but also from psychosocial problems, as a side effect of cer-tain medications, alcohol or drugs, or from impaired nerve function. Erectile dysfunction is associated with an increased risk of cardiovascular morbidity and mor-tality. The approach to the patient should include a thorough cardiovascular, endocrine, neurological, uro-logical and psychological evaluation. In patients with arterial hypertension, diuretics and beta-blockers may impair erectile function while beneficial effects of angi-otensin receptor blockers, ACE inhibitors, and nebivo-lol have been demonstrated. PDE-5-inhibitors may be considered in stable patients with controlled arterial hypertension but refractory erectile dysfunction

Female spontaneously hypertensive rats are more dependent on ANG (1-7) to mediate effects of low-dose AT1 receptor blockade than males

ANG (1-7) contributes to the blood pressure (BP)-lowering effect of angiotensin receptor blockers (ARBs) in male experimental animals. Females have greater ANG (1-7) concentrations than males; however, the contribution of ANG (1-7) to ARB-mediated decreases in BP in females is unknown. The current study tested the hypothesis that female spontaneously hypertensive rats (SHR) have a larger ANG (1-7) contribution to the BP-lowering effects of the ARB candesartan than male SHR. Twelve-week-old male and female SHR were randomized to receive candesartan (0.5 mg·kg(-1)·day(-1); 7 days), candesartan plus ANG II (200 ng·kg(-1)·min(-1); 7 days), the ANG (1-7) antagonist A-779 (48 μg·kg(-1)·h(-1)) plus candesartan and ANG II. Candesartan decreased basal BP in males and females (baseline vs. candesartan: 142 ± 2 vs. 122 ± 3 and 129 ± 1 vs. 115 ± 1 mmHg, respectively; P < 0.05); however, the decrease was greater in males. ANG II increased BP in males in the presence of candesartan (149 ± 2 mmHg; P < 0.05); candesartan blocked ANG II-induced increases in BP in females (116 ± 1 mmHg). Pretreatment with A-779 abolished candesartan-mediated decreases in BP in females, but not males. A-779 also exacerbated ANG II-induced proteinuria (26 ± 6 vs. 77 ± 11 μg·kg(-1)·day(-1), respectively; P < 0.05) and nephrinuria (20 ± 5 vs. 202 ± 58 μg·kg(-1)·day(-1), respectively; P < 0.05) in candesartan-treated female SHR, with no effect in males. In conclusion, females are more sensitive to the BP-lowering effect of ARBs during ANG II infusion, whereas males are more sensitive under basal conditions. In addition, ANG (1-7) has a greater contribution to ARB-mediated decreases in BP, protein, and nephrin excretion in females relative to males.

Mechanisms of angiotensin converting enzyme inhibitor-induced IOP reduction in normotensive rats

Angiotensin converting enzyme inhibitors (ACEIs) have been shown to lower intraocular pressure (IOP). Since, the ACEIs cause increased tissue prostaglandin levels, we hypothesized that the mechanisms of ACEI-induced IOP reduction have similarity with those of prostaglandin analogs. The present study investigated the involvement of matrix metalloproteinases (MMPs) and cytokine activity modulation as the underlying mechanisms of ACEI-induced ocular hypotension. The IOP lowering effect of single drop of enalaprilat dehydrate 1% was evaluated in rats pretreated with a broad spectrum MMP inhibitor or a cytokine inhibitor. Effect of angiotensin receptor blocker, losartan potassium 2%, was also studied to evaluate involvement of angiotensin II receptor type 1 (AT1) in IOP lowering effect of ACEI. Topical treatment with single drop of enalaprilat resulted in significant IOP reduction in treated eye with mean peak reduction 20.3% at 3h post-instillation. Treatment with losartan resulted in a peak IOP reduction of 13.3%, which was significantly lower than enalaprilat, indicating involvement of mechanisms in addition to AT1 blockade. Pretreatment with a broad spectrum MMP inhibitor or a cytokine inhibitor significantly attenuated the enalprilat-induced IOP reduction with mean peak IOP reduction of 11.2% and 13.6% respectively. The IOP-lowering effect of enalaprilat seems to be attributed to reduced angiotensin II type 1 receptor stimulation and modulation of MMP and cytokines activities.

Efficacy and Safety Profile of Aliskiren: Practical Implications for Clinicians

Renin-angiotensin-system (RAS) is an enzymatic cascade that plays a pivotal role in the development of arterial hypertension, kidney disease and cardiovascular disease. Inhibition of the RAS with angiotensin converting enzyme (ACE) inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) has proved to be a successful strategy for the treatment of hypertension and related cardiovascular disorders. However, by reducing feedback inhibition of renin release, the effects of ACE-Is and ARBs lead to an increase in plasma renin concentration (PRC) and activity (PRA), limiting a complete inhibition of the RAS. Consequently the effects of a different pharmacological strategy that completely blocks the RAS upstream has been assessed in the last years. In this context, aliskiren is the first representative of a new class of non-peptide orally active renin inhibitor that blocks the RAS at its rate-limiting step and induces a net reduction in PRA, angiotensin II and aldosterone levels. Aliskiren effectively reduces blood pressure as a monotherapy as well in combination therapy. In addition, aliskiren has a placebo-like tolerability profile at the licensed doses of 150 mg and 300 mg. Aliskiren also exhibits additive effects on blood pressure reduction when combined with drugs that lead to a reactive increase in the PRA, such as diuretics, ACE-Is or ARBs. In previous studies, aliskiren showed beneficial effects in patients with arterial hypertension and associated clinical conditions. However, later trials indicated that the use of aliskiren should be avoided in patients with renal failure or receiving ACE-Is or ARBs. The main aim of this review is to summarize the available data on its efficacy and safety profile, highlighting clinical implications from recent trials.

Abstract 171: Effect of Long-Term Treatment With Fimasartan on Transient Focal Ischemia in Rat Brain

Background and purpose: Fimasartan is a novel angiotensin receptor blocker (ninth), and its safety and efficacy have been established as an antihypertensive drug. Anti-apoptotic or anti-inflammatory effects of angiotensin receptor blockers were reported. However, few studies have elaborated on the effects of long-term treatment with low-dose ARB on cerebral ischemia independent of blood pressure lowering. Methods: Noninvasive blood pressure monitoring was performed in Sprague-Dawley rats which 0.5 mg/kg of fimasartan or phosphate-buffered saline (PBS) were administered for 4 weeks. Fimasartan (0.5, 1 or 3 mg/kg) was administered intraorally for 4 weeks, and we induced ischemia-reperfusion injury in rats. Infarct volume and the number of TUNEL-positive apoptotic cells were measured at 7 days. Functional outcomes were evaluated by modified limb placing test. To identify the anti-inflammatory effect of fimasartan, the number of inflammatory cells (OX6-positive cells) was measured. To identify mediators, phospho-STAT3 and IkB proteins were measured via Western blot analyses at 48 hours. Results: Blood pressures were decreased after administration of 1 mg/kg or 3 mg/kg of fimasartan for 4 weeks, but were not decreased in 0.5 mg/kg group. All doses of fimasartan decrease infarct volumes, and low-dose fimasartan (0.5 mg/kg) maximally reduced infarct volume up to 70% of those of the control group ( p &lt; 0.05). Quantitative analysis showed that the number of TUNEL-positive cells was remarkably decreased in the low-dose fimasartan group (622 ± 57 cell/mm 3 vs. 235 ± 48 cells/mm 3 ; p &lt; 0.05). Low-dose fimasartan improved functional outcomes at 14 days (74% recovery in fimasartan group vs. 43% in control group; p &lt; 0.05). The low-dose fimasartan group exhibited a lower number of OX6-positive cells (fimsartan group: 157 ± 17 cells/mm 3 ; control: 86 ± 11 cell/mm 3 ; p &lt; 0.05). The IkB degradation as a marker of NF-kB activation, was delayed, and phospho-STAT3 was decreased in the low-dose fimasartan group ( p &lt; 0.05). Conclusion: We demonstrate that long-term treatment with fimasartan improves neurological outcome in transient focal ischemia in rats. This protective effect of fimasartan is independent blood pressure lowering.

Effects of Inhibitors of the Renin-Angiotensin System on the Efficacy of Interferon beta-1b: A post hoc Analysis of the BEYOND Study

Background: In experimental autoimmune encephalomyelitis, inhibition of the renin-angiotensin system with angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme (ACE) inhibitors resulted in a significantly ameliorated disease course. We evaluated the effects of ARBs and ACE inhibitors on the efficacy of interferon beta-1b in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: In this post hoc analysis of the BEYOND (Betaferon Efficacy Yielding Outcomes of a New Dose) study, clinical and MRI end points were compared between patients treated with interferon beta-1b 250 or 500 µg and concomitant ARBs or ACE inhibitors and patients treated with interferon beta-1b 250 or 500 µg only (reference group). Results: Patients in the ARB group (n = 22) tended to have a higher relapse rate (0.48 vs. 0.23, p = 0.051) and a higher number of new gadolinium-enhancing lesions (0.6 vs. 0.3, p = 0.057) than patients in the reference group. Patients in the ACE inhibitor group (n = 49) also tended to have a higher relapse rate (0.29 vs. 0.22, p = 0.357). No differences were observed for the other end points. Conclusion: In the BEYOND study cohort, a concomitant medication with ARBs or ACE inhibitors did not have a beneficial effect in patients with RRMS treated with interferon beta-1b. As patients appeared to have a higher relapse rate, our results warrant further investigation.

Histological and immunohistochemical study on nitric oxide synthase and effects of angiotensin receptor blockade in early phase of diabetes in rat kidney

Background Several studies have demonstrated that the pathophysiological and morphological changes in early diabetic nephropathy were mediated by an increase or decrease in nitric oxide (NO) production and/or activity. There are few reports suggesting a relationship between NO and the renin–angiotensin system. Aim of the work The present study was designed to determine the effects of early diabetic state on NO production and also to assess the possible effects of angiotensin receptor blockers (ARBs) on these changes. Materials and methods Thirty adult male albino rats were included in this study. Twenty were injected with streptozotocin for induction of diabetes. The other 10 were injected with the vehicle and served as control. Two days after injection, the diabetic animals were randomly divided into two groups of 10 animals each. One group was given valsartan as an ARB and the other group received no further treatment. Three weeks later, all animals were sacrificed and the kidneys were processed for obtaining paraffin sections. The sections were stained with H&E, Masson’s trichrome, and periodic acid–Schiff. The sections were also stained with an immunohistochemical stain against endothelium-derived nitric oxide synthase (eNOS). Results Diabetes induced histological changes in the form of glomerular hypertrophy, increased glomerular matrix, focal areas of tubular atrophy, medullary congestion, and slight fibrosis. Immunostaining was present in the control kidney in the glomeruli and in the collecting tubules of the medulla. Diabetes induced a positive reaction in the proximal and distal convoluted tubules and increased immunoreactivity in the collecting tubules. Treatment with valsartan resulted in an improvement in the morphology of the kidney and a reduction in the intensity of eNOS immunostaining. Conclusion NO increases in early diabetic kidney and ARB in the form of valsartan could be recommended for preventing the development of diabetic nephropathy.

Estimated GFR Decline as a Surrogate End Point for Kidney Failure: A Post Hoc Analysis From the Reduction of End Points in Non–Insulin-Dependent Diabetes With the Angiotensin II Antagonist Losartan (RENAAL) Study and Irbesartan Diabetic Nephropathy Trial (IDNT)

A doubling of serum creatinine value, corresponding to a 57% decline in estimated glomerular filtration rate (eGFR), is used frequently as a component of a composite kidney end point in clinical trials in type 2 diabetes. The aim of this study was to determine whether alternative end points defined by smaller declines in eGFR would improve the statistical power of these clinical trials. Post hoc analyses of 2 multinational randomized controlled trials (Reduction of End Points in Non-Insulin-Dependent Diabetes With the Angiotensin II Antagonist Losartan [RENAAL] and Irbesartan Diabetic Nephropathy Trial [IDNT]) that assessed the treatment effect of the angiotensin receptor blockers (ARBs) losartan and irbesartan. 1,513 (RENAAL) and 1,715 (IDNT) adult patients with type 2 diabetes and nephropathy. Established versus alternative end points defined as a confirmed doubling of serum creatinine level versus confirmed eGFR decline of 57%, 40%, 30%, or 20% as a component of a composite end point of end-stage renal disease or eGFR < 15mL/min/1.73m(2). Numbers of patients reaching end points, precision (standard error), and significance (z score) of ARB treatment effect (HR) during follow-up. Lesser eGFR declines resulted in a greater number of patients reaching end points in both treatment groups and lower standard error of the HR, but the effect on z score was counterbalanced by attenuation of the HR. When calculating the eGFR decline from month 3, attenuation of the HR was less pronounced. Post hoc analysis. Despite increases in precision of the treatment effect, eGFR declines less than a doubling of serum creatinine value did not consistently improve statistical power of the clinical trials due to attenuation of the treatment effect. Attenuation of the treatment effect appears to be due in part to acute effects of ARBs on eGFR. These findings should be taken into account when using lesser eGFR declines as alternative end points for clinical trials.

Effects of Losartan on Left Ventricular Hypertrophy and Fibrosis in Patients With Nonobstructive Hypertrophic Cardiomyopathy

The aim of this study was to evaluate the effects of losartan on left ventricular (LV) hypertrophy and fibrosis in patients with nonobstructive hypertrophic cardiomyopathy (HCM). Despite evidence that myocardial hypertrophy and fibrosis are mediated by angiotensin II and are important determinants of morbidity and mortality in patients with HCM, no prior studies have evaluated the effects of angiotensin receptor blockers on LV hypertrophy and fibrosis with cardiac magnetic resonance imaging. In double-blind fashion, 20 patients (3 women, 17 men; age: 51 ± 13 years) with HCM were randomly assigned to receive placebo (n= 9) or losartan 50 mg twice a day (n= 11) for 1 year. Cardiac magnetic resonance imaging was performed at baseline and 1 year to measure LV mass and extent of fibrosis as assessed by late gadolinium enhancement. There was a trend toward a significant difference in the percent change in LV mass (median [interquartile range]:+5% [-4% to+21%] with placebo vs.-5% [-11% to-0.9%] with losartan; p= 0.06). There was a significant difference in the percent change in extent of late gadolinium enhancement, with the placebo group experiencing a larger increase (+31% ± 26% with placebo vs.-23% ± 45% with losartan; p= 0.03). This pilot study suggests attenuation of progression of myocardial hypertrophy and fibrosis with losartan in patients with nonobstructive HCM. Confirmation of these results in a larger trial is required to confirm a place for angiotensin receptor blockers in the management of patients with HCM. (Effect of Losartan in Patients With Nonobstructive Hypertrophic Cardiomyopathy; NCT01150461).

A meta-analysis of the effect of angiotensin receptor blockers and calcium channel blockers on blood pressure, glycemia and the HOMA-IR index in non-diabetic patients

ObjectiveThis study compared the efficacy of angiotensin receptor blockers (ARBs) and calcium channel blockers (CCBs) in the effect of insulin resistance (IR) as assessed using the homeostasis model assessment of insulin resistance (HOMA-IR) in non-diabetic patients. MethodsThe MEDLINE, EMBASE, and Cochrane Library databases were searched to identify studies published before December 2012 that investigated the use of ARBs and CCBs to determine the effect on the HOMA-IR index in non-diabetics. Parameters on IR and blood pressure were collected. Review Manager 5.2 and Stata 12.0 were used to perform the meta-analysis. Fixed and random effects models were applied to various aspects of the meta-analysis, which assessed the therapeutic effects of the two types of drug using the HOMA-IR index in non-diabetic patients. ResultsThe meta-analysis included five clinical trials. Patient comparisons before and after treatment with ARBs and CCBs revealed that ARBs reduced the HOMA-IR index (weighted mean difference (WMD) −0.65, 95% confidence interval (CI) −0.93 to −0.38) and fasting plasma insulin (FPI) (WMD −2.01, 95% CI −3.27 to −0.74) significantly more than CCBs. No significant differences in the therapeutic effects of these two types of drug on blood pressure were observed. ConclusionGiven that there are no significant differences in the therapeutic effects of ARBs and CCBs on blood pressure, as ARBs are superior to CCBs in their effect on the HOMA-IR index in non-diabetics, they might be a better choice in hypertension patients without diabetes.

Abstract 634: Suppression of Ang II Inhibits Sodium Retention During Mental Stress

Background: We hypothesized that stress-induced increases in Ang-II would increase the retained sodium load over the course of a day in a significant percentage of African-Americans (AAs). Methods: We tested this hypothesis with a double blind placebo-controlled trial which examined the effect of an angiotensin receptor antagonist blocker (irbesartan) on the pressure natriuresis response to one hour of mental stress induced by a competitive video game task in 93 healthy, normotensive AAs with a mean age of 26 years. The 3-hour protocol consisted of a 1-hour stress period preceded and followed by a 1-hour rest period. Blood and urine were collected hourly and blood pressure at 15 minute intervals. The subjects were divided into those who increased (excreters, upper panel) or decreased (retainers, lower panel) U Na V with stress in the placebo condition. Results: The ARB increased the change in U Na V during stress by 10.2 mEq, or approximately 235 mgs in Retainers but had no effect in Excreters. The ARB also had a beneficial effect on the blood pressure levels in Retainers but not Excreters, lowering levels throughout the protocol in this group. Conclusions: Assuming 4 episodes of stress during a day, the additional sodium load induced by Ang II would be approximately 1,000 mgs, which would increase the average intake by an estimated one third. From a prevention perspective, these individuals would need to reduce their sodium intake by a third to compensate for the amount of sodium reabsorbed during episodes of mental stress throughout the day. Figure. Effect of angiotensin receptor blocker on sodium excretion (UnaV) in response to stress in AA excreters vs. retainers.