Angiotensin II Receptor Blockers Administration Research Articles

PS-C26-8: UNIQUE PROPERTIES OF DEPRESSOR, RENAL, AND ALDOSTERONE RESPONSES TO ALISKIREN THERAPY IN HYPERTENSIVE PATIENTS WITH NEPHROPATHY

Objective: Blood pressure (BP) control using renin-angiotensin system (RAS) inhibitor as a first choice is recommended in hypertension accompanied by chronic kidney disease (CKD), and RAS localized in the kidney is known to exist independent of circulating RAS. Aliskiren, direct renin inhibitor (DRI), is most excellent in kidney tissue migration among RAS inhibitors despite it has been reported to cause aldosterone breakthrough like angiotensin II receptor blocker (ARB) in essential hypertension. Therefore, DRI-induced antihypertensive, renoprotective and aldosterone-suppressing effects were investigated as compared to those of ARB in hypertensive CKD patients. Design and method: 168 hypertensive patients with CKD (stage G1–4) were employed in this study. Home BP in the morning, estimated glomerular filtration rate (eGFR), urinary protein/creatinine ratio (UPCR), urinary liver-type fatty-acid-binding protein (U-LFABP) as an indicator of tubular dysfunction, plasma and urinary aldosterone concentration (PAC and UAC) were measured before and 0.5 to 5 years after administration of ARB or DRI and assessed retrospectively. Aldosterone breakthrough was defined as any increase in PAC from the baseline level following treatment with a RAS inhibitor. Results: In ARB-treated group, BP and UPCR decreased significantly at 6 months, but sufficient declines were not observed 1st year onward. In DRI-treated group, a significant reduction in BP was sustained until 3 years and BP unchanged decreasing tendency even 4 years later, meanwhile UPCR decreased significantly for 2 years and was below the pretreatment value 3 years after. ARB raised BP and UPCR again in patients with CKD G3–4 prior to those with CKD G1–2, however, DRI expressed no difference between stages. Although PAC diminished up to 6 months in ARB group and 1 year in DRI group, it turned up 1 year and 2 years after, respectively. PAC-ascensive rate and maximum elevation in PAC were higher and greater in ARB group than in DRI group (48.7 vs 22.6%, 56.1 vs 29.3pg/ml). All significant differences in rising PAC cases disappeared by 5 years, whereas in non-rising PAC cases, only DRI reduced U-LFABP without deterioration in eGFR and UAC further lowered while PAC was maintained. Conclusions: In comparison with ARB, aliskiren prolongs hypotensive and proteinuria-lowering effects with retained eGFR regardless of CKD severity possibly via improvement of tubular disorders and less PAC reascent in hypertensive nephropathy. Aliskiren given to CKD patients might elicit mild and delayed aldosterone breakthrough rather than ARB due to a direct action against aldosterone derived from the kidney.

689 IMPACT OF RENIN-ANGIOTENSIN SYSTEM INHIBITORS ON CLINICAL OUTCOME IN HYPERTENSIVE PATIENTS WITH SEVERE AORTIC STENOSIS UNDERGOING TRANSCATHETER AORTIC VALVE IMPLANTATION: INSIGHT FROM THE EFFECTAVI REGISTRY

Abstract Aims Left ventricular pressure overload is connected with cardiac renin–angiotensin system activation, which may lead to myocardial fibrosis and poorer clinical outcomes. Hypertensive patients with symptomatic, severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI) in the EffecTAVI registry were evaluated for the association between baseline treatment with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) and clinical outcomes. Methods and results The research comprised 373 patients with moderate, high, or prohibitive risk who had TAVI in the EffecTAVI registry (NCT05235555). Using Kaplan–Meier event rates and study-stratified multivariable Cox proportional hazards regression models, we evaluated clinical outcomes at 2 years according to ACEi/ARB therapy status at baseline. Among the 327 patients with hypertension included in the present study, 222 (67.9%) were treated with ACEI/ARB at baseline, whereas 105 (32.1%) were not. Treatment with ACEI/ARB was related with decreased all-cause mortality (HR=0.46, 95% CI 0.25-0.90, p=0.011), although this association was not statistically significant after multivariable adjustment for important covariates. Analyzing pre-procedural ACEi and ARBs separately, ARBs administration was related with a 58% decrease in all-cause mortality (HR=0.42, 95% CI 0.18-0.98, p=0.04), which was confirmed in multivariate analysis. Conclusion In a small cohort of hypertensive patients with severe symptomatic AS from the EffecTAVI registry, ARBs treatment at baseline was independently associated with a lower risk of 2-year all-cause mortality.

Seasonal pattern of vitamin D hydroxyl metabolite concentrations and their association with cardiac medications – An observational study

ObjectivesThe sun is the primary source of vitamin D production, and seasonal changes can substantially influence vitamin D levels, which hardly any study has examined in cardiac patients. This research aims to measure 25(OH)D3 and 25(OH)D2 concentrations and assess their relation to the seasons and medications given to cardiac patients. MethodsWe collected 116 blood samples from 58 patients in autumn-winter and spring-summer seasons. Ultra-high-performance liquid chromatography-tandem mass spectrometry method was applied to determine 25(OH)D3 and 25(OH)D2 concentrations. The statistical assessment was performed using Statistica 13.3 with Plus Kit 3.0. ResultsOnly 9% of patients had 25(OH)D3 concentrations in the recommended range of 30–50 ng/mL. We found significantly higher 25(OH)D3 average levels in spring-summer period compared with autumn-winter period (P = 0.001). Older patients had a higher risk of vitamin D deficiency in autumn-winter (OR = 1.08; P = 0.011, OR = 0.32; P = 0.015, respectively). Average 25(OH)D2 concentrations between seasons were insignificant (Z = 1.04; P = 0.3). Vitamin D deficiency was significantly correlated with administration of angiotensin-II receptor blocker (OR = 7.49; P = 0.025), steroidal antiandrogen*age (OR = 1.039; P = 0.022). Other medications did not correlate with vitamin D deficiency, 9%NaCl (OR = 0.2; P = 0.04) and thiazide (0.076; P = 0.015). ConclusionThe prevalence of vitamin D deficiency and therapeutic drug monitoring are substantial in the observed group of cardiovascular patients, considering those with higher risk factors. Cardiac patients may benefit from vitamin D supplementation or dietary intervention to correct vitamin D levels. Further studies on more patients are required to confirm our results and identify other factors influencing 25(OH)D concentrations in cardiac patients.

Effective Combination Therapy of Angiotensin-II Receptor Blocker and Rifaximin for Hepatic Fibrosis in Rat Model of Nonalcoholic Steatohepatitis.

The progression of nonalcoholic steatohepatitis (NASH) is complicated. The multiple parallel-hits theory is advocated, which includes adipocytokines, insulin resistance, endotoxins, and oxidative stress. Pathways involving the gut–liver axis also mediate the progression of NASH. Angiotensin-II receptor blockers (ARB) suppress hepatic fibrosis via the activation of hepatic stellate cells (HSCs). Rifaximin, a nonabsorbable antibacterial agent, is used for the treatment of hepatic encephalopathy and has been recently reported to improve intestinal permeability. We examined the inhibitory effects on and mechanism of hepatic fibrogenesis by combining ARB and rifaximin administration. Fischer 344 rats were fed a choline-deficient/l-amino acid-defined (CDAA) diet for 8 weeks to generate the NASH model. The therapeutic effect of combining an ARB and rifaximin was evaluated along with hepatic fibrogenesis, the lipopolysaccharide–Toll-like receptor 4 (TLR4) regulatory cascade, and intestinal barrier function. ARBs had a potent inhibitory effect on hepatic fibrogenesis by suppressing HSC activation and hepatic expression of transforming growth factor-β and TLR4. Rifaximin reduced intestinal permeability by rescuing zonula occludens-1 (ZO-1) disruption induced by the CDAA diet and reduced portal endotoxin. Rifaximin directly affect to ZO-1 expression on intestinal epithelial cells. The combination of an ARB and rifaximin showed a stronger inhibitory effect compared to that conferred by a single agent. ARBs improve hepatic fibrosis by inhibiting HSCs, whereas rifaximin improves hepatic fibrosis by improving intestinal permeability through improving intestinal tight junction proteins (ZO-1). Therefore, the combination of ARBs and rifaximin may be a promising therapy for NASH fibrosis.

Coronavirus disease 2019 (COVID-19): angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and cardiovascular disease.

Coronavirus disease 2019 (COVID-19): angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and cardiovascular disease.

6128Losartan vs Nebivolol vs the association of both on the progression of aortic root dilation in genotyped Marfan Syndrome: 48 months open label randomized controlled phase III trial

Abstract Background Marfan Syndrome (MFS) is a rare multisystemic genetic disease caused by mutations in the Fibrillin 1 (FBN1) gene. Aortic root aneurysm, potentially evolving to dissection and rupture, is the most important clinical complication. Beta blockers (BB) and Angiotensin II receptor blockers (ARB), these latter exerting an anti-TGFbeta1 effect, are current cornerstones of medical therapy in patients diagnosed with MFS and presenting aortic root aneurysm. The study aimed at comparing the effect of single drug (nebivolol and losartan) vs. the combination of both (losartan + nebivolol) in limiting the progression of the growth of the aortic root diameter (ARD) in FBN1 genotyped patients with aortic root aneurysm (z-score>2), who had not undergone prior aortic surgery. Methods We designed a controlled, open-label, single-blinded, 1:1:1 randomized, phase III single-centre study [NCT00683124]. Calculated sample size was 291 (power 90%, type I error 5%, 20% attrition, expected dropout 20%). ARD data collection was performed with annual 2D-transthoracic echocardiograms for four years. ARDs were measured with 2D-transthoracic echocardiogram as absolute values, aortic root ratio (ARR), and z-score. The primary endpoint was the modification of ARD z-score at 48 months. The analysis of the primary endpoint aimed at showing differences of ARD z-score comparing: – The combined treatment arm (group A). – The group aggregating both single treatment arms (group B). – The nebivolol arm (group C). – The losartan arm (group D). Results We enrolled 262 patients (126 adults, aged 17–55, and 136 children, aged 1–16); 236/262 (22 dropout; 4 lost at follow-up) completed the planned follow-up: 81 in the group A, 79 in the BB in the group C and 76 in the group D. No patient developed acute aortic dissection. Both drugs administered either individually or in combination were well tolerated without evidence of side effects. At 48 months, the ARD Z-score decreased from baseline to end-follow-up in all treatment arms. The decrease was significantly higher in the combined treatment arm (A) than in the single treatment aggregated arm (group B) with a difference in ARD z-score change of 0.17 (p=0.009) in the combined arm (A). Similarly, the decrease of z-score was inferior in the nebivolol arm and in the losartan arm than in the combined arm (by 0.16, p=0.032, and by 0.18, p=0.019, respectively). After Bonferroni correction for these post-hoc comparisons only the decrease of z-score in the losartan arm remained significantly inferior (p<0.025). Conclusions This study shows that the current cornerstones of medical therapy in MFS (ARB and BB) are effective in limiting the progression of the growth of the aortic root diameter: their combination exploits a synergistic effect. The combined administration of BB and ARB in patients with aortic root aneurysm is a sustainable, well tolerated treatment that effectively limits the rate of progression of aortic root dilation. Acknowledgement/Funding The financial support of Telethon, Italy (Grant no. GGP08238) is gratefully acknowledged.The drugs are a gift of Menarini and MSD

Two cases of advanced stage rapidly progressive diabetic nephropathy effectively treated with combination therapy including RAS blocker, GLP-1 receptor agonist and SGLT-2 inhibitor

We herein report two cases of advanced stage rapidly progressive diabetic nephropathy that were effectively treated with combination therapy including renin-angiotensin-aldosterone system (RAS) blocker [angiotensin II receptor blocker (ARB)], glucagon-like peptide-1 (GLP-1) receptor agonist and sodium glucose transporter-2 (SGLT-2) inhibitor. A 30-year-old woman with advanced stage diabetic nephropathy [estimated glomerular filtration rate (eGFR): 20.7mL/min/1.73m2; proteinuria: 13.2g/gCr], showing a rapidly progressive pattern (annual eGFR change: - 60.0mL/min/1.73m2/year), had improvement in proteinuria (5.9g/gCr) and eGFR change (+ 4.3mL/min/1.73m2 over 15 weeks) after administration of ARB (irbesartan 25mg/day), GLP-1 receptor agonist (liraglutide 0.3mg/day) and SGLT-2 inhibitor (canagliflozin 50mg/day). A 59-year-old man with advanced stage diabetic nephropathy (eGFR: 32.4mL/min/1.73m2; proteinuria: 8.90g/gCr), showing a rapidly progressive pattern (annual eGFR change: - 21.2mL/min/1.73m2/year), had an improvement in proteinuria (0.02g/gCr) and annual eGFR change (+ 0.1mL/min/1.73m2/year) after combination therapy with ARB (olmesartan 40mg/day), GLP-1 receptor agonist (liraglutide 0.9mg/day) and SGLT-2 inhibitor (tofogliflozin 10mg/day). These results suggest that this triple combination therapy has renoprotective effects on advanced stage rapidly progressive diabetic nephropathy.

Pathological presentation of cardiac mitochondria in a rat model for chronic kidney disease.

BackgroundMitochondria hold crucial importance in organs with high energy demand especially the heart. We investigated whether chronic kidney disease (CKD), which eventually culminates in cardiorenal syndrome, could affect cardiac mitochondria and assessed the potential involvement of angiotensin II (AngII) in the process.MethodsMale Lewis rats underwent 5/6 nephrectomy allowing CKD development for eight months or for eleven weeks. Short-term CKD rats were administered with AngII receptor blocker (ARB). Cardiac function was assessed by echocardiography and cardiac sections were evaluated for interstitial fibrosis and cardiomyocytes’ hypertrophy. Electron microscopy was used to explore the spatial organization of the cardiomyocytes. Expression levels of mitochondrial content and activity markers were tested in order to delineate the underlying mechanisms for mitochondrial pathology in the CKD setting with or without ARB administration.ResultsCKD per-se resulted in induced cardiac interstitial fibrosis and cardiomyocytes’ hypertrophy combined with a marked disruption of the mitochondrial structure. Moreover, CKD led to enhanced cytochrome C leakage to the cytosol and to enhanced PARP-1 cleavage which are associated with cellular apoptosis. ARB treatment did not improve kidney function but markedly reduced left ventricular mass, cardiomyocytes’ hypertrophy and interstitial fibrosis. Interestingly, ARB administration improved the spatial organization of cardiac mitochondria and reduced their increased volume compared to untreated CKD animals. Nevertheless, ARB did not improve mitochondrial content, mitochondrial biogenesis or the respiratory enzyme activity. ARB mildly upregulated protein levels of mitochondrial fusion-related proteins.ConclusionsCKD results in cardiac pathological changes combined with mitochondrial damage and elevated apoptotic markers. We anticipate that the increased mitochondrial volume mainly represents mitochondrial swelling that occurs during the pathological process of cardiac hypertrophy. Chronic administration of ARB may improve the pathological appearance of the heart. Further recognition of the molecular pathways leading to mitochondrial insult and appropriate intervention is of crucial importance.

Involvement of local renin-angiotensin system in immunosuppression of tumor microenvironment.

To improve current cancer immunotherapies, strategies to modulate various immunosuppressive cells including myeloid derived suppressor cells (MDSC) which were shown to be negative factors in immune‐checkpoint blockade therapy, need to be developed. In the present study, we evaluated the role of the local renin‐angiotensin system (RAS) in the tumor immune‐microenvironment using murine models bearing tumor cell lines in which RAS was not involved in their proliferation and angiogenetic ability. Giving angiotensin II receptor blockers (ARB) to C57BL/6 mice bearing murine colon cancer cell line MC38 resulted in significant enhancement of tumor antigen gp70 specific T cells. ARB administration did not change the numbers of CD11b+ myeloid cells in tumors, but significantly reduced their T‐cell inhibitory ability along with decreased production of various immunosuppressive factors including interleukin (IL)‐6, IL‐10, vascular endothelial growth factor (VEGF), and arginase by CD11b+ cells in tumors. ARB also decreased expression of immunosuppressive factors such as chemokine ligand 12 and nitric oxide synthase 2 in cancer‐associated fibroblasts (CAF). Last, combination of ARB and anti‐programmed death‐ligand 1 (PD‐L1) antibodies resulted in significant augmentation of anti‐tumor effects in a CD8+ T cell‐dependent way. These results showed that RAS is involved in the generation of an immunosuppressive tumor microenvironment caused by myeloid cells and fibroblasts, other than the previously shown proliferative and angiogenetic properties of cancer cells and macrophages, and that ARB can transform the immunosuppressive properties of MDSC and CAF and could be used in combination with PD‐1/PD‐L1 immune‐checkpoint blockade therapy.

Angiotensin II receptor blockers following intravenous nicardipine administration to lower blood pressure in patients with hypertensive intracerebral hemorrhage: a prospective randomized study.

In patients with hypertensive intracerebral hemorrhage (HICH), intravenous nicardipine is primarily used to lower blood pressure (BP). However, there are few studies investigating the role of oral antihypertensives administered after intravenous nicardipine to prevent BP from rising. Angiotensin II receptor blockers (ARBs) may be beneficial in HICH patients not only as antihypertensives but also by lowering plasma catecholamine levels. A prospective randomized study was conducted between January 2015 and March 2016 to comparatively evaluate the efficacy of two ARBs (azilsartan vs. candesartan) following intravenous nicardipine administration on BP reduction. Thirty conscious HICH patients presenting within 6 h of symptom onset were enrolled (15 in each arm). After administering intravenous nicardipine for 24-48 h, the patients were randomized either to the azilsartan (20 mg) arm or to the candesartan (8 mg) arm. Frequency of hematoma expansion, 30-day modified Rankin scale, and temporal profiles of systolic blood pressure (SBP) and plasma norepinephrine/aldosterone were compared. Substantial hematoma expansion occurred in two (13%) azilsartan patients and in one (7%) candesartan patient (P=1.00). SBPs were maintained at lower than 140±20 mmHg in both arms. Neither SBPs nor plasma norepinephrine/aldosterone levels differed significantly. All 30 patients had 30-day modified Rankin scale scores of 1-2. Administration of ARBs following intravenous nicardipine effectively prevented BP from rising in HICH patients. However, whether BP should be strictly managed after 24 h of symptom onset should be addressed in future studies focusing not only on neurologic but also on cardiovascular and renal functions of HICH patients.

PP.13.10] EFFICACY AND SAFETY OF TWO DIFFERENT DOSAGES OF CANRENONE AS ADD-ON THERAPY IN HYPERTENSIVE PATIENTS TAKING ACE-INHIBITORS OR SARTANS AND DIURETICS AT MAXIMUM DOSAGE

Objective: To evaluate the efficacy on blood pressure reduction, safety and tolerability of two different dosages of canrenone as add-on therapy in patients already treated with Angiotensin Converting-Enzyme Inhibitors (ACE-I) or Angiotensin II Receptor Blockers (ARBs) and diuretics at the maximum dosage. In this multi-centre, phase IV, randomized, controlled, open-label, parallel groups trial, we enrolled 165 Caucasian patients affected by uncomplicated, essential hypertension, not well controlled by concomitant administration of ACE-I or ARBs and diuretics at the maximum dosage. At baseline patients were randomized to canrenone, 50 mg, or canrenone 100 mg once a day, in addition to their current therapy, for three months. We evaluated at the baseline, and after 3 months: systolic (SBP) and diastolic blood pressure (DBP), pulse pressure (PP), heart rate, fasting plasma glucose (FPG), homeostasis model assessment insulin (HOMA-index), lipid profile, electrolytes, uric acid, estimated glomerular filtration rate (eGFR), plasmatic urea. We observed a reduction of SBP, DBP, and PP with both the dosages of canrenone (p < 0.01 vs baseline for both), with a greater decrease recorded with canrenone 100 mg compared to 50 mg (p < 0.05). We did not record any variation of hearth rate, FPG, HOMA-index with neither of two treatments. Regarding lipid profile, we observed a slight increase of triglycerides with canrenone 50 mg (p < 0.05 vs baseline), not significant in group to group comparison. Regarding electrolytes, we recorded an increase of potassium in both groups (p < 0.05 vs baseline with canrenone 50 mg, and p < 0.01 vs baseline with canrenone 100 mg), even if potassium level reached with canrenone 100 mg was higher compared to canrenone 50 mg (p < 0.05). Considering renal function, there was an increase of creatinine and plasmatic urea compared to baseline with canrenone 100 mg (p < 0.01 vs baseline). Despite a slightly greater decrease of blood pressure, canrenone 100 mg seems to give a greater increase of potassium, and an increase of creatinine not recorded with canrenone 50 mg although non clinically relevant. Both treatments did not result in any increase of adverse events. Canrenone should be recommended in hypertensive patients already taking ACE-I or ARBs and diuretic at the maximum dosage.

Candesartan Induces a Prolonged Proangiogenic Effect and Augments Endothelium-Mediated Neuroprotection after Oxygen and Glucose Deprivation: Role of Vascular Endothelial Growth Factors A and B

Angiogenesis is a key component of recovery after stroke. Angiotensin II receptor blocker (ARB) treatment improves neurobehavioral outcome and is associated with enhanced angiogenesis after stroke. The purpose of this study is to investigate the temporal pattern of the ARB proangiogenic effect in the ischemic brain and its association with vascular endothelial growth factors VEGF-A and VEGF-B. Wistar rats were exposed to 90-minute middle cerebral artery occlusion and treated with candesartan (1 mg/kg) at reperfusion. The proangiogenic potential of the cerebrospinal fluid was determined at 8, 24, 48, and 72 hours using an in vitro Matrigel tube formation assay. In addition, the expression of VEGF-A and VEGF-B was measured in brain homogenates using Western blotting at the same time points. A single candesartan dose induced a prolonged proangiogenic effect and a prolonged upregulation of VEGF-A and VEGF-B in vivo. In the ischemic hemisphere, candesartan treatment was associated with stabilization of hypoxia-inducible factor-1α and preservation of angiopoietin-1. The effect of ARB treatment on endothelial cells was studied in vitro. Our results identified brain endothelial cells as one target for the action of ARBs and a source of the upregulated VEGF-A and VEGF-B, which exerted an autocrine angiogenic response, in addition to a paracrine neuroprotective effect. Taken together, this study highlights the potential usefulness of augmenting the endogenous restorative capacity of the brain through the administration of ARBs.

Abstract 194: BDNF Knockdown Abrogates AT1 Blockade -Induced Improvement in Stroke Outcome

Background: Brain derived neurotrophic factor has been shown to play an important role in long term functional recovery after stroke. Unfortunately, the clinical exploitation of this protein is limited due to the lack of pharmacological interventions that regulate its expression. Angiotensin II receptor blockers (ARBs) increase BDNF expression in both normotensive and hypertensive animals. We investigated the possible interaction between acute ARB treatment and BDNF in terms of long term functional recovery after stroke. Methods: Male normotensive wistar rats received bilateral ICV injections with lentiviruses expressing either BDNF shRNA or vector. 14 days after injection, animals were subjected to 90 minutes MCAO and randomized to either candesartan 1mg/kg or saline at the time of reperfusion. Functional recovery was assessed 24 hours after stroke and every 72 hours for 14 days using a blinded battery of validated behavioral tests. Animals were then sacrificed and their brains processed for immunohistochemistry. Results: Bilateral injection with shRNA reduced the expression of BDNF by more than 70% (p=0.0045). Acute ARB administration ameliorated stroke induced functional deficits throughout the follow-up period after stroke in all used tests and Day 14 data is shown on the Table. This pro-recovery effect was totally ablated in BDNF knocked down animals. Acute ARB therapy also increased the number of new brain blood vessels (CD31/Ki67 positive cells) which was also BDNF dependent. Conclusion: 1. Acute ARB- induced functional recovery after stroke is BDNF dependent. 2. This pro-recovery effect is associated with a BDNF dependent proangiogenic state. Table 1: Experimental data summary. SD are shown in parenthesis. a,b,c. Pairs of means with different letters are significantly different from each other

Prognostic Value of Renin–Angiotensin System Blockade in Non-muscle-invasive Bladder Cancer

To determine whether the administration of renin-angiotensin system (RAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), affect disease outcome in non-muscle-invasive bladder cancer (NMIBC). A total of 330 patients with initially diagnosed NMIBC were identified. We retrospectively investigated the clinical outcomes after transurethral resection of bladder tumor (TUR-BT) in patients who did or did not receive RAS inhibitors. The median follow-up period was 4.1years. A total of 128 patients (38.8%) experienced subsequent tumor recurrence, and stage progression was observed in 17 patients (5.2%) during follow-up. Fifty-one patients (15.5%) had received ACEI or ARB administration at transurethral resection. Multivariate analysis demonstrated that tumor multiplicity, absence of bacillus Calmette-Guérin instillation, and no administration of ACEI or ARB (P=0.010, hazard ratio 2.26) were independent risk factors for subsequent tumor recurrence. The 5-year recurrence-free survival rate was 78.4% in patients administered ACEIs or ARBs, and 53.3% in their counterparts (P=0.011). The absence of RAS inhibitor administration was an independent risk factor for subsequent tumor recurrence in patients with initially diagnosed NMIBC. Our data support further investigation of the role of RAS inhibitors as a potential therapy to decrease tumor recurrence in NMIBC.

P37 Muscle mass in COPD patients receiving angiotensin II receptor blockers and ACE-inhibitors

BackgroundSkeletal muscle dysfunction is well recognised in chronic obstructive pulmonary disease (COPD) and is associated with increased morbidity and mortality. Considerable circumstantial evidence supports a role for renin-angiotensin systems in...

Influence of renin–angiotensin system on serum parathyroid hormone levels in uremic patients

The aim of this study was to investigate the factors influencing serum parathyroid (PTH) levels, including medications for treating chronic kidney disease-mineral and bone metabolism disorder (CKD-MBD) in patients with end-stage renal disease. We enrolled 1,076 patients in nine Japanese facilities who had begun hemodialysis (HD) due to ESRD. We investigated the relationships between intact PTH (iPTH) levels and clinical parameters and medications just prior to beginning HD. Significant decreases in serum iPTH levels were seen in males, in the presence of diabetes mellitus (DM), and with administration of renin-angiotensin system inhibitors (RASIs). Significant correlations were found between serum calcium and iPTH levels. In the patients administered RASIs, there was a significant decrease in serum iPTH levels with DM, male gender, and administration of active vitamin D sterols (VDs) compared with those not administered RASIs, although serum-corrected calcium levels were not different. Multiple regression analysis found gender, age, presence of DM, and serum calcium and phosphate levels to be significant contributing factors. In addition, administration of angiotensin II receptor blockers (ARBs) may also be a contributing factor to iPTH levels at the beginning HD (p=0.050). In this study, serum iPTH levels were related to administration of ARBs besides gender, age, the presence of DM and serum calcium levels. Our study suggests that the RA system involve serum iPTH levels in uremic patients.

Acute angiotensin II receptor blockade improves insulin-induced microvascular function in hypertensive individuals

Objective An effect of insulin that is crucial for stimulating glucose uptake is its ability to increase the number of perfused capillaries, and thereby enhance its own delivery, and that of glucose, to muscle cells. To unravel possible mechanisms involved in the insulin-sensitizing effects of angiotensin II receptor blockers (ARBs) in hypertensive individuals we investigated the effect of single-dose ARB administration on insulin-mediated microvascular perfusion in hypertensive individuals. Methods We examined the effects of ARB administration on hyperinsulinemia-associated capillary density by measuring baseline skin capillary density, capillary density during reactive hyperemia (hyperemic capillary recruitment), and capillary density during venous congestion in 17 hypertensive individuals in the basal state, during a hyperinsulinemic euglycemic clamp, and during a hyperinsulinemic clamp with acute ARB administration (600 mg irbesartan), acute calcium channel blockade (CCB; 10 mg felodipine ER), as a control for the reduction in blood pressure, or placebo. In addition, insulin sensitivity and blood pressure were measured. Results Compared to the basal state, hyperinsulinemia increased baseline capillary density (57.3 ± 6.8 vs. 60.3 ± 7.9 n/mm 2, P < 0.01), but not hyperemic capillary recruitment. ARB and CCB treatment induced similar blood pressure reductions. Compared to placebo, ARB, but not CCB, increased hyperinsulinemia-associated baseline capillary density (+ 2.3 ± 3.4 ( P = 0.02) and − 0.4 ± 4.4 n/mm 2, respectively). Hyperinsulinemia-associated hyperemic capillary recruitment was not altered by either treatment. Compared to placebo, neither ARB nor CCB treatment enhanced insulin sensitivity. Conclusions Acute ARB administration increases insulin-induced microvascular perfusion in mildly hypertensive individuals; this beneficial effect on microvascular perfusion was however not associated with increased insulin-mediated glucose uptake.

Changes in renal vessels following the long-term administration of an angiotensin II receptor blocker in Zucker fatty rats

The nephro-protective effects of angiotensin II receptor blockers (ARBs) are widely known; however, there are few reports of long-term effects focusing on the renal vessels. We studied afferent arteriolar changes induced by the long-term administration of an ARB. Thirty-two 6-week-old male Zucker fatty rats (ZFRs) were divided into following four groups (n = 8 in each): ZFR Group and ZFR+High Group fed a standard or high-salt diet, respectively; ZFR+ARB Group and ZFR+High+ARB Group fed a standard or high-salt diet with ARB (Olmesartan, 5 mg/kg/day), respectively. Blood pressure, proteinuria, morphological examinations and glomerular haemodynamics in vivo were studied. Marked proliferative changes in the afferent arteriolar smooth muscle cells (SMCs) were frequently observed in the two groups given ARBs; in the ZFR+ARB group (77.3±10.3%) compared with the two groups without ARB (1.7%, p < 0.005; 1.2%, p < 0.0005) and 37.4±15.6% in the ZFR+High+ARB group. Proteinuria markedly decreased in the groups treated with ARBs, but the glomerular erythrocyte velocities showed no differences. Our findings indicate that long-term ARB administration induced unusual proliferative changes in SMCs of afferent arterioles of ZFRs. These changes could narrow arteriolar lumens and reduce intraglomerular pressure, but they could cause also irreversible damage to the arterioles.

Pleiotropic Effects of ARB in Metabolic Syndrome

Metabolic syndrome comprises of a cluster of several risk factors including abdominal obesity, dyslipidemia, elevated blood pressure, and insulin resistance. Many manifestations occur in sequence which is also referred to as the metabolic domino. Because the renin-angiotensin system (RAS) seems to be involved in this domino effect, RAS blockade by angiotensin II receptor blockers (ARB) offers a therapeutic tool for treating hypertension and ultimately the metabolic syndrome itself. In this paper, I describe the effects of ARBs on adiponectin, blood pressure, and fatty liver. Several clinical studies have reported that ARBs elevate adiponectin. ARBs that activate the PPARγ may be more effective than others. In terms of blood pressure, transient ARB administration may prevent the development of hypertension and high doses of ARB may regress mild hypertension. In terms of fatty liver, several research studies have indicated that ARBs may prevent triglyceride accumulation in liver. Again, ARBs that activate PPARγ may be more effective than others. Thus, PPARγ-activating ARBs offer the most hopeful treatment for metabolic syndrome. Further studies are needed to confirm this hypothesis.

Hyperkalemia from preoperative non-steroidal anti-inflammatory drugs and angiotensin II receptor blockers in patients with nephropathy

Hyperkalemia is sometimes life-threatening and is common in patients with severe renal insufficiency [1]. Some medications such as cyclooxygenase (COX-1, COX-2) inhibitors, angiotensin converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs) reduce the elimination of renal potassium resulting in hyperkalemia. Non-steroidal anti-inflammatory drugs (NSAIDs) are often prescribed as pain killers but have known adverse effects on kidney function. Thus, the elderly and patients at risk for diabetic nephropathy, long-lasting hypertension, or dehydration are more susceptible to the adverse effects of these drugs [2]. An episode of decreased renal function can be underestimated when the signs are asymptomatic, transitory, and non-anuric. Recently, ARBs have been prescribed in patients with hypertension to maintain appropriate renal perfusion by decreasing the glomerular filtration burden. ARBs protect renal and cardiac function by lowering oxidative stress, which is associated with chronic changes in the kidneys, heart, and blood vessels. However, ARBs decrease renal blood flow and reduce the elimination of potassium through the kidney under relatively dehydrated conditions [3] and a hypertensive state. Oral administration of ARBs in patients with chronic renal failure has resulted in serum potassium increases of up to 2 mEq/L during an operation. Although the patient was not suspected to have diabetic nephropathy because of normal creatinine clearance and negative urine protein, a preoperative ACE inhibitor and ARB prescription could lead to hyperkalemia and an abnormal electrocardiogram during an operation [4]. Dehydration has been discussed as a factor in reducing renal blood flow [5]. Thus, chronic administration of ARBs overlapped on possible preoperative dehydration can affect the elimination of potassium resulting in hyperkalemia. In addition to chronic treatment with an ARB, renal side effects of NSAIDs are relatively common and as prevalent as 5%. NSAIDs affect kidney function in two ways: interstitial nephritis due to an immunological reaction and prerenal failure due to reduced renal plasma flow [2]. Activating the renninangiotensin system to increase glomerular filtration pressure is necessary to maintain sufficient filtration. This physiological mechanism requires sufficient local synthesis of vasodilatory prostaglandins (PGE2, PGI2, PGD2) to counteract the action of angiotensin II on vascular tone. Because NSAIDs inhibit the PG-mediated vasodilation of afferent arterioles and glomerular capillaries, renal blood flow is critically affected in those patients at risk [2]. It is also advisable for anesthesiologists to consider the possibility of renal dysfunction in patients at risk with medication even though there is little chance to identify abnormal signs or abnormal laboratory nephropathy findings. It is more important to perform careful monitoring preoperatively and to evaluate renal function and effective circulatory volume.