ARB Treatment Research Articles

Abstract 623: Angiotensin Receptor Activation Contributes to Glucose Intolerance and Increased Insulin Resistance Independent of Elevated Systolic Blood Pressure, Adiposity and Dyslipidemia in a Model of Metabolic Syndrome

Activation of the renin-angiotensin system (RAS) leads to an increase in blood pressure and onset of insulin resistance (IR); however, the contributions of increased blood pressure and AT1 activation independently on the manifestation of IR are not well defined. The goal of this study was to determine the contribution of elevated blood pressure, independent of RAS, to the onset of IR in a model of metabolic syndrome. To address the hypothesis that AT1 activation, and not elevated blood pressure independently, is the principal contributor of obesity-associated IR, we measured changes in systolic blood pressure (SBP), adiposity, plasma triglycerides (TG), glucose tolerance, and insulin resistance index (IRI) in four groups of rats: 1) lean strain-control Long Evans Tokushima Otsuka (LETO; n=5), 2) obese Otsuka Long-Evans Tokushima Fatty (OLETF; n=7), 3) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg; n=8), and 4) OLETF + calcium channel blocker (CCB; 5 mg amlodipine/kg; n=7). ARB treatment alleviated the obesity-related increase in mean SBP, while the decrease with CCB remained 10.2 mmHg greater than LETO. ARB (0.51 g/100g body mass) and CCB (0.64 g/100g body mass) reduced mean relative retroperitoneal fat mass and mean plasma triglycerides (28.4 and 27.4 mg/dL respectively) compared to OLETF, but both remained greater (1.7, 1.57 g/100g body mass and 28.94, 29.94 mg/dL respectively) than LETO. ARB improved glucose tolerance by 4605.94 of 34965.94 and mean calculated IRI by 5581429.5 of 17398363, but CCB had no detectable effect on either. Despite relatively similar reductions in SBP, adiposity and plasma TG (principal components of metabolic syndrome), CCB did not improve glucose tolerance and IRI (additional metrics of metabolic syndrome), while ARB did, demonstrating that AT1 activation is the primary factor contributing to the development of impaired glucose metabolism and regulation during metabolic syndrome, independent of the hypertension, adiposity and dyslipidemia. Thus, targeting RAS to improve the consequences of metabolic syndrome appears to be prudent and effective.

Angiotensin receptor-mediated oxidative stress is associated with impaired cardiac redox signaling and mitochondrial function in insulin-resistant rats

Activation of angiotensin receptor type 1 (AT1) contributes to NADPH oxidase (Nox)-derived oxidative stress during metabolic syndrome. However, the specific role of AT1 in modulating redox signaling, mitochondrial function, and oxidative stress in the heart remains more elusive. To test the hypothesis that AT1 activation increases oxidative stress while impairing redox signaling and mitochondrial function in the heart during diet-induced insulin resistance in obese animals, Otsuka Long Evans Tokushima Fatty (OLETF) rats (n = 8/group) were treated with the AT1 blocker (ARB) olmesartan for 6 wk. Cardiac Nox2 protein expression increased 40% in OLETF compared with age-matched, lean, strain-control Long Evans Tokushima Otsuka (LETO) rats, while mRNA and protein expression of the H₂O₂-producing Nox4 increased 40-100%. ARB treatment prevented the increase in Nox2 without altering Nox4. ARB treatment also normalized the increased levels of protein and lipid oxidation (nitrotyrosine, 4-hydroxynonenal) and increased the redox-sensitive transcription factor Nrf2 by 30% and the activity of antioxidant enzymes (SOD, catalase, GPx) by 50-70%. Citrate synthase (CS) and succinate dehydrogenase (SDH) activities decreased 60-70%, whereas cardiac succinate levels decreased 35% in OLETF compared with LETO, suggesting that mitochondrial function in the heart is impaired during obesity-induced insulin resistance. ARB treatment normalized CS and SDH activities, as well as succinate levels, while increasing AMPK and normalizing Akt, suggesting that AT1 activation also impairs cellular metabolism in the diabetic heart. These data suggest that the cardiovascular complications associated with metabolic syndrome may result from AT1 receptor-mediated Nox2 activation leading to impaired redox signaling, mitochondrial activity, and dysregulation of cellular metabolism in the heart.

Angiotensin Receptor Blockade Reduces Oxidative Stress while Improving Redox Signaling and Mitochondrial Function in the Heart of Diet‐induced Obese Insulin Resistant Rats

The contributions of angiotensin receptor type 1 (AT1) activation to NADPH oxidase (Nox)‐derived oxidative stress during hypertension and diabetes are well established. The role of AT1 in modulating redox signaling, mitochondrial function and oxidative stress in the heart during metabolic syndrome, however, remains elusive. To test the hypothesis that AT1 activation increases oxidative stress while impairing mitochondrial function and redox signaling in the heart during metabolic syndrome, diet‐induced obese, insulin resistant (OLETF) rats were treated with the AT1 blocker (ARB) Olmesartan for 6 weeks. Cardiac Nox2 expression increased 40% in OLETF compared to age‐matched lean (LETO) rats while expression of the H2O2‐producing Nox4 increased 40%. ARB treatment prevented the increase in Nox2 without altering Nox4. ARB treatment also normalized increased protein and lipid oxidation and increased the redox‐sensitive transcription factor Nrf2 30%, and antioxidant enzymes by 50–70%. Mitochondrial aconitase activity increased 60% in OLETF compared to LETO whereas succinate decreased 35%; ARB treatment normalized both. These data demonstrate that AT1 activation contributes to increased Nox2‐derived oxidative stress and to impaired redox signaling and mitochondrial activity, and suggests that, besides its anti‐hypertensive effects, ARB treatment may improve myocardial function during metabolic syndrome.

Olmesartan is More Effective Than Other Angiotensin Receptor Antagonists in Reducing Proteinuria in Patients With Chronic Kidney Disease Other Than Diabetic Nephropathy

BackgroundAngiotensin II receptor antagonists (ARBs) have a protective effect in patients with chronic kidney disease (CKD) by suppressing progression, possibly by controlling hypertension. One marker of progression in such patients is the degree of proteinuria. ObjectiveWe aimed to retrospectively examine the protective effect of ARBs (olmesartan, losartan, candesartan, and valsartan) on CKD patients without a history of diabetic nephropathy. MethodsData were retrieved from medical records of patients with a diagnosis of CKD (serum creatinine [Cre] <3.0 mg/dL [265.2 μmol/L] and urinary protein of 0.3–3.5 g/g Cre) who were treated with ARBs and those with diabetic nephropathy were excluded. Blood pressure, serum Cre, urinary protein, urinary Cre, and estimated glomerular filtration rate were measured before the research began and at 1, 3, 6, 12, and 24 months after the ARB treatment was started. ResultsForty-four patients completed the research protocol. Of these, 10 took olmesartan, 13 took losartan, 9 took candesartan, 9 took valsartan, and 3 took telmisartan. Systolic blood pressure was decreased in all cases. The extent of this decrease 1 month after starting ARB treatment was greater for olmesartan than for candesartan (P < 0.05), and after 2 years, it was greater than for losartan (P < 0.05). Diastolic blood pressure decreased in all patients; this decrease was significantly greater with olmesartan 1 month after treatment started than with candesartan (P < 0.05). Olmesartan significantly decreased daily urinary protein compared with that with the other ARBs during follow-up. This decrease 1 month after starting ARB treatment was greater for olmesartan than losartan, valsartan, and candesartan (P < 0.01, P < 0.01, and P < 0.05, respectively), and after 2 years, this effect was still significant (P < 0.05, P < 0.01, and P < 0.01, respectively). ConclusionsOlmesartan is more effective in reducing urinary protein than other ARBs, suggesting that the renal protective effects of olmesartan may be better than those of other ARBs.

Amelioration of circulating lipoprotein profile and proteinuria in a patient with LCAT deficiency due to a novel mutation (Cys74Tyr) in the lid region of LCAT under a fat-restricted diet and ARB treatment

Familial lecithin-cholesterol acyltransferase (LCAT) deficiency is a hereditary disease characterized by an abnormal lipid profile, corneal opacity, anemia and progressive renal disease. We report a patient with complete loss of LCAT activity due to a novel lcat gene mutation of Cys74Tyr in the lid region of LCAT protein. Esterification of cholesterol in this patient was disturbed by disruption of a substrate binding loop of Cys50-Cys74 in LCAT protein. She had progressive renal dysfunction, proteinuria, corneal opacity, anemia and an abnormal lipid profile. Her serum lipids showed a significant increase in abnormal lipoproteins at the original position in agarose gel electrophoresis and VLDL-cholesterol, and a severe decrease in serum HDL-cholesterol. Lipoprotein analyzes also revealed the presence of an abnormal midband lipoprotein, and a maturation disturbance of HDL particles. Renal function and proteinuria improved following the adoption of a fat-restricted diet and administration of an angiotensin II receptor blocker. The abnormal lipoproteins also decreased after this treatment.

Angiotensin II receptor blockers improve endothelial dysfunction associated with sympathetic hyperactivity in metabolic syndrome

Renin-angiotensin system inhibitors are preferred for the treatment of hypertension with metabolic syndrome (MetS). Underlying endothelial dysfunction and sympathetic nervous system (SNS) activation are critically involved in the pathogenesis of hypertension in MetS. We investigated whether treatment with angiotensin II type 1 receptor blockers (ARBs) improves endothelial and autonomic function in patients with MetS. We conducted a prospective, randomized, open-label, blinded endpoint trial. Sixty patients with MetS were randomized into three treatment groups: telmisartan, candesartan, or diet therapy (control; n = 20 each), and treated for 6 months. To evaluate the endothelial function of forearm resistance arteries, blood flow and vascular resistance were measured using a strain-gauge plethysmograph during intra-arterial infusion of acetylcholine (ACh) or sodium nitroprusside (SNP). At 6 months, both telmisartan and candesartan comparably decreased blood pressure. Furthermore, ARB treatment ameliorated impaired forearm vasodilation in response to ACh. Telmisartan had a greater effect than candesartan on ACh-induced forearm vasodilation. In contrast, forearm vasodilation in response to SNP was comparable between the telmisartan and candesartan-treated groups. ARB treatment increased high-molecular-weight (HMW) adiponectin levels and baroreflex sensitivity, but telmisartan had a stronger effect than candesartan. In addition, only telmisartan treatment significantly decreased plasma norepinephrine concentrations, blood pressure variability, and heart rate variability based on spectral analysis. These findings indicate that ARBs improve impaired endothelial and baroreflex function, and increase HMW adiponectin levels in patients with MetS. Telmisartan exhibited more beneficial effects than candesartan, and only telmisartan reduced sympathetic hyperactivity, despite similar depressor effects.

Decreased Pancreatic Insulin Secretion is associated with increased AT1 Activation during Glucose Supplementation in a Model of Metabolic Syndrome

Blockade of the renin‐angiotensin‐system improves glucose intolerance, insulin resistance and beta cell function. The contributions of angiotensin receptor activation and glucose supplementation to impaired insulin secretion in the pathogenesis of metabolic syndrome are, however, not well defined. After 6 weeks of glucose supplementation and ARB treatment, an oral glucose tolerance test (oGTT) was performed to assess insulin resistance in 5 groups of rats: 1) untreated, lean LETO, 2) untreated, obese OLETF, 3) OLETF + ARB (olmesartan; 10 mg/kg/d; OLETF ARB), 4) OLETF + 5% glucose water (OLETF HG), and 5) OLETF + HG + ARB (OLETF HG/ARB). ARB treatment reduced the oGTT response 19% and increased pancreatic insulin secretion 64% and 113% in OLETF ARB and OLETF HG/ARB, respectively. ARB treatment in OLETF ARB and OLETF HG/ARB did not have an effect on insulin signaling proteins in skeletal muscle; however, it reduced pancreatic AT1 protein expression 20% and 27%, increased pancreatic GLP‐1r protein expression 41% and 88%, respectively, and increased fasting plasma GLP‐1 approximately 2.5‐fold in OLETF ARB. The results suggest that improvement of glucose intolerance is independent of an improvement in muscle insulin signaling, but rather by improved glucose‐stimulated insulin secretion associated with decreased pancreatic AT1 activation, and increased GLP‐1 signaling. (NIH NCMHD 9T37MD001480)

High Dietary Glucose Intake Increases Hepatic Triglyceride Content and Oxidative Stress: Contributions of Angiotensin Receptor

Excessive glucose intake exacerbates the deposition of adipose and plasma lipid levels and can subsequently increase organ‐specific oxidative damage during insulin resistance. To test our hypothesize that angiotensin receptor contributes to increased hepatic triglyceride content and oxidative stress following increased glucose intake in a model of metabolic syndrome, we studied 5 groups of rats: 1) LETO (lean control strain), 2) OLETF (15 wk), 3) OLETF + ARB (10 mg olmesartan mg/kg/d), 4) OLETF + high glucose (HG; 5% in water) and 5) OLETF + ARB + HG. HG had increased plasma triglycerides (TG) (35%), plasma glycerol (87%), free fatty acids (FFA) (28%) and body mass (BM) (37%), indicative of dislipidemia, as well as increased (74%) hepatic lipid peroxidation (4‐HNE). ARB treatment in HG reduced plasma TG (15%), plasma glycerol (23%), FFA (14%), BM (12%), and hepatic TG content (42%). ARB treatment in HG also decreased hepatic nitrotyrosine and increased UCP2 protein expression (59%), aconitase (40%) and antioxidant enzyme activities 50–120% suggesting that AT1 activation contributes to protein oxidation, lipid metabolism, fat deposition and lipid‐associated hepatic oxidative stress. Thus, besides the antihypertensive effects of ARB treatment, ARBs can also improve the condition of metabolic syndrome by improving the lipid profile and reducing adiposity and oxidative stress. Funded by NIH NCMHD 9T37MD001480 &amp; P20MD005049.

Long-Term Renoprotective Effect of Candesartan in Renal Transplant Patients

BackgroundThe renoprotective effects of angiotensin II type 1 receptor blockers (ARBs) have been demonstrated in a number of clinical studies, but there are few evaluations of long-term ARB treatment. We measured blood pressure, urine protein, and estimated glomerular filtration rate (eGFR) among patients under long-term (up to 9 years) treatment with candesartan cilexetil to evaluate its safety and effectiveness to protect renal graft function. MethodsThis study of 41 patients (31 male and 10 female) who presented with proteinuria and hypertension (blood pressure >140/90 mm Hg) after receiving a renal graft. Their serum creatinine level at baseline was 1.51 ± 0.53 mg/dL. Cyclosporine or tacrolimus were concomitantly prescribed for 18 (43.9%) and 22 (53.7%) subjects, respectively. The ARB treatment period was ≥12 months (up to 9 years, mean 4.8 years). Combination with other antihypertensive drugs (calcium antagonists) was necessary in 14/41 subjects (34.1%). ResultsSignificant declines in blood pressure were observed during the treatment period; blood pressure reduction target (blood pressure <130/80 mm Hg) was met in 56.1% for systolic and 68.3% for diastolic pressure. No significant increase in serum creatinine level or eGFR was observed. Urinary protein was reduced to negative or marginal in 63.4% of the subjects, demonstrating a significant decrease. ConclusionsCandesartan cilexetil was considered to be safe even for long-term treatment in renal transplant patients, and effective to protect renal graft function.

Abstract P161: Improved Gender and Racial-Ethnic Disparities in the Management of Acute Myocardial Infarction. Experience from a Community Hospital Serving a Large Hispanic Population in USA

Introduction: Disparities in medical therapies and revascularization procedures have been reported for women and Hispanics in the management of Acute Myocardial Infarction (AMI) in USA. Objectives: A paucity of recent data on this subject from facilities with a large Hispanic patient (pts) base motivated this study. Methods: Records of consecutive 525 pts (55% women, 289 of 525) admitted between 2005-2007 with a suspected AMI to a Southern California non-profit Community Hospital. Results: Race/ethnicity was unknown in 40 pts; 48%, 252 of 525, were Hispanic; 30 %, 155 of 525, Non Hispanic Whites and 14%, 78 of 525, African-Americans and Asians. No gender differences in age (66.9±14.8), diabetes, hypertension, dyslipidemia, medical insurance were found. Men had more AMI (93%, 219 of 236 v/s 51%, 147 of 289, p&lt;0.001), death (7.6%, 18 of 238 v/s 3.8%, 11 of 289, p&lt;0.05), smoking, CATH, PTCA and CABG than women. However, there were no gender or Hispanic ethnicity differences in the proportion of procedures performed when an AMI was confirmed (Fig1). Hispanic women (HW) showed no differences in death, AMI, CATH, CABG and Stress Test as compared to Non Hispanic White Women (NHWW) with the exception of PTCA (31%, 22 of 71, vs. 50%, 21 of 42, p &lt;0.03). A trend (NS) for more AMI in NHWW and CABG in HW was noted. Non Hispanic Whites had more private/commercial insurance than Hispanics (61%, 95 of 155 vs. 32.1%, 81 of 252, p&lt;0.01), regardless of gender. No differences were found in the composite (admission, discharge) use of ASA/Antiplatelets, B-blockers, ACEI /ARB and lipid lowering treatment. Conclusions: No Gender and Hispanic race/ethnicity disparities in the management of AMI were found for most services. HW received less PTCA than NHWW, difference that may be multifactorial. Medical insurance inequalities between Non Hispanic Whites and Hispanics persist but apparently did not affect the AMI care. It is uncertain if these results are applicable to facilities in USA with different socioeconomic, racial/ethnic mix or resources.

Angiotensin Receptor Blockade Increases Pancreatic Insulin Secretion and Decreases Glucose Intolerance during Glucose Supplementation in a Model of Metabolic Syndrome

Renin-angiotensin system blockade improves glucose intolerance and insulin resistance, which contribute to the development of metabolic syndrome. However, the contribution of impaired insulin secretion to the pathogenesis of metabolic syndrome is not well defined. To assess the contributions of angiotensin receptor type 1 (AT₁) activation and high glucose intake on pancreatic function and their effects on insulin signaling in skeletal muscle and adipose tissue, an oral glucose tolerance test (oGTT) was performed in five groups (n = 10/group) of rats: 1) lean strain-control 2) obese Otsuka Long-Evans Tokushima Fatty (OLETF), 3) OLETF + angiotensin receptor blocker (ARB; 10 mg/kg · d olmesartan for 6 wk; OLETF ARB), 4) OLETF + 5% glucose water (HG) for 6 wk (OLETF HG), and 5) OLETF + HG + ARB (OLETF HG/ARB). The glucose response to the oGTT increased 58% in OLETF compared with lean-strain control, whereas glucose supplementation increased it an additional 26%. Blockade of angiotensin receptor reduced the oGTT response 19% in the ARB-treated groups and increased pancreatic insulin secretion 64 and 113% in OLETF ARB and OLETF HG/ARB, respectively. ARB treatment in OLETF ARB and OLETF HG/ARB did not have an effect on insulin signaling proteins in skeletal muscle; however, it reduced pancreatic AT₁ protein expression 20 and 27%, increased pancreatic glucagon-like peptide-1 (GLP-1) receptor protein expression 41 and 88%, respectively, and increased fasting plasma GLP-1 approximately 2.5-fold in OLETF ARB. The results suggest that improvement of glucose intolerance is independent of an improvement in muscle insulin signaling, but rather by improved glucose-stimulated insulin secretion associated with decreased pancreatic AT₁ activation and increased GLP-1 signaling.

Abstract P102: Apelin Regulates the Function of Angiotensin II Type 1 Receptor Through APJ

Apelin and its G protein-coupled receptor (GPCR) APJ, which is most closely related to the angiotensin II (Ang II) type 1 receptor (AT 1 ) but Ang II does not bind to APJ, are potent regulators of the cardiovascular system. Although recent studies have suggested that apelin-APJ reverses the function of Ang II-AT 1 , the mechanism remains unclear because the accumulating evidences indicates that apelin-APJ may contribute to both cardioprotection and pathological progression. In APJ and AT 1 co-expression human embryonic kidney (HEK) 293 cells, we found that APJ and AT 1 created receptor heterodimers. Co-expression with APJ significantly suppressed the phosphorylated extracellular signal-regulated kinases 1/2 (pERK1/2) induced by Ang II-AT 1 , whereas apelin eliminated this ligand-independent function of APJ out of relation to its heterodimerization. The pharmacologically non-activated APJ upon apelin stimulation elicited by the Gi/o-specific inhibitor pertussis toxin (PTX) restituted the pERK1/2 level similar to that of AT 1 and APJ co-expression without apelin stimulation. However, the co-expression of the beta-2-adrenergic receptor (β 2 AR) or the pharmacologically non-activated Ang II type 2 receptor (AT 2 ) induced by the AT 2 -specific antagonist, PD123319, did not suppress pERK1/2 through Ang II-AT 1 . Pretreatment with 30 nM of the AT 1 blocker (ARB) TA-606A suppressed 50% of the AT 1 -mediated pERK1/2, whereas this suppression raised to 75% when the non-activated APJ was co-expressed. In contrast, 120 nM of TA-606A only reached 34% suppression when it was co-expressed with activated APJ with apelin. Taken together, we demonstrated that apelin may regulate the function of AT 1. Non-activated APJ may suppress Ang II-AT 1 signaling, whereas this ligand-independent function was diminished with apelin activation. These results may contribute to ARB treatment in the clinical setting.

Abstract 18088: The Geriatric Assessment Score is a Proper Clinical Tool to Stratify Older Old Patients Admitted with Heart Failure for In-Hospital and Two-Year Survival

OBJECTIVES. - To determine the influence of physical, cognitive function and other comprehensive geriatric assessment (CGA) components on in-hospital and two-year mortality of older adults admitted with acute heart failure (HF). METHODS - Prospective study of 581 individuals aged &gt;75 years admitted due to HF. Demographic, clinical, echocardiographic and analytical data were recorded. CGA included dependence in activities of daily living (ADL), mobility, cognitive status, screening for depression, comorbidity and pharmachological prescriptions. A Geriatric Assessment Score (range 0-10 p) was constructed. Mean follow-up of 533 hospitalization survivors was 77+52 weeks. A logistic regression model to determine factors independently related with in-hospital mortality and a Cox regression model to identify those related with two years mortality were constructed. RESULTS - Mean age 85.8±5.8 y., 67% women, 75% preserved ejection fraction, mean comorbidity index 3.97±3.01. Cognitive impairment was present in 45%, depression in 49%, 66% had mobility problems and 50% dependence in &gt;1 ADL. In-hospital fatality was 8.2%. Variables associated with in-hospital mortality included NYHA class III (OR 4.1, 95% CI 1.5-10.8) or IV (OR 19.6, 95% CI 6.3-60.9), pulmonary oedema (OR 3, 95% CI 1.3-6.6), renal failure (OR 2.8, 95% CI 1.2-6.2) and the Geriatric Assessment Score (OR per point of increment 1.2, 95% CI 1-1.4). Two-year mortality related factors included age (OR 1.06, 95% CI 1.03-1.09), Geriatric Assessment Score (OR 1.17, 95% CI 1.09-1.27), NYHA functional class III (OR 1.62, 95% CI 1.18-2.23) or IV (OR 3.02, 95% CI 1.49-6.10), left ventricle systolic dysfunction (OR 1.67, 95% CI 1.20-2.31), comnorbidity index (OR 1.07, 95% CI 1.02-1.12), AF (OR 1.57, 95% CI 1.15-2.15), ACEI or ARB treatment (OR 0.66, 95% CI 0.49-0.90) and renal failure (OR 1.01, 95% CI 1.00-1.01). COCNLUSIONS - In very elderly heart failure patients, an index incorporating comorbidities, total number of prescription drugs, cognitive, functional and mobility status predicts in-hospital and two-year survival. In addition to other variables previously known, these should be considered for a better stratification of elderly patients admitted with HF.

Abstract 8236: Effect of Telmisartan on Paroxymal Atrial Fibrillation in Hypertensive Patients with Different Left Atrial Size

Aim of this study was to evaluate the effect of telmisartan (T) and amlodipine (A) on atrial fibrillation (AF) recurrence in hypertensive patients with paroxymal AF and normal or increased left atrial (LA) size. We studied 288 mild hypertensive outpatients in sinus rhythm but will at least 2 ECG-documented episodes of AF in the previous 6 months; half of them had an inferior-superior LA dimension &lt;45 mm, and the other half &gt;45 mm. The patients were randomized to T 80-160 mg/od (n=72 with LA &lt;45 mm, n= 72 with LA &gt;45 mm) or to A 5-10 mg/od (n=72 with LA &lt;45 mm, n= 72 with LA &gt;45 mm) for one year. Blood pressure and a 24 h ECG were evaluated monthly. Patients were asked to report any episode of symptomatic AF and to perform an ECG as early as possible. SBP and DBP were significantly and similarly reduced by the 2 treatments (p&lt;0.001 vs baseline) in the 4 groups of patients. Among those with LA dimension &gt;45 mm a total of 35 (48.6%) patients treated with A had a recurrence of AF as did 18 (25%) patients treated with T (p&lt;0.05 vs A) Among the patients with LA dimension &lt;45 mm a total of 23 (31.9%) patients treated with A had a recurrence of AF as did 8 (11.1%) patients treated with T (p&lt;0.01 vs A). Despite a similar BP lowering T was more effective than A in preventing new episodes of AF and it was particularly evident in patients with normal LA size. It suggest that in this type of patients ARB treatment is to prefer to Ca blocker treatment and that earlier it is begun greater is the prevention of AF recurrences.

Abstract P60: The Effect of Angiotensin Receptor Blocker/Calcium Channel Blocker Single Pill Combination Therapy on Adherence to Antihypertensive Treatment

Objective: To evaluate the impact of ARB/CCB single pill combination therapy on adherence to antihypertensive (AHY) treatment. Methods: A retrospective data analysis was performed using pharmacy claims data from a national pharmacy benefit management company. The study included patients who were newly initiated on ARB/CCB treatment between 01/01/2007 and 08/31/2008, age ≥18 years, and continuously enrolled in the same health plan for 6 months prior to and 13 months after starting ARB/CCB treatment. Patients who started either valsartan and amlodipine or amlodipine and olmesartan medoxomil ARB/CCB single pill combinations were assigned to the single pill combination (SPC) group. The ARB/CCB free combination (FC) group included patients who used a combination of single-agent ARB and CCB treatment. Outcome variables were persistence, defined as time to discontinuation of therapy, and adherence, defined as proportion of days covered (PDC) ≥0.80. Propensity score weighted multivariable regression models were used to estimate the impact of combination pill therapy. Covariates included age, gender, baseline comorbidities, insurance type, geographic region, copayment, and history of other AHY use. Results: The final sample contained 2,312 patients in the ARB/CCB FC group and 2,213 patients in the ARB/CCB SPC group. After adjustment for differences in baseline characteristics, a Cox proportional hazards model showed that patients in the SPC group were 24% less likely to discontinue ARB/CCB therapy as compared to patients in the FC group (HR 0.76, 95% CI 0.73-0.79, p&lt;0.0001). A logistic model showed that patients in the SPC pill group had a 90% greater odds of being adherent compared to patients in the FC group (OR 1.90, 95% CI 1.75-2.08, p&lt;0.0001). In both models, higher copayment (copayment $50 and above) was associated with poorer persistence and adherence in comparison to patients who faced copayment $0-$5: HR=1.15, p&lt;0.001 and OR=0.67, p&lt;0.0001. Conclusion: Patients using single pill combination ARB/CCB therapy were more likely to be persistent and adherent to treatment as compared to patients taking free combination therapy.

AT1 receptor-mediated augmentation of angiotensinogen, oxidative stress, and inflammation in ANG II-salt hypertension

Augmentation of intrarenal angiotensinogen (AGT) synthesis, secretion, and excretion is associated with the development of hypertension, renal oxidative stress, and tissue injury during ANG II-dependent hypertension. High salt (HS) exacerbates hypertension and kidney injury, but the mechanisms remain unclear. In this study, we determined the consequences of HS intake alone compared with chronic ANG II infusion and combined HS plus ANG II on the stimulation of urinary AGT (uAGT), renal oxidative stress, and renal injury markers. Sprague-Dawley rats were subjected to 1) a normal-salt diet [NS, n = 5]; 2) HS diet [8% NaCl, n = 5]; 3) ANG II infusion in NS rats [ANG II 80 ng/min, n = 5]; 4) ANG II infusion in HS rats [ANG II+HS, n = 5]; and 5) ANG II infusion in HS rats treated with ANG II type 1 receptor blocker (ARB) [ANG II+HS+ARB, n = 5] for 14 days. Rats fed a HS diet alone did not show changes in systolic blood pressure (SBP), proteinuria, cell proliferation, or uAGT excretion although they did exhibit mesangial expansion, collagen deposition, and had increased NADPH oxidase activity accompanied by increased peroxynitrite formation in the kidneys. Compared with ANG II rats, the combination of ANG II infusion and a HS diet led to exacerbation in SBP (175 ± 10 vs. 221 ± 8 mmHg; P < 0.05), proteinuria (46 ± 7 vs. 127 ± 7 mg/day; P < 0.05), and uAGT (1,109 ± 70 vs.. 7,200 ± 614 ng/day; P < 0.05) associated with greater collagen deposition, mesangial expansion, interstitial cell proliferation, and macrophage infiltration. In both ANG II groups, the O(2)(-) levels were increased due to increased NADPH oxidase activity without concomitant increases in peroxynitrite formation. The responses in ANG II rats were prevented or ameliorated by ARB treatment. The results indicate that HS independently stimulates ROS formation, which may synergize with the effect of ANG II to limit peroxynitrite formation, leading to exacerbation of uAGT and greater injury during ANG II salt hypertension.

Additional stimulation of sGC on top of standard treatment with ARB`s may offer a new therapeutic approach for the treatment of diabetic nephropathy resistant to ARB treatment alone

Background Riociguat is the first of a new class of drugs, the soluble guanylate cyclase (sGC) stimulators. Riociguat has a dual mode of action: it sensitizes sGC to the body’s own NO and can also increase sGC activity in the absence of NO. The NO-sGC-pathway is impaired in many cardiovascular diseases such as heart failure, pulmonary hypertension and diabetic nephropathy (DN). DN leads to high cardiovascular morbidity and mortality. There is still a high unmet medical need. The urinary albumin excretion rate is a predictive biomarker for these clinical events. Therefore, we investigated the effect of riociguat, alone and in combination with the angiotensin II receptor antagonist (ARB) telmisartan on the progression of DN in diabetic eNOS knock out mice, a new model closely resembling human pathology.

The treatment results of retreatment pulmonary tuberculosis patients in our clinic

164 human immunodeficiency virus (HIV) seronegative pulmonary tuberculosis cases treated in our clinic between January 1997 to December 2005 and included in category two treatment group were evaluated retrospectively. All the cases were male. The mean age was 43.72 ± 12.73 years. The mean duration of disease was 3.96 ± 4.80 years. The patients had used mean 4.62 ± 0.86 types of drugs. The patients were hospitalized for mean 100.54 ± 67.43 days. 23 (14%) patients were defined as treatment failure. 42 (25.6%) patients were relapse and 99 (60.4%) were defaulter. Mean time of conversion was 2.62 ± 1.84 months. Conversion rate was higher in relapse cases (76.2%) compared with treatment failure (56.5%) and defaulter (57.6%). In 140 patients, resistance tests were performed. 73 (52.1%) patients had any drug resistance. 45 (32.1%) patients had multidrug resistance. Among all the patients, 7 (4.3%) patients had died. 48 (29.3%) patients defaulted. 33 (20.1%) had treatment failure. 76 (46.3%) had cured. The cure rate was 65.5% in patients who were in control. 36.4% of defaulters were out of control. This rate was significantly higher than relapse and treatment failure cases (p= 0.014). Cure rate in defaulters (38.4%) were significantly lower than relapses (61.9%) and treatment failures (52.2%). There was a significant relationship between any drug resistance and cure and conversion. There was also a significant relationship between positive second and third ARB and culture and treatment success. As a result, a chance to retreatment regimen can be given in relapses and treatment failures before deciding minor drug therapy because they have higher cure rates than defaulters. Defaulters are hard to cure. They have the tendency to default again and they have higher resistance rates. The multi drug resistance rate in all patients was about 32% and 46.7% of these have cured with retreatment regimen. Bacteriological follow up of treatment outcome is effective in management of therapy.

Non-activated APJ suppresses the angiotensin II type 1 receptor, whereas apelin-activated APJ acts conversely

Apelin and its G-protein-coupled receptor APJ are potent regulators of the cardiovascular system. Recent studies have suggested that apelin-APJ reverses the function of angiotensin II (Ang II)-the Ang II type 1 receptor (AT(1)). However, the mechanism remains unclear because of the accumulating evidences that apelin-APJ may contribute to both cardioprotection and pathological progression. In human embryonic kidney 293 cells, we found that coexpression with APJ significantly suppressed the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) induced by Ang II-AT(1), whereas apelin abolished this attenuation through activated APJ independently of its heterodimerization. Pretreatment with the Gi/o-specific inhibitor pertussis toxin (PTX) restituted the ERK1/2 phosphorylation level similar to that found with AT(1) and APJ coexpression without apelin stimulation. In contrast, coexpression of the beta-2-adrenergic receptor or the pharmacologically non-activated Ang II type 2 receptor (AT(2)) pretreated with the AT(2)-specific antagonist, PD123319, did not affect ERK1/2 phosphorylation through AT(1). Pretreatment with 30 nM of the AT(1) blocker (ARB) TA-606A suppressed 50% of the AT(1)-mediated ERK1/2 phosphorylation, whereas 30 nM of TA-606A achieved 75% suppression when the non-activated APJ was coexpressed without ligand or PTX. However, 120 nM of TA-606A failed to reach the target phosphorylation when it was coexpressed with activated APJ with apelin. Based on these results, we demonstrated that non-activated APJ may suppress Ang II-AT(1) signaling, whereas this ligand-independent function was diminished with apelin activation. These results may be relevant to the potential contribution of apelin-APJ to ARB treatment in the clinical realm.

Temporary Treatment With AT1 Receptor Blocker, Valsartan, From Early Stage of Hypertension Prevented Vascular Remodeling

The present study examined the inhibitory action of temporary treatment with an angiotensin type 1 (AT(1)) receptor blocker (ARB) on vascular remodeling using hypertensive mice with overexpression of the human renin (hRN) and angiotensinogen (hANG) genes. hRN/hANG transgenic mice (hRN/hANG-Tg) were treated with an ARB, valsartan, from 4 weeks of age. In some mice, valsartan treatment was stopped at 8 weeks of age (temporary treatment). Inflammatory vascular injury was induced by polyethylene-cuff placement around the femoral artery at the age of 10 weeks. Compared with wild-type (WT) mice, hRN/hANG-Tg showed higher blood pressure (BP) and enhancement of oxidative stress and medial thickening even before cuff placement. Inflammatory vascular remodeling and oxidative stress after cuff placement were further enhanced in hRN/hANG-Tg. Temporary treatment with valsartan continuously lowered BP even after cessation of administration, and inhibited these changes. In contrast, administration of hydralazine lowered BP to a similar level to that with valsartan, but did not inhibit medial thickening and inflammatory vascular remodeling. In contrast to the valsartan treatment, BP immediately increased to the untreated level after cessation of hydralazine. These results indicate that temporary ARB treatment leads to prolonged effect of BP lowering and prevents vascular remodeling in hypertensive mice induced by activation of the human renin-angiotensin system. The inhibitory action of valsartan is not due to the BP lowering but is at least in part due to a decrease in oxidative stress and inflammation.