Role of olmesartan in combination therapy in blood pressure control and vascular function

Angiotensin receptor blockers have emerged as a first-line therapy in the management of hypertension and hypertension-related comorbidities. Since national and international guidelines have stressed the need to control blood pressure to <140/90 mmHg in uncomplicated hypertension and <130/80 mmHg in those with associated comorbidities such as diabetes or chronic kidney disease, these goal blood pressures can only be achieved through combination therapy. Of several drugs that can be effectively combined to attain the recommended blood pressure goals, fixed-dose combinations of angiotensin receptor blockers and the calcium channel blocker amlodipine provide additive antihypertensive effects associated with a safe profile and increased adherence to therapy. In this article, we review the evidence regarding the beneficial effects of renin–angiotensin system blockade with olmesartan medoxomil and amlodipine in terms of blood pressure control and improvement of vascular function and target organ damage

TRASPLANTE SIMULTÿNEO DE PANCREAS-RIÿÿN. CONCEPTOS ACTUALES Y EXPERIENCIA EN CLÿNICA LAS CONDES

RESUMENEl trasplante de páncreas-riñón (TPR) para pacientes portadores de diabetes mellitus tipo 1 (DM1) con insuficiencia renal crónica terminal, ha demostrado ser una terapia eficaz para alcanzar el estado de normoglicemia de manera estable, con la consecuente disminución de las complicaciones crónicas de la DM y mejoría de la expectativa y calidad de vida. Actualmente, en casos seleccionados, se ha planteado el trasplante de páncreas (TP) como una alternativa para los pacientes con diabetes mellitus tipo 2 (DM2) considerando la diferencia entre los pacientes del tipo 1 y 2. Si bien es menos frecuente en la experiencia mundial, trasplantar pacientes con DM2 demuestra cifras alentadoras y comparables con el TP en enfermos portadores de DM1. En general, pacientes que desarrollan enfermedad renal terminal secundaria a diabetes 1 o 2 que requieren insulina, no obesos, deben ser considerados para el trasplante de páncreas con riñón simultáneo o secuencial. Clínica Las Condes es la de mayor experiencia en Chile, con resultados muy comparables a centros de gran importancia a nivel internacional.ObjetivoDar a conocer la situación actual del trasplante de páncreas y sus modalidades en el mundo y mostrar la experiencia en TPR en Clínica Las Condes en la sobrevida de los pacientes, de injerto de páncreas e injerto de riñón en 10 años y sus complicaciones, además de las técnicas quirúrgicas realizadas.MétodoSe recolectó la información de 16 pacientes sometidos a trasplante páncreas-riñón en Clínica Las Condes entre 1994-2014, analizando las variables con estadística descriptiva.ResultadosDe los 16 enfermos, 9 de ellos fueron hombres, la edad promedio fue 38,7 años al momento del trasplante, el tiempo promedio de diabetes fue 23,5+/-7.3 años. Todos los injertos pancreáticos fueron anastomosados a los vasos ilíacos comunes derechos en forma término-terminal y el duodeno fue anastomosado en 8 casos a la vejiga y en los últimos 8 al íleon. La sobrevida de los pacientes a 10 años fue del 81%, del injerto de páncreas el 82% y del injerto renal el 65%. La complicación post operatoria más importante fue sepsis, causando la muerte en 2 pacientes. Y entre las complicaciones de tipo inmunológico, 8 pacientes presentaron rechazo agudo, siendo manejados con terapia esteroidal de rescate o timo globulina.SUMMARYCombined kidney pancreas trasplant (PKT) in diabetes mellitus type 1 (DM1) patients with end stage renal disease, has proven to be an effective therapy to reach normoglicemia stability, with the consequent reduction of diabetes chronic complications an improvement in life expectancy and Quality of Life. Currently in selected cases of type 2 diabetes mellitus (DM2) patients with terminal nephropathy it has been proposed pancreas transplantation (PT) as an effective alternative. The results have been comparable between DM1 and DM2 patients. Patients who develop end stage renal disease secondary to type 1 or 2 DM, insulin dependent, non obese, should be considered for PKT. Clínica Las Condes has one of the mayor experience in Chile, in PKT, with comparable results to centers of great importance of International Level.ObjectiveTo show the situation of Pancreas Transplantation and its different modalities in the world. Also to show the experience in PKT at Clinica Las Condes, in 10 years patient's survival, in pancreas and kidney graft survival and complications and the surgical techniques.MethodInformation collected from 16 patients undergoing PKT at Clinica Las Condes between 1994-2014, analyzing the variables with descriptive statistics.ResultsOf the 16 patients, 9 were men, average age 38.7 years at transplant time; the average time of diabetes was 23.5+/-7.3 years. All pancreatic grafts were term-terminal to anastomosed the right iliac common vessels and duodenum was anastomosed is 8 cases to the bladder and in the last 8 to the ileum. Patient survival at 10 years was 81%, pancreatic graft 82% and 65% renal graft. The most relevant postoperative complication was sepsis, killing two patients. The immune complications were presented in eight patients. It was acute rejection, being managed with steroid therapy or thymoglobuline

Mineralocorticoid receptor antagonism attenuates vascular apoptosis and injury via rescuing protein kinase B activation

This article may also be found at the publisher's website at http://hyper.ahajournals.org/cgi/content/abstract/53/2/158?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=habibi&searchid=1&FIRSTINDEX=0&resourcetype=HWCITEmerging evidence indicates that mineralocorticoid receptor (MR) blockade reduces the risk of cardiovascular events beyond those predicted by its blood pressure-lowering actions; however, the underlying mechanisms remain unclear. To investigate whether protection elicited by MR blockade is through attenuation of vascular apoptosis and injury, independently of blood pressure lowering, we administered a low dose of the MR antagonist spironolactone or vehicle for 21 days to hypertensive transgenic Ren2 rats with elevated plasma aldosterone levels. Although Ren2 rats developed higher systolic blood pressures compared with Sprague-Dawley littermates, low-dose spironolactone treatment did not reduce systolic blood pressure compared with untreated Ren2 rats. Ren2 rats exhibited vascular injury as evidenced by increased apoptosis, hemidesmosome-like structure loss, mitochondrial abnormalities, and lipid accumulation compared with Sprague-Dawley rats, and these abnormalities were attenuated by MR antagonism. Protein kinase B activation is critical to vascular homeostasis via regulation of cell survival and expression of apoptotic genes. Protein kinase B serine473 phosphorylation was impaired in Ren2 aortas and restored with MR antagonism. In vivo MR antagonist treatment promoted antiapoptotic effects by increasing phosphorylation of BAD serine136 and expression of Bcl-2 and Bcl-xL, decreasing cytochrome c release and BAD expression, and suppressing caspase-3 activation. Furthermore, MR antagonism substantially reduced the elevated NADPH oxidase activity and lipid peroxidation, expression of angiotensin II, angiotensin type 1 receptor, and MR in Ren2 vasculature. These results demonstrate that MR antagonism protects the vasculature from aldosterone-induced vascular apoptosis and structural injury via rescuing protein kinase B activation, independent of blood pressure effects

Chymase-Dependent Generation of Angiotensin II from Angiotensin-(1-12) in Human Atrial Tissue

Since angiotensin-(1-12) [Ang-(1-12)] is a non-renin dependent alternate precursor for the generation of cardiac Ang peptides in rat tissue, we investigated the metabolism of Ang-(1-12) by plasma membranes (PM) isolated from human atrial appendage tissue from nine patients undergoing cardiac surgery for primary control of atrial fibrillation (MAZE surgical procedure). PM was incubated with highly purified 125I-Ang-(1-12) at 37°C for 1 h with or without renin-angiotensin system (RAS) inhibitors [lisinopril for angiotensin converting enzyme (ACE), SCH39370 for neprilysin (NEP), MLN-4760 for ACE2 and chymostatin for chymase; 50 µM each]. 125I-Ang peptide fractions were identified by HPLC coupled to an inline γ-detector. In the absence of all RAS inhibitor, 125I-Ang-(1-12) was converted into Ang I (2±2%), Ang II (69±21%), Ang-(1-7) (5±2%), and Ang-(1-4) (2±1%). In the absence of all RAS inhibitor, only 22±10% of 125I-Ang-(1-12) was unmetabolized, whereas, in the presence of the all RAS inhibitors, 98±7% of 125I-Ang-(1-12) remained intact. The relative contribution of selective inhibition of ACE and chymase enzyme showed that 125I-Ang-(1-12) was primarily converted into Ang II (65±18%) by chymase while its hydrolysis into Ang II by ACE was significantly lower or undetectable. The activity of individual enzyme was calculated based on the amount of Ang II formation. These results showed very high chymase-mediated Ang II formation (28±3.1 fmol×min−1×mg−1, n = 9) from 125I-Ang-(1-12) and very low or undetectable Ang II formation by ACE (1.1±0.2 fmol×min−1×mg−1). Paralleling these findings, these tissues showed significant content of chymase protein that by immunocytochemistry were primarily localized in atrial cardiac myocytes. In conclusion, we demonstrate for the first time in human cardiac tissue a dominant role of cardiac chymase in the formation of Ang II from Ang-(1-12)

Attenuation of NADPH Oxidase Activation and Glomerular Filtration Barrier Remodeling With Statin Treatment

Activation of reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase by angiotensin II is integral to the formation of oxidative stress in the vasculature and the kidney. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibition is associated with reductions of oxidative stress in the vasculature and kidney and associated decreases in albuminuria. Effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibition on oxidative stress in the kidney and filtration barrier integrity are poorly understood. To investigate, we used transgenic TG(mRen2)27(Ren2) rats, which harbor the mouse renin transgene and renin-angiotensin system activation, and an immortalized murine podocyte cell line. We treated young, male Ren2 and Sprague-Dawley rats with rosuvastatin (20 mg/kg IP) or placebo for 21 days. Compared with controls, we observed increases in systolic blood pressure, albuminuria, renal NADPH oxidase activity, and 3-nitrotryosine staining, with reductions in the rosuvastatin-treated Ren2. Structural changes on light and transmission electron microscopy, consistent with periarteriolar fibrosis and podocyte foot-process effacement, were attenuated with statin treatment. Nephrin expression was diminished in the Ren2 kidney and trended to normalize with statin treatment. Angiotensin II- dependent increases in podocyte NADPH oxidase activity and subunit expression (NOX2, NOX4, Rac, and p22phox) and reactive oxygen species generation were decreased after in vitro statin treatment. These data support a role for increased NADPH oxidase activity and subunit expression with resultant reactive oxygen species formation in the kidney and podocyte. Furthermore, statin attenuation of NADPH oxidase activation and reactive oxygen species formation in the kidney/podocyte seems to play roles in the abrogation of oxidative stress-induced filtration barrier injury and consequent albuminuria

Impact of early pericardial fluid chymase activation after cardiac surgery

INTRODUCTION: Chymase is a highly destructive serine protease rapidly neutralized in the circulation by protease inhibitors. Here we test whether pericardial fluid (PCF) chymase activation and other inflammatory biomarkers determine intensive care unit length of stay, and explore mechanisms of chymase delivery by extracellular vesicles to the heart. METHODS: PCF was collected from adult patients (17 on-pump; 13 off-pump) 4 h after cardiac surgery. Extracellular vesicles (EVs) containing chymase were injected into Sprague-Dawley rats to test for their ability to deliver chymase to the heart. RESULTS: The mean intensive care unit (ICU) stay and mean total length of stay was 2.17 ± 3.8 days and 6.41 ± 1.3 days respectively. Chymase activity and 32 inflammatory markers did not differ in on-pump vs. off-pump cardiac surgery. Society of Thoracic Surgeons Predicted Risk of Morbidity and Mortality Score (STS-PROM), 4-hour post-surgery PCF chymase activity and C-X-C motif chemokine ligand 6 (CXCL6) were all independent predictors of ICU and total hospital length of stay by univariate analysis. Mass spectrometry of baseline PCF shows the presence of serine protease inhibitors that neutralize chymase activity. The compartmentalization of chymase within and on the surface of PCF EVs was visualized by immunogold labeling and transmission electron microscopy. A chymase inhibitor prevented EV chymase activity (0.28 fmol/mg/min vs. 14.14 fmol/mg/min). Intravenous injection of PCF EVs obtained 24 h after surgery into Sprague Dawley rats shows diffuse human chymase uptake in the heart with extensive cardiomyocyte damage 4 h after injection. DISCUSSION: Early postoperative PCF chymase activation underscores its potential role in cardiac damage soon after on- or off-pump cardiac surgery. In addition, chymase in extracellular vesicles provides a protected delivery mechanism from neutralization by circulating serine protease inhibitors

Uptake and Metabolism of the Novel Peptide Angiotensin-(1-12) by Neonatal Cardiac Myocytes

Angiotensin-(1-12) [Ang-(1-12)] functions as an endogenous substrate for the productions of Ang II and Ang-(1-7) by a non-renin dependent mechanism. This study evaluated whether Ang-(1-12) is incorporated by neonatal cardiac myocytes and the enzymatic pathways of ¹²⁵I-Ang-(1-12) metabolism in the cardiac myocyte medium from WKY and SHR rats.The degradation of ¹²⁵I-Ang-(1-12) (1 nmol/L) in the cultured medium of these cardiac myocytes was evaluated in the presence and absence of inhibitors for angiotensin converting enzymes 1 and 2, neprilysin and chymase. In both strains uptake of ¹²⁵I-Ang-(1-12) by myocytes occurred in a time-dependent fashion. Uptake of intact Ang-(1-12) was significantly greater in cardiac myocytes of SHR as compared to WKY. In the absence of renin angiotensin system (RAS) enzymes inhibitors the hydrolysis of labeled Ang-(1-12) and the subsequent generation of smaller Ang peptides from Ang-(1-12) was significantly greater in SHR compared to WKY controls. ¹²⁵I-Ang-(1-12) degradation into smaller Ang peptides fragments was significantly inhibited (90% in WKY and 71% in SHR) in the presence of all RAS enzymes inhibitors. Further analysis of peptide fractions generated through the incubation of Ang-(1-12) in the myocyte medium demonstrated a predominant hydrolytic effect of angiotensin converting enzyme and neprilysin in WKY and an additional role for chymase in SHR.These studies demonstrate that neonatal myocytes sequester angiotensin-(1-12) and revealed the enzymes involved in the conversion of the dodecapeptide substrate to biologically active angiotensin peptides

Mineralocorticoid Receptor Blockade Attenuates Chronic Overexpression of the Renin-Angiotensin- Aldosterone System Stimulation of Reduced Nicotinamide Adenine Dinucleotide Phosphate Oxidase and Cardiac Remodeling

doi: 10.1210/en.2006-1691The renin-angiotensin-aldosterone system contributes to cardiac remodeling, hypertrophy, and left ventricular dysfunction. Angiotensin II and aldosterone (corticosterone in rodents) together generate reactive oxygen species (ROS) via reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which likely facilitate this hypertrophy and remodeling. This investigation sought to determine whether cardiac oxidative stress and cellular remodeling could be attenuated by in vivo mineralocorticoid receptor (MR) blockade in a rodent model of the chronically elevated tissue renin-angiotensin-aldosterone system, the transgenic TG (mRen2) 27 rat (Ren2). The Ren2 overexpresses the mouse renin transgene with resultant hypertension, insulin resistance, proteinuria, and cardiovascular damage. Young (6- to 7-wk-old) male Ren2 and age-matched Sprague-Dawley rats were treated with spironolactone or placebo for 3 wk. Heart tissue ROS, immunohistochemical analysis of 3-nitrotyrosine,and NADPH oxidase (NOX) subunits (gp91phox recently renamed NOX2, p22phox, Rac1, NOX1, and NOX4) were measured. Structural changes were assessed with cine-magnetic resonance imaging, transmission electron microscopy, and light microscopy. Significant increases in Ren2 septal wall thickness (cine-magnetic resonance imaging) were accompanied by perivascular fibrosis, increased mitochondria, and other ultrastructural changes visible by light microscopy and transmission electron microscopy. Although there was no significant reduction in systolic blood pressure, significant improvements were seen with MR blockade on ROS formation and NOX subunits (each P < 0.05). Collectively, these data suggest that MR blockade, independent of systolic blood pressure reduction, improves cardiac oxidative stress-induced structural and functional changes, which are driven, in part, by angiotensin type 1 receptor-mediated increases in NOX.This research was supported by National Institutes of Health (NIH) Grants R01 HL73101-01A1 (to J.R.S.) and P01 HL-51952 (to C.F.), the Veterans Affairs Merit System (0018) (to J.R.S.), and Advanced Research Career Development (to C.S.). Male transgenic Ren2 rats and male Sprague-Dawley controls were kindly provided by C.F. through the Transgenic Core Facility supported in part by NIH Grant HL-51952