1.
Phosphorylation of Vasodilator-Stimulated Phosphoprotein (VASP) Dampens Hepatic Ischemia-Reperfusion Injury.
Source
Department of Anesthesiology and Intensive Care Medicine, University Hospital, Tübingen, Germany.
Abstract
Recent work has demonstrated that the formation of platelet neutrophil complexes (PNCs) affects inflammatory tissue injury. Vasodilator-stimulated phosphoprotein (VASP) is crucially involved into the control of PNC formation and myocardial reperfusion injury. Given the clinical importance of hepatic IR injury we pursued the role of VASP during hepatic ischemia followed by reperfusion. We report here that VASP(-/-) animals demonstrate reduced hepatic IR injury compared to wildtype (WT) controls. This correlated with serum levels of lactate dehydrogenase (LDH), aspartate (AST) and alanine (ALT) aminotransferase and the presence of PNCs within ischemic hepatic tissue and could be confirmed using repression of VASP through siRNA. In studies employing bone marrow chimeric mice we identified hematopoietic VASP to be of crucial importance for the extent of hepatic injury. Phosphorylation of VASP on Ser(153) through Prostaglandin E1 or on Ser(235) through atrial natriuretic peptide resulted in a significant reduction of hepatic IR injury. This was associated with a reduced presence of PNCs in ischemic hepatic tissue. Taken together, these studies identified VASP and VASP phosphorylation as crucial target for future hepatoprotective strategies.
- PMID:
- 22216296
- [PubMed - in process]
CB1 cannabinoid receptor mediates glucocorticoid effects on hormone secretion induced by volume and osmotic changes.
Source
Department of Physiology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Brazil.
Abstract
This work provides the first in vivo evidence that the CB1 cannabinoid receptor mediates dexamethasone effects on hormone release induced by changes in circulating volume and osmolality in male adult rats. The CB1 antagonist rimonabant potentiated oxytocin (OT) secretion induced by hypertonic extracellular volume expansion (H-EVE) and completely reversed the inhibitory effects of dexamethasone administration under the same experimental conditions. These data suggest that the modulation of OT release by glucocorticoids is mediated by the CB1 receptor. Although dexamethasone did not affect vasopressin (AVP) secretion induced by H-EVE, the administration of rimonabant potentiated AVP release in response to the same stimulus, supporting the hypothesis that the CB1 receptor regulates AVP secretion independently of glucocorticoid-mediated signalling. Dexamethasone alone did not affect atrial natriuretic peptide (ANP) release stimulated by isotonic (I-) and H-EVE. However, pretreatment with rimonabant potentiated ANP secretion induced by H-EVE, suggesting a possible role for the CB1 receptor in the control of peripheral factors that modulate cardiovascular function. Rimonabant also reversed dexamethasone inhibitory effects on H-EVE induced corticosterone secretion, reinforcing the hypothesis that the CB1 receptor may be involved in negative feedback exerted by glucocorticoids on the activity of the hypothalamic-pituitary-adrenal axis. Collectively, these results indicate that the CB1 receptor modulates neurohypophyseal hormone secretion and systemic factors, such as corticosterone and ANP, thus participating in homeostatic responses to altered extracellular volume and plasma tonicity. © 2011 The Authors Clinical and Experimental Pharmacology and Physiology © 2011 Blackwell Publishing Asia Pty Ltd.
© 2011 The Authors Clinical and Experimental Pharmacology and Physiology © 2011 Blackwell Publishing Asia Pty Ltd.
Telmisartan acts through the modulation of ACE-2/ANG 1-7/mas receptor in rats with dilated cardiomyopathy induced by experimental autoimmune myocarditis.
Source
Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan.
Abstract
AIM:
Recent findings have suggested that a therapeutic approach to amplify or stimulate the angiotensin-converting enzyme-2 [ACE-2]-angiotensin 1-7 [ANG 1-7] mas axis could provide protection against the development of cardiovascular diseases. We investigated the cardioprotective effects of telmisartan in rats with dilated cardiomyopathy [DCM] after experimental autoimmune myocarditis [EAM].
MAIN METHODS:
DCM was elicited in Lewis rats by immunization with cardiac myosin, and twenty-eight days after immunization, the surviving Lewis rats were divided into two groups and treated with either telmisartan (10mg/kg/day) or vehicle.
KEY FINDINGS:
Telmisartan treatment effectively suppressed myocardial protein and mRNA expressions of inflammatory markers [CD68, iNOS, NF-kB, interleukin-1β, interferon-γ, monocyte chemotactic protein-1] in comparison to vehicle-treated rats. In contrast, myocardial protein levels of ACE-2 and ANG 1-7 mas receptor were upregulated in the telmisartan-treated group compared with vehicle-treated rats. Telmisartan treatment significantly reduced fibrosis and hypertrophy and their marker molecules [OPN, CTGF, TGF-β1 and collagens I and III and atrial natriuretic peptide and GATA-4, respectively] compared with those of vehicle-treated rats. In addition, telmisartan treatment significantly lowered the protein expressions of NADPH oxidase subunits p47phox, p67phox, and superoxide production when compared with vehicle-treated rats. Telmisartan treatment significantly decreased the expression levels of mitogen-activated protein kinase (MAPK) signaling molecules than with those of vehicle-treated rats. Also, telmisartan treatment significantly improved LV systolic and diastolic function.
SIGNIFICANCE:
These results indicate that telmisartan treatment significantly improved LV function and ameliorated the progression of cardiac remodeling through modulation of the ACE-2/ANG 1-7/Mas receptor axis in rats with DCM after EAM.
Copyright © 2011. Published by Elsevier Inc.
Altered regulation of nitric oxide and natriuretic peptide system in cisplatin-induced nephropathy.
Source
Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea.
Abstract
Cisplatin is a chemotherapeutic agent used for treating solid tumors. However, nephrotoxicity is the dose-limiting factorin its clinical use. The present study was aimed to determine whether altered regulation of the local nitric oxide (NO) andnatriuretic peptide (NP) systems is involved in the pathogenesis of cisplatin-induced nephropathy. Cisplatin (6mg/kg) was injected intraperitoneally into male Sprague-Dawley rats. The control group was not treated with cisplatin. Expression levels of nitric oxide synthase (NOS), nitrotyrosine, soluble guanylyl cyclase and neutral endopeptidase (NEP) in the kidneys were determined 4days after treatment by semiquantitative immunoblotting. mRNA expression of NPs and natriuretic peptide receptors (NPRs) was determined by real-time polymerase chain reaction. The activities of soluble and particulate guanylyl cyclase were determined by measuring the amount of cyclic 3',5'-guanosine monophosphate (cGMP) generated in responses to sodium nitroprusside and atrial natriuretic peptide (ANP), respectively. In the test rats, creatinine clearance was decreased, while sodium and water excretion were increased. The expression of inducible NOS (iNOS) and nitrotyrosine was increased in the cortex/outer stripe of outer medullar and inner medullar, while that of endothelial and neuronal NOS was decreased in the inner medullar. Excretion of NO metabolites was increased in these rats. The catalytic activity of soluble guanyly cyclase was blunted in the papilla after cisplatin was administered. The mRNA expression of ANP, brain natriuretic peptide, and C-type natriuretic peptide was increased, while that of NPR-A and NPR-C were decreased in the test rats. The catalytic activity of soluble and particulate guanylyl cyclase in the papilla was blunted after cisplatin was administered. In conclusion, increased production of NO by iNOS may contribute to cytotoxic injury, resulting in cisplatin-induced nephropathy, while the up-regulation of renal natriuretic peptide synthesis together with the down-regulation of NEP and NPR-C may contribute to the natriuresis and diuresis seen in cisplatin-induced nephropathy.
Copyright © 2011. Published by Elsevier B.V.
Stress-dependent dilated cardiomyopathy in mice with cardiomyocyte-restricted inactivation of cyclic GMP-dependent protein kinase I.
Source
Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany.
Abstract
AimsCardiac hypertrophy is a common and often lethal complication of arterial hypertension. Elevation of myocyte cyclic GMP levels by local actions of endogenous atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) or by pharmacological inhibition of phosphodiesterase-5 was shown to counter-regulate pathological hypertrophy. It was suggested that cGMP-dependent protein kinase I (cGKI) mediates this protective effect, although the role in vivo is under debate. Here, we investigated whether cGKI modulates myocyte growth and/or function in the intact organism.Methods and resultsTo circumvent the systemic phenotype associated with germline ablation of cGKI, we inactivated the murine cGKI gene selectively in cardiomyocytes by Cre/loxP-mediated recombination. Mice with cardiomyocyte-restricted cGKI deletion exhibited unaltered cardiac morphology and function under resting conditions. Also, cardiac hypertrophic and contractile responses to β-adrenoreceptor stimulation by isoprenaline (at 40 mg/kg/day during 1 week) were unaltered. However, angiotensin II (Ang II, at 1000 ng/kg/min for 2 weeks) or transverse aortic constriction (for 3 weeks) provoked dilated cardiomyopathy with marked deterioration of cardiac function. This was accompanied by diminished expression of the [Ca(2+)](i)-regulating proteins SERCA2a and phospholamban (PLB) and a reduction in PLB phosphorylation at Ser(16), the specific target site for cGKI, resulting in altered myocyte Ca(2+)(i) homeostasis. In isolated adult myocytes, CNP, but not ANP, stimulated PLB phosphorylation, Ca(2+)(i)-handling, and contractility via cGKI.ConclusionThese results indicate that the loss of cGKI in cardiac myocytes compromises the hypertrophic program to pathological stimulation, rendering the heart more susceptible to dysfunction. In particular, cGKI mediates stimulatory effects of CNP on myocyte Ca(2+)(i) handling and contractility.
Renal actions of dendroaspis natriuretic peptide in rabbits.
Source
Department of Physiology, Institute for Medical Sciences, Center for Healthcare Technology Development, Chonbuk National University Medical School, Jeonju 561-180, Republic of Korea.
Abstract
Dendroaspis natriuretic peptide (DNP) is one of four members of the natriuretic peptide family sharing functional and structural properties. The purpose of the present study was to elucidate the physiological role of DNP on renal functions and its cellular mechanism in the rabbit kidney. DNP (5μg/kg/min) infused intravenously increased urine volume and urinary excretion of electrolytes. These renal actions induced by DNP were more pronounced than those caused byatrial natriuretic peptide (ANP). We compared profiles of (125)I-ANP and (125)I-DNP by reverse-phase HPLC during incubation in rabbit plasma at 37°C for 1, 2, and 4h. While (125)I-ANP was quickly degraded within 1h, (125)I-DNP was still stable in plasma for 4h. DNP induced the greatest cyclic guanosine monophosphate (cGMP) production in the glomeruli in a dose-dependent manner, when compared to other renal structures including cortical tubules, outer medullary tubules, and inner medullary tubules. Affinity cross-linking analysis revealed NPR-A is selective receptor for DNP in glomeruli. Forskolin, a stimulator of adenylyl cyclase, significantly decreased cGMP production in the renal glomeruli but not in the renal medulla. In summary, DNP is a more effective activator of renal functions than ANP, possibly because of the degradation resistance of DNP against the endogenous peptidases in plasma or tissues. These findings suggest that DNP plays a pivotal role as a renal regulating peptide via specific natriuretic peptide receptors with a guanylyl cyclase domain.
Copyright © 2011 Elsevier Inc. All rights reserved.
Renal regulation of potassium homeostasis in calves in the first week of life including the role of atrial natriuretic peptide.
Source
Department of Physiology, Cytobiology and Proteomics, Faculty of Biotechnology and Animal Husbandry, The West Pomeranian University of Technology, Doktora Judyma 6, 71-466 Szczecin, Poland.
Abstract
The experiment was carried out on 10 clinically healthy Polish-Friesian var. Black-and-White cow calves, during the first seven days of postnatal life. The results indicate that renal removal of potassium depends primarily on the quantity reabsorbed in the tubules, whereas clearance of the electrolyte, due to stable levels in the blood plasma, depends on the amount excreted in the urine. With stable tubular reabsorption of potassium, a relatively unchanging amount of excreted potassium was observed in the urine. However, reduced tubular reabsorption caused a significant increase in excretion and clearance of the electrolyte. Changes in the amount of filtered potassium play a minor role in the regulation of excretion. Small changes in the blood plasma potassium concentration observed primarily resulted from changes in glomerular filtration rate and tubular reabsorption, since the concentration of electrolyte in the blood after birth remained within the physiological range. The results ofthis study suggest that neonate calf kidneys are sufficiently prepared to regulate kalemia. Atrial natriuretic peptide is not directly involved in the regulation of tubular reabsorption of potassium in calves in the first week of life, although it is highly likely that the peptide is involved in the excretion of potassium in the urine in calves during the first seven days of life.
- PMID:
- 22195470
- [PubMed - in process]
Clinical features of patients with left atrial thrombus undergoing anticoagulant therapy.
Source
Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
Abstract
PURPOSE:
Left atrial (LA) thrombus was sometimes found by transesophageal echocardiography (TEE) in non-valvularatrial fibrillation (AF), even in the setting of continuous warfarin therapy. A D-dimer cutoff level of 0.50 μg/mL appears to be a useful marker to rule out venous vein thrombosis. This study analyzed the clinical features of patients with LA thrombi who received anticoagulant therapy and whether the D-dimer test is useful to exclude LA thrombus.
METHODS:
Two hundred twenty-five consecutive patients with AF (149 with paroxysmal and 76 with persistent) were enrolled. All patients received continuous warfarin therapy with the prothrombin time-international normalized ratio (PT-INR) between 1.6 and 3.0 for more than 3 months and TEE was performed.
RESULTS:
LA thrombi were present in 23 and absent in 202 patients. Age, gender, and PT-INR (1.96 ± 0.59 vs. 1.98 ± 0.53) were not different between the two groups. Persistent AF (65 vs. 30%; p < 0.005), LA diameter (44 ± 5 vs. 40 ± 7 mm; p < 0.005), ejection fraction (57 ± 13 vs. 65 ± 9%; p < 0.005), brain natriuretic peptide levels (203 ± 209 vs. 105 ± 166 pg/mL; p < 0.05), D-dimer (0.55 ± 0.70 vs. 0.16 ± 0.20 μg/mL; p < 0.001), LA appendage flow velocity (33 ± 15 vs. 54 ± 19 cm/s; p < 0.001), CHADS(2) scores (2 ± 1 vs. 1 ± 1; p < 0.005), and CHA(2)DS(2)-VASc scores (3 ± 2 vs. 2 ± 1; p < 0.005) were significantly different in both groups. Although multivariate analysis showed that D-dimer and LA appendage flow velocity were significant independent predictors of LA thrombus, D-dimer levels below 0.5 μg/mL were found in 19 of 23 patients with LA thrombi.
CONCLUSION:
D-dimer levels below 0.5 μg/mL is not enough to rule out LA thrombus in AF patients with well-controlled anticoagulation.
Efficacy and Safety of Bosentan in Adults with Simple and Complex Eisenmenger's Syndrome.
Source
Ahmanson/UCLA Adult Congenital Heart Disease Center, David Geffen School of Medicine, Los Angeles, Calif, USA.
Abstract
Background. Eisenmenger's syndrome (ES) is associated with decreased longevity and reduced functional capacity. Targeted pharmacologic therapies improve functional capacity and survival in these patients. We sought to compare the response of patients with simple vs. complex ES following initiation of bosentan. Methods. ES patients with a history of bosentan use were identified by chart review. Simple ES was defined as ES associated with atrial septal defect, ventricular septal defect, or patent ductus arteriosus. Complex ES consisted of patients with truncus arteriosus and single ventricle congenital heart disease. Six-minute walking distance (6MWD), maximal oxygen consumption (VO(2) max), brain natriuretic peptide (BNP), and resting oxygen saturation were compared between simple and complex ES patients before and after bosentan treatment. Results. Twenty-four patients were included (11 simple, 13 complex). Resting oxygen saturation, 6MWD, VO(2) max, and BNP were not significantly different between the two groups prior to bosentan initiation. Ten patients received bosentan monotherapy, and bosentan was used in combination with sildenafil in 13 (five simple, eight complex). One patient received bosentan with iloprost. Mean duration of therapy was 38 ± 14 months in the simple group and 40 ± 8.1 months in the complex group (P= NS). Posttreatment, 6MWD increased from 274 ± 135 m to 326 ± 106 m in simple ES patients (P= .32). 6MWD in patients with complex ES increased from 332 ± 51 m to 364 ± 109 (P= .028). VO(2) max improved from 13.4 ± 3.8 to 17 ± 6 (P= .54) in the simple group, while VO(2) max in the complex group improved from 12.7 ± 2.3 to 15.5 ± 2.2 (P= .17). There was minimal change in BNP or resting oxygen saturation between the groups. Conclusions. Treatment with bosentan is both safe and effective in patients with both simple and complex forms of ES.
© 2011 Wiley Periodicals, Inc.
- PMID:
- 22188797
- [PubMed - as supplied by publisher]
Cardiovascular Biomarker Midregional Proatrial Natriuretic Peptide During and After Preeclamptic Pregnancies.
Source
Department of Obstetrics and Department of Gynaecology, Women and Children's Division, Oslo University Hospital, Ullevål, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway; Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max-Delbrueck Center for Molecular Medicine, Berlin, Germany; Department of Cardiology, Campus Virchow-Klinikum, Charité, Berlin, Germany; HELIOS Clinic, Berlin, Germany.
Abstract
Preeclampsia is associated with increased risk of cardiovascular disease. Midregional proatrial natriuretic peptide (MR-proANP), a precursor of the atrial natriuretic peptide, is a biomarker for cardiovascular disease. We obtained plasma from 184 pregnant women in gestational weeks 24 to 42 (normotensive pregnancies: n=77, preeclampsia: n=107), from 25 of these women at 5 to 8 years after index pregnancy (normotensive pregnancies: n=11, preeclampsia: n=14), and from 49 normotensive, nonpregnant women and analyzed them by immunoassay for MR-proANP. To investigate potential sources, placental and decidual atrial natriuretic peptide mRNA expression levels were analyzed by quantitative real-time PCR in 21 normotensive and 23 preeclamptic pregnancies, as well as in human heart and kidney samples. For further confirmation, we measured circulating MR-proANP and performed expression studies in a transgenic rat model for preeclampsia. MR-proANP was significantly elevated in maternal plasma in preeclampsia compared with normotensive pregnancies (135 versus 56 pmol/L; P<0.001). However, 5 to 8 years after pregnancy, there was no difference (formerly preeclamptic women versus formerly normotensive in pregnancy: 53 versus 49 pmol/L; P=0.5). Our preeclamptic rat model confirmed the acute MR-proANP differences between preeclamptic and normotensive pregnancies (10.9±1.9 versus 4.3±0.3 pmol/L; P=0.05). Atrial natriuretic peptide expression was high in the heart but negligible in the uteroplacental unit in both normotensive humans and rats, whereas expression in maternal and fetal hearts in the preeclamptic rats was significantly increased, compared with controls. MR-proANP is a serviceable biomarker in preeclampsia, both in humans and a rat model, probably reflecting cardiovascular hemodynamic stress.
Evaluation of Multiple Biomarkers of Cardiovascular Stress for Risk Prediction and Guiding Medical Therapy in Patients with Stable Coronary Disease.
Source
1 Brigham and Women's Hospital & Harvard Medical School, Boston, MA;
Abstract
BACKGROUND:
Circulating biomarkers can offer insight into subclinical cardiovascular stress and thus have the potential to aid in risk stratification and tailoring of therapy.
METHODS AND RESULTS:
We measured plasma levels of 4 cardiovascular biomarkers, midregional pro-atrial natriuretic peptide (MR-proANP), midregional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1) and copeptin, in 3717 patients with stable CAD and preserved left ventricular ejection fraction (LVEF) who were randomized to trandolapril or placebo as part of the Prevention of Events with Angiotensin Converting Enzyme (PEACE) trial. After adjustment for clinical cardiovascular risk predictors and LVEF, elevated levels of MR-proANP, MR-proADM, and CT-proET-1 were independently associated with the risk of cardiovascular death or heart failure (HRs per 1-SD of log-transformed biomarker levels of 1.97, 1.48, and 1.47, respectively; P≤0.002 for each biomarker). These three biomarkers also significantly improved metrics of discrimination when added to a clinical model. Trandolapril significantly reduced the risk of cardiovascular death or heart failure in patients who had elevated levels of 2 or more these biomarkers (HR 0.53, 95% CI 0.36-0.80), whereas there was no benefit in patients with elevated levels of 0 or 1 biomarkers (HR 1.09, 95% CI 0.74-1.59) (P(interaction)=0.012).
CONCLUSIONS:
In patients with stable CAD and preserved LVEF, our results suggest elevated levels of novel biomarkers of cardiovascular stress may help identify patients who are at higher risk of cardiovascular death and heart failure and may be useful to select patients who derive significant benefit from ACE inhibitor therapy.
Depletion of 14-3-3 Protein Exacerbates Cardiac Oxidative Stress, Inflammation and Remodeling Process via Modulation of MAPK/NF-ĸB Signaling Pathways after Streptozotocin-induced Diabetes Mellitus.
Source
Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Niigata city, Japan.
Abstract
Diabetic cardiomyopathy is associated with increased oxidative stress and inflammation. Mammalian 14-3-3 proteins are dimeric phosphoserine-binding proteins that participate in signal transduction and regulate several aspects of cellular biochemistry. The aim of the study presented here was to clarify the role of 14-3-3 protein in the mitogen activated protein kinase (MAPK) and nuclear factor-kB (NF-κB) signaling pathway after experimental diabetes by using transgenic mice with cardiac-specific expression of a dominant-negative 14-3-3 protein mutant (DN 14-3-3). Significant p-p38 MAPK activation in DN 14-3-3 mice compared to wild type mice (WT) after diabetes induction and with a corresponding up regulation of its downstream effectors, p-MAPK activated protein kinase 2 (MAPKAPK-2). Marked increases in cardiac hypertrophy, fibrosis and inflammation were observed with a corresponding up-regulation of atrial natriuretic peptide, osteopontin, connective tissue growth factor, tumor necrosis factor α, interleukin (IL)-1β, IL-6 and cellular adhesion molecules. Moreover, reactive oxygen species, left ventricular expression of NADPH oxidase subunits, p22 phox, p67 phox, and Nox4, and lipid peroxidation levels were significantly increased in diabetic DN 14-3-3mice compared to diabetic WT mice. Furthermore, myocardial NF-κB activation, inhibitor of kappa B-α degradation and mRNA expression of proinflammatory cytokines were significantly increased in DN 14-3-3 mice compared to WT mice after diabetes induction. In conclusion, our data suggests that depletion of 14-3-3 protein induces cardiac oxidative stress, inflammation and remodeling after experimental diabetes induction mediated through p38 MAPK, MAPKAPK-2 and NF-κB signaling.
Copyright © 2011 S. Karger AG, Basel.
Association of 2238T>C Polymorphism of the Atrial Natriuretic Peptide Gene With Coronary Artery Disease in Afro-Caribbeans With Type 2 Diabetes.
Source
Cardiology Unit, University Hospital of Pointe-à-Pitre, Guadeloupe, French West Indies, France.
Abstract
BackgroundThe atrial natriuretic peptide (ANP) is known mainly for its effects on kidney function and blood pressure homeostasis. We investigated the association between two ANP polymorphisms and pre-existing coronary artery disease (CAD) in patients of African descent with type 2 diabetes (T2D).MethodsWe conducted a cross-sectional and retrospective study of 218 volunteer Afro-Caribbean patients with T2D. Two polymorphisms (rs5064, 708C>T; and rs5065, 2238T>C) of ANP were genotyped using PCR-restriction fragment length polymorphism analysis. ANCOVA, χ(2)-test, and logistic regression were used for statistical analysis.ResultsAmong these patients (92 men; 128 women), 67 (30.7%) had CAD, of whom 75% had had myocardial infarction. The frequency of rs5065-C carriers (TC/CC) was significantly lower in patients with CAD than in those without CAD (24 vs. 41%, P = 0.01). The frequency of hypertension did not differ significantly according to genotype. Univariate logistic regression revealed that male sex, age, dyslipidemia, hypertension, and rs5065-C carrier status were associated significantly with CAD. After adjustment for the variables of interest, the odds ratio (ORs) of CAD for rs5065-C carriers (TC/CC) was 0.50 (0.26-0.96; P = 0.038). No association was found between the rs5064 (708C>T) single-nucleotide polymorphisms (SNPs) and pre-existing CAD or cardiovascular risk factors.ConclusionsThe ANP rs5065 (2238T>C) C allele seems to exert a protective effect against CAD in T2D patients of African descent. The relevance of ANP polymorphisms for CAD should be determined in different populations.American Journal of Hypertension (2011). doi:10.1038/ajh.2011.233.
Relation of left ventricular end-diastolic pressure and N-terminal pro-brainnatriuretic peptide level with left atrial deformation parameters.
Source
Erzurum Education and Research Hospital, Erzurum, Turkey.
Abstract
AIMS:
It has been shown that speckle-tracking echocardiography (STE) is a feasible and reproducible method to assess left atrial (LA) function. The relationship between left ventricular end-diastolic pressure (LVEDP) and brain natriureticpeptide (BNP) with LA deformation parameters has not been studied comprehensively. Therefore, we propose to investigate the effects of invasively obtained LVEDP and BNP level on LA deformation parameters assessed by STE and to show the relationship between them.
METHODS AND RESULTS:
The study population consisted of 62 patients who underwent cardiac catheterization. LVEDP was obtained with a fluid-filled catheter. All patients underwent standard two-dimensional echocardiography. In STE analysis for LA, the peak LA strain at the end of the ventricular systole (LAs-strain) and the LA strain with LA contraction (LAa-strain) were obtained. N-terminal pro-BNP (NT-pro-BNP) levels were measured. The univariate correlation analysis demonstrated that the LAs-strain and LAa-strain had good inverse correlation with LVEDP, and the LAs-strain and LAa-strain only had a moderate correlation with NT-pro-BNP. The area under the receiver-operating characteristic curve of the LAs-strain was 0.96 (0.86-0.99, P < 0.001), and for the LAa-strain, the area was 0.88 (0.74-0.96, P < 0.001) to predict increased LVEDP. A multiple regression analysis demonstrated that the LAs-strain, LAV(max), and LV ejection fraction were independent predictors of increased LVEDP among the covariates examined; however, the LAa-strain and LV mass index were not independent predictors. A borderline statistical significance was found for NT-pro-BNP.
CONCLUSION:
LAs-strain more closely related with LVEDP and NT-pro-BNP level than LAa-strain. LAs-strain thus might be used clinically to predict increased LVEDP.
Ouabain increases iNOS-dependent nitric oxide generation which contributes to the hypertrophic effect of the glycoside: possible role of peroxynitrite formation.
Source
Department of Physiology & Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, N6A 5C1, Canada.
Abstract
In addition to inotropic effects, cardiac glycosides exert deleterious effects on the heart which limit their use for cardiac therapeutics. In this study, we determined the possible contribution of ouabain-induced iNOS stimulation to the resultant hypertrophic as well as cytotoxic effects of the glycoside on cultured adult rat ventricular myocytes. Myocytes were treated with ouabain (50 μM) for up to 24 h. Ouabain significantly increased gene and protein levels of inducible nitric oxide synthase (iNOS) which was associated with significantly increased release of NO from myocytes as well as increased total release of reactive oxygen species (ROS), superoxide anion (O(2) (-)), and increased peroxynitrite formation as assessed by protein tyrosine nitration. Administration of ouabain was also associated with increased levels of myocyte toxicity as determined by myocyte morphology, trypan blue staining and lactate dehydrogenase (LDH) efflux. The nonspecific NOS inhibitor Nω-nitro-L: -arginine methyl ester and the more selective iNOS inhibitor 1400W both abrogated the increase in LDH release but had no significant effect on either morphology or trypan blue staining. Ouabain also significantly increased both myocyte surface area and expression of atrial natriuretic peptide indicating a hypertrophic response with both parameters being completely prevented by NOS inhibition. The effects of iNOS inhibitors were associated with diminished ouabain tyrosine nitration as well as abrogation of ouabain-induced p38 and ERK phosphorylation. Our study shows that ouabain is a potent inducer of NO formation, iNOS upregulation, and increased production of ROS. Inhibition of ouabain-dependent peroxynitrite formation may contribute to the antihypertrophic effect of iNOS inhibition possibly by preventing downstream MAPK activation.
NT-pro-brain natriuretic peptide levels after valve replacement.
Source
elasfar_egy@hotmail.com.
Abstract
Elevated plasma N-terminal pro-brain natriuretic peptide levels have been demonstrated in patients with chronic valvular disease. To assess whether changes in N-terminal pro-brain natriuretic peptide levels after mitral, aortic, and double-valve replacement reflect changes in heart failure symptoms, a prospective observational nonrandomized study was undertaken in 24 consecutive patients (mean age, 55.3 ± 16.2 years; 58% male) undergoing mitral and/or aortic valve replacement. Mitral valve replacement was carried out in 12 patients, aortic valve replacement in 8, and combined mitral and aortic valve replacement in 4. N-terminal pro-brain natriuretic peptide measurements, echocardiography, and functional class assessment were performed before and 6 months after surgery. A decrease in N-terminal pro-brain natri-uretic peptide at 6 months postoperatively was significantly associated with decreased left atrial dimension, left ventricular end-diastolic and end-systolic dimensions, increased ejection fraction, and improvement in functional class. Thus we can hypothesize that measurement of N-terminal pro-brain natriuretic peptide might allow early detection of any clinical deterioration as well as assessment of the long-term outcome in valve replacement patients.
Impact of chronic atrial fibrillation in patients with severe heart failure and indication for CRT : Data of two registries with 711 patients (1999-2006 and 2007-6/2008).
Source
Department of Cardiology, Schuechtermann-Klinik, Heart Center Osnabrueck-Bad Rothenfelde, Ulmenallee 11, 49214, Bad Rothenfelde, Germany, g.luedorff@schuechtermann-klink.de.
Abstract
AIMS:
Atrial fibrillation (AF) is a relevant comorbidity in heart failure (HF) patients. In milestone cardiac resynchronization therapy (CRT) studies, patients with AF were excluded. We sought to investigate the influence of chronic atrial fibrillation (AF) on patients with CRT. AV node (AVN) ablation is frequently recommended. Converting AF to sinus rhythm (SR) is not a standard concept.
METHODS:
A total of 584 consecutive patients with CRT devices were included in a single-center registry from 1999-2006 (retrospective registry) and 127/324 patients from 2007-06/2008 (prospective registry). The impact of persistent AF (group 1) on clinical and echocardiographic improvement compared with patients in SR (group 2) after 12 (6) months follow-up were analyzed. Re-establishing SR after initial cardioversion or need for AVN ablation was examined.
RESULTS:
In the retrospective registry, 139 (24%) patients presented with AF (group 1) and 445 with SR (group 2). The groups differed in age, gender, and left atrium (LA) size but not in NYHA class, ejection fraction (EF), left ventricular end-diastolic dimension (LVEDD), B-type natriuretic peptide (BNP) levels, QRS width, and underlying disease. After 1 year, CRT improvement of NYHA class and EF was similar with higher mortality in group 1 (12% vs. 7%; OR 1.80; 95% confidence interval 0.95-3.4). The AF group presented with SR in 33/82 (40%) patients and 11% needed AVN ablation. The prospective data showed 27 (21%) patients in AF with conversion to SR in 41% after 6 months.
CONCLUSION:
Patients with severe HF and chronic AF had a comparable improvement with CRT as those in SR. CRT is a successful treatment option in patients with chronic AF offering the potential to restore SR in a significant number of patients.
Inhibition of signal transducer and activator of transcription 3 (stat3) attenuates interleukin-6 (IL-6) induced collagen synthesis and resultant hypertrophy in rat heart.
Source
University of Calcutta, India;
Abstract
Abstract INHIBITION OF SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 (STAT3) ATTENUATES INTERLEUKIN-6 (IL-6) INDUCED COLLAGEN SYNTHESIS AND RESULTANT HYPERTROPHY IN RAT HEART Saiful Anam Mir, Arunachal Chatterjee, Arkadeep Mitra, Kanchan Pathak, Sushil K. Mahata, Sagartirtha Sarkar IL-6 has been shown to play a major role in collagen upregulation process during cardiac hypertrophy, though the precise mechanism is still not known. In this study, we have analysed the mechanism by which IL-6 modulates cardiac hypertrophy. For in vitro model, IL-6 treated cultured cardiac fibroblasts were used whereas in vivo cardiac hypertrophy model was generated by renal artery ligation in adult male Wistar rats (Rattus norvegicus). During induction of hypertrophy, increased phosphorylation of STAT1, STAT3, MAPK and ERK proteins was observed both in vitro and in vivo. Treatment of fibroblasts with specific inhibitors for STAT1 (Fludarabine, 50 μM), STAT3 (S31-201, 10 μM), p38 MAPK (SB203580, 10 μM) and ERK1/2 (U0126, 10 μM) resulted in downregulation of IL-6 induced phosphorylation of specific proteins, however only S31-201 and SB203580 inhibited collagen biosynthesis. In ligated rats in vivo, only STAT3 inhibitors resulted in significant decrease in collagen synthesis and hypertrophy markers such as atrial natriuretic factor and beta- myosin heavy chain. In addition, decreased heart weight to body weight ratio and improved cardiac function as measured by echocardiography, was evident in animals treated with STAT3 inhibitor or siRNA. Compared to IL-6 neutralization, more pronounced downregulation of collagen synthesis and regression of hypertrophy was observed with STAT3 inhibition, suggesting that STAT3 is the major downstream signaling molecule and a potential therapeutic target for cardiac hypertrophy.
Action of ANP on the nongenomic dose-dependent biphasic effect of aldosterone on NHE1 in proximal S3 segment.
Source
Department of Physiology and Biophysics, Instituto de Ciências Biomédicas, University of São Paulo, Av. Prof. Lineu Prestes, 1524, Cidade Universitária, 05508-900 SP, Brazil.
Abstract
The rapid (2min) nongenomic effects of aldosterone (ALDO) and/or spironolactone (MR antagonist), RU 486 (GR antagonist), atrial natriuretic peptide (ANP) and dimethyl-BAPTA (BAPTA) on the intracellular pH recovery rate (pHirr) via NHE1 (basolateral Na(+)/H(+) exchanger isoform), after the acid load induced by NH(4)Cl, and on the cytosolic free calcium concentration ([Ca(2+)](i)) were investigated in the proximal S3 segment isolated from rats, by the probes BCECF-AM and FLUO-4-AM, respectively. The basal pHi was 7.15±0.008 and the basal pHirr was 0.195±0.012pHunits/min (number of tubules/number of tubular areas=16/96). Our results confirmed the rapid biphasic effect of ALDO on NHE1: ALDO (10(-12)M) increases the pHirr to approximately 59% of control value, and ALDO (10(-6)M) decreases it to approximately 49%. Spironolactone did not change these effects, but RU 486 inhibited the stimulatory effect and maintained the inhibitory effect. ANP (10(-6)M) or BAPTA (5×10(-5)M) alone had no significant effect on NHE1 but prevented both effects of ALDO on this exchanger. The basal [Ca(2+)](i) was 104±3nM (15), and ALDO (10(-12) or 10(-6)M) increased the basal [Ca(2+)](i) to approximately 50% or 124%, respectively. RU 486, ANP and BAPTA decreased the [Ca(2+)](i) and inhibited the stimulatory effect of both doses of ALDO. The results suggest the involvement of GR on the nongenomic effects of ALDO and indicate a pHirr-regulating role for [Ca(2+)](i) that is mediated by NHE1, stimulated/impaired by ALDO, and affected by ANP or BAPTA with ALDO. The observed nongenomic hormonal interaction in the S3 segment may represent a rapid and physiologically relevant regulatory mechanism in the intact animal under conditions of volume alterations.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Effect of potassium supplementation on renal tubular function, ambulatory blood pressure and pulse wave velocity in healthy humans.
Source
Departments of Medical Research and Medicine, Holstebro Regional Hospital and University of Aarhus , Holstebro , Denmark.
Abstract
Background. Potassium is the main intracellular cation, which contributes to keeping the intracellular membrane potential slightly negative and elicits contraction of smooth, skeletal and cardiac muscle. A change in potassium intake modifies both cardiovascular and renal tubular function. The purpose of the trial was to investigate the effect of dietary potassium supplementation, 100 mmol daily in a randomized, placebo-controlled, crossover trial of healthy participants during two periods of 28 days duration. The participants (N = 21) received a diet that was standardized regarding energy requirement, and sodium and water intake. Methods. 24-hour ambulatory blood pressure (ABP) and applanation tonometry were used to assess blood pressure, pulse wave velocity (PWV), augmentation index (AIx) and central blood pressure (CBP). Immunoassays were used for measurements of plasma concentrations of vasoactive hormones: renin (PRC), angiotensin II (Ang II), aldosterone (Aldo), atrial natriuretic peptide (ANP), vasopressin (AVP), pro-brain natriureticpeptide (pro-BNP),endothelin (Endo), urinary excretions of aquaporin 2 (AQP2), cyclic AMP (cAMP), and the β-fraction of the epithelial sodium channel (ENaC(ß)). Results. AQP2 excretion increased during potassium supplementation, and free water clearance fell. The changes in urinary potassium excretion and urinary AQP2 excretion were significantly and positively correlated. Aldo increased. GFR, u-ENaC- β, PRC, Ang II, ANP, BNP, Endo, blood pressure and AI were not significantly changed by potassium supplementation, whereas PWV increased slightly. Conclusions. Potassium supplementation changed renal tubular function and increased water absorption in the distal part of the nephron. In spite of an increase in aldosterone in plasma, blood pressure remained unchanged after potassium supplementation. ClinicalTrials.Gov Identifier: NCT00801034.
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