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Atrial Natriuretic Peptide (atrial + natriuretic_peptide)
Selected AbstractsWithdrawal of Selective Serotonin Reuptake Inhibitors (SSRIs) May Cause Increased Atrial Natriuretic Peptide (ANP) and Persistent Sexual Arousal in Women?THE JOURNAL OF SEXUAL MEDICINE, Issue 2 2006David Goldmeier MD [source] Biological Activity of Endogenous Atrial Natriuretic Peptide During Cardiopulmonary BypassARTIFICIAL ORGANS, Issue 10 2000Nobuhiko Hayashida Abstract: To evaluate the effect of cardiopulmonary bypass (CPB) on atrial natriuretic peptide (ANP) biological activity in patients undergoing cardiac operations, we conducted a prospective study. Ten patients undergoing mitral valve surgery were enrolled. Plasma levels of ANP and cyclic guanosine monophosphate (cGMP), hemodynamic variables, and renal function parameters were assessed perioperatively. The molar ratio of cGMP to ANP (as a marker for ANP biological activity) decreased significantly (p < 0.05) during CPB despite similar plasma ANP levels. The ratio correlated inversely with the duration of CPB (r = ,0.85, p = 0.002). The ratio also correlated with fractional sodium excretion (r = 0.65, p = 0.04) and correlated inversely with pulmonary vascular resistance (r = ,0.79, p = 0.009) and atrial filling pressure (r = ,0.84, p = 0.003) postoperatively. CPB decreased the molar ratio of cGMP to ANP, which may represent ANP biological activity, such as vasodilation and natriuresis. The phenomenon may contribute to water,sodium retention and pulmonary hypertension after cardiac surgery. [source] Homologous desensitization of guanylyl cyclase A, the receptor for atrial natriuretic peptide, is associated with a complex phosphorylation patternFEBS JOURNAL, Issue 11 2010Juliane Schröter Atrial natriuretic peptide (ANP), via its guanylyl cyclase A (GC-A) receptor and intracellular guanosine 3,,5,-cyclic monophosphate production, is critically involved in the regulation of blood pressure. In patients with chronic heart failure, the plasma levels of ANP are increased, but the cardiovascular actions are severely blunted, indicating a receptor or postreceptor defect. Studies on metabolically labelled GC-A-overexpressing cells have indicated that GC-A is extensively phosphorylated, and that ANP-induced homologous desensitization of GC-A correlates with receptor dephosphorylation, a mechanism which might contribute to a loss of function in vivo. In this study, tandem MS analysis of the GC-A receptor, expressed in the human embryonic kidney cell line HEK293, revealed unambiguously that the intracellular domain of the receptor is phosphorylated at multiple residues: Ser487, Ser497, Thr500, Ser502, Ser506, Ser510 and Thr513. MS quantification based on multiple reaction monitoring demonstrated that ANP-provoked desensitization was accompanied by a complex pattern of receptor phosphorylation and dephosphorylation. The population of completely phosphorylated GC-A was diminished. However, intriguingly, the phosphorylation of GC-A at Ser487 was selectively enhanced after exposure to ANP. The functional relevance of this observation was analysed by site-directed mutagenesis. The substitution of Ser487 by glutamate (which mimics phosphorylation) blunted the activation of the GC-A receptor by ANP, but prevented further desensitization. Our data corroborate previous studies suggesting that the responsiveness of GC-A to ANP is regulated by phosphorylation. However, in addition to the dephosphorylation of the previously postulated sites (Ser497, Thr500, Ser502, Ser506, Ser510), homologous desensitization seems to involve the phosphorylation of GC-A at Ser487, a newly identified site of phosphorylation. The identification and further characterization of the specific mechanisms involved in the downregulation of GC-A responsiveness to ANP may have important pathophysiological implications. Structured digital abstract ,,MINT-7713870, MINT-7713887: PMCA (uniprotkb:P20020) and GC-A (uniprotkb:P18910) colocalize (MI:0403) by fluorescence microscopy (MI:0416) [source] Clinical validation of a proANP 31-67 fragment ELISA in the diagnosis of heart failure in the dogJOURNAL OF SMALL ANIMAL PRACTICE, Issue 3 2003A. Boswood Atrial natriuretic peptide (ANP) is a polypeptide hormone found in increased concentrations in the plasma of dogs with heart failure. However, problems arise in using ANP as a diagnostic marker for heart failure because of its short half-life in plasma, proteolysis post-collection and the necessity for a radioimmunoassay. The diagnostic utility of a proANP 31-67 ELISA for the detection of heart failure in dogs was evaluated using plasma collected from 31 dogs with clinical and radiographic signs of heart failure and control samples from 40 dogs considered to be free of cardiac disease. Log proANP 31-67 levels were significantly higher in the heart failure group (P<0·001). In this population of dogs, using a cut-off value of 1750 fmol/ml, the sensitivity and specificity of the assay were 83·9 per cent and 97·5 per cent, respectively. Using a cut-off of 1350 fmol/ml, the sensitivity and specificity were 93·5 per cent and 72·5 per cent, respectively. It is concluded that a proANP 31·67 fragment ELISA should prove to be a useful diagnostic aid in naturally occurring canine heart failure. [source] Downregulation of oxytocin receptors in right ventricle of rats with monocrotaline-induced pulmonary hypertensionACTA PHYSIOLOGICA, Issue 2 2010T. L. Broderick Abstract Aim:, Pulmonary hypertension (PH) in the rat leads to right ventricular (RV) hypertrophy, inflammation and increased natriuretic peptide (NP) levels in plasma and RV. Because the release of nitric oxide (NO) and atrial natriuretic peptide (ANP) is a function of the oxytocin receptor (OTR), we examined the effect of PH on gene and protein expression of OTR, NP (A, atrial; B, brain) and receptors (NPRs), nitric oxide synthases (NOS), interleukin (IL)-1,, IL-6 and tumour necrosis factor-, in the hypertrophied RV in a model of PH. Methods:, RV hypertrophy was induced in male Sprague,Dawley rats with monocrotaline (MCT; 60 mg kg,1) and was confirmed by the presence of an increased RV weight and RV-to-[left ventricle (LV) and septum] ratio. Results:, In the RV of MCT-treated rats, a ,40% reduction in OTR mRNA and protein was observed compared with the RV of control rats. This reduction was associated with increased transcripts of ANP and BNP in both ventricles and a corresponding increase in NP receptor mRNA expression for receptors A, B and C. Protein expression of inducible NOS was increased in the RV, whereas endothelial NOS transcripts were increased only in the LV of MCT-treated rats. In the RV of MCT-treated rats, downregulation of OTR was also associated with increased mRNA expression of IL-1, and IL-6. Conclusion:, Our results show that downregulation of the OTR in the RV of MCT-treated rats is associated with increased expression of NP and their receptors as well as IL-1, and IL-6. This reduction in OTR in RV myocardium may have an impact on cardiac function in the MCT-induced model of PH. [source] Fat as a fuel: emerging understanding of the adipose tissue,skeletal muscle axisACTA PHYSIOLOGICA, Issue 4 2010K. N. Frayn Abstract The early pioneers in the field of metabolism during exercise such as Lindhard and Krogh understood the importance of fat as a fuel for muscle contraction. But they could not have understood the details of the pathways involved, as neither the metabolic role of adipose tissue nor the transport role of non-esterified fatty acids (NEFA) in the plasma was clearly understood at the time. We now recognize that the onset of muscular contraction coincides with an increase in the delivery of NEFA from adipose tissue, probably coordinated by the sympatho-adrenal system. During light exercise, adipose tissue-derived NEFA make up the majority of the oxidative fuel used by muscle. As exercise is prolonged, the importance of NEFA increases. The onset of exercise is marked by an increased proportion of NEFAs entering ,-oxidation rather than re-esterification and recycling. At moderate intensities of exercise, other sources of fat, potentially plasma- and intramyocellular-triacylglycerol, supplement the supply of plasma NEFA. The delivery of NEFA is augmented by increased adipose tissue blood flow and by other stimuli such as atrial natriuretic peptide. Only during high-intensity exercise is there a failure of adipose tissue to deliver sufficient fatty acids for muscle (which is coupled with an inability of muscle to use them, even when fatty acids are supplied artificially). This limitation of adipose tissue NEFA delivery may reflect some feedback inhibition of lipolysis, perhaps via lactate, or possibly ,-adrenergic inhibition of lipolysis at very high catecholamine concentrations. [source] Cardiac natriuretic peptides and continuously monitored atrial pressures during chronic rapid pacing in pigsACTA PHYSIOLOGICA, Issue 2 2000Changes in atrial natriuretic peptide (ANP), N-terminal proatrial natriuretic peptide and brain natriuretic peptide (BNP) were evaluated in relation to continuously monitored atrial pressures in a pacing model of heart failure. Pigs were subjected to rapid atrial pacing (225 beats min,1) for 3 weeks with adjustments of pacing frequencies if the pigs showed overt signs of cardiac decompensation. Atrial pressures were monitored by a telemetry system with the animals unsedated and freely moving. Left atrial pressure responded stronger and more rapidly to the initiation of pacing and to alterations in the rate of pacing than right atrial pressure. Plasma natriuretic peptide levels were measured by radioimmunoassay and all increased during pacing with BNP exhibiting the largest relative increase (2.9-fold increase relative to sham pigs). Multiple regression analysis with dummy variables was used to evaluate the relative changes in natriuretic peptides and atrial pressures and the strongest correlation was found between BNP and left atrial pressure with R,2=0.81. Termination of pacing resulted in rapid normalization of ANP values in spite of persistent elevations in atrial pressures. This may reflect an increased metabolism or an attenuated secretory response of ANP to atrial stretch with established heart failure. In conclusion, 3 weeks of rapid pacing induced significant increases in atrial pressures and natriuretic peptide levels. All the natriuretic peptides correlated with atrial pressures with BNP appearing as a more sensitive marker of cardiac filling pressures than ANP and N-terminal proatrial natriuretic peptide. [source] Chronic erythropoietin treatment affects different molecular pathways of diabetic cardiomyopathy in mouseEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 9 2009N. Shushakova Abstract Background, Recent studies in mice experimental models with acute ischaemic injury revealed that erythropoietin (EPO) has numerous tissue-protective effects in the heart, brain and kidneys. We therefore explored the tissue-protective properties of chronic EPO treatment in an experimental model of the db/db mouse with diabetic heart injury. Material and methods, We randomly treated 11 db/db mice with placebo (saline), 0·4 ,g of the continuous erythropoietin receptor activator (CERA) per week (n = 11) or 1·2 ,g CERA per week (n = 11) for 14 weeks, and analysed cardiac tissue. The lower CERA dose was a non-haematologically effective dose, whereas the second increased the haematocrit. Results, Compared with mice in the placebo group, CERA-treated mice had a reduction in TGF-,1 and collagen I expression in cardiac tissue (P < 0·01 vs. higher dose CERA). In addition, an increased expression of the pro-survival intracellular pathway p-AKT was observed (P < 0·05 vs. higher dose CERA). The values for the lower C.E.R.A had an intermediate nonsignificant effect. Furthermore, we were able to show that atrial natriuretic peptide (ANP) expression was increased in both CERA groups. Conclusions, Chronic treatment with CERA protects cardiac tissue in diabetic animals, i.e. it inhibits molecular pathways of cardiac fibrosis, and the effects are dose-dependent. [source] Four peptide hormones decrease the number of human breast adenocarcinoma cellsEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 1 2005B. A. Vesely Abstract Background, A family of six hormones, i.e. atrial natriuretic peptide, brain natriuretic peptide, C-natriuretic peptide, long-acting natriuretic peptide, vessel dilator, and kaliuretic peptide's main known biologic properties are sodium and water excreting and blood pressure lowering. Methods and materials, These six hormones, each at their 1-µm concentrations, were evaluated for their ability to decrease the number and/or proliferation of breast adenocarcinoma cells in culture for 24, 48, 72, and 96 h. Results, Within 24 h, vessel dilator, long-acting natriuretic peptide, kaliuretic peptide, atrial natriuretic peptide and 8-bromo-cyclic GMP, a cell-permeable analogue of their intracellular mediator cyclic GMP (each at 1 µm), decreased the number of breast adenocarcinoma cells 60%, 31%, 27%, 40%, and 31%, respectively. There was no proliferation in the 3 days following this decrease in breast adenocarcinoma cell number. These same hormones decreased DNA synthesis 69% to 85% (P < 0·001). Brain natriuretic peptide and CNP did not decrease the number of breast adenocarcinoma cells or inhibit their DNA synthesis. Vessel dilator, long-acting natriuretic peptide, kaliuretic peptide and 8-bromo-cyclic GMP (each at 1 µM) decreased the number of cells in the S phase of the cell cycle by 62%, 33%, 50%, and 39%, respectively (all P < 0·05). Natriuretic peptide receptors-A and -C were present in the breast adenocarcinoma cells. Conclusions, Four peptide hormones significantly decrease the number of human breast adenocarcinoma cells within 24 h and inhibit the proliferation of these cells for at least 96 h. Their mechanism of doing so involves inhibition of DNA synthesis and a decrease in cells in the S phase of the cell cycle mediated in part by cyclic GMP. [source] Neuroendocrine pathways of addictive behaviourADDICTION BIOLOGY, Issue 3-4 2004F Kiefer Alcohol intake is known to modulate plasma concentrations of neuroendocrine peptides. However, recent results suggest that the endocrine system may not only respond passively to alcohol intake but that, vice versa, it also actively modulates alcohol intake behaviour. The most coherent body of data concerns the hypothalamo,-,pituitary,-,adrenocortical (HPA) axis, with low corticotrophin-releasing hormone (CRH) being associated with more intense craving and increased probability of relapse after acute detoxification. Leptin, ,-endorphin and atrial natriuretic peptide (ANP), which indirectly regulate the HPA system, also may modulate the intensity of craving or the intensity of the alcohol withdrawal syndrome. Although most of the currently available data demonstrate association rather than causality between neuroendocrine changes and alcohol-related behaviours, they do provide testable hypotheses and open up perspectives of treating alcohol dependence via manipulation of the neuroendocrine axis. [source] Central nitric oxide blocks vasopressin, oxytocin and atrial natriuretic peptide release and antidiuretic and natriuretic responses induced by central angiotensin II in conscious ratsEXPERIMENTAL PHYSIOLOGY, Issue 5 2007Wagner Luis Reis The presence of nitric oxide synthase (NOS), the enzyme that catalyses the formation of nitric oxide (NO), in the circumventricular organs and magnocellular neurones suggests an important role of NO in the modulation of vasopressin (AVP) and oxytocin (OT) release. Intracerebroventricular (i.c.v.) injection of angiotensin II (Ang II) stimulates the release of AVP, OT and atrial natriuretic peptide (ANP), with the resultant antidiuretic and natriuretic effects. This study investigated the interaction between nitrergic and angiotensinergic pathways on the release of AVP, OT and ANP and on urinary volume and sodium excretion in water-loaded rats. Unanaesthetized, freely moving, male Wistar rats received two water loads followed by an injection into the lateral ventricle of an inhibitor of NOS (l -NAME), a NO donor [3-morpholinylsydnoneimine chloride (SIN-1) or S -nitroso- N -acetyl penicillamine (SNAP)] or vehicle (isotonic saline) and, 20 min after, they received a second i.c.v. injection of Ang II or vehicle. Injections of l -NAME or Ang II produced an increase in plasma levels of AVP, OT and ANP, a reduction in urinary volume and an increase in sodium excretion. Pretreatment with l -NAME enhanced the Ang II-induced increase in AVP, OT and ANP release, as well as the antidiuresis and natriuresis. Injection of SIN-1 or SNAP did not modify hormonal plasma levels and urinary parameters. In contrast SNAP blocked the AVP, OT and ANP release, as well as antidiuretic and natriuretic responses induced by ANG-II. Thus, the central nitrergic system can act to inhibit AVP, OT and ANP secretion and the antidiuretic and natriuretic effects in response to Ang II. [source] Homologous desensitization of guanylyl cyclase A, the receptor for atrial natriuretic peptide, is associated with a complex phosphorylation patternFEBS JOURNAL, Issue 11 2010Juliane Schröter Atrial natriuretic peptide (ANP), via its guanylyl cyclase A (GC-A) receptor and intracellular guanosine 3,,5,-cyclic monophosphate production, is critically involved in the regulation of blood pressure. In patients with chronic heart failure, the plasma levels of ANP are increased, but the cardiovascular actions are severely blunted, indicating a receptor or postreceptor defect. Studies on metabolically labelled GC-A-overexpressing cells have indicated that GC-A is extensively phosphorylated, and that ANP-induced homologous desensitization of GC-A correlates with receptor dephosphorylation, a mechanism which might contribute to a loss of function in vivo. In this study, tandem MS analysis of the GC-A receptor, expressed in the human embryonic kidney cell line HEK293, revealed unambiguously that the intracellular domain of the receptor is phosphorylated at multiple residues: Ser487, Ser497, Thr500, Ser502, Ser506, Ser510 and Thr513. MS quantification based on multiple reaction monitoring demonstrated that ANP-provoked desensitization was accompanied by a complex pattern of receptor phosphorylation and dephosphorylation. The population of completely phosphorylated GC-A was diminished. However, intriguingly, the phosphorylation of GC-A at Ser487 was selectively enhanced after exposure to ANP. The functional relevance of this observation was analysed by site-directed mutagenesis. The substitution of Ser487 by glutamate (which mimics phosphorylation) blunted the activation of the GC-A receptor by ANP, but prevented further desensitization. Our data corroborate previous studies suggesting that the responsiveness of GC-A to ANP is regulated by phosphorylation. However, in addition to the dephosphorylation of the previously postulated sites (Ser497, Thr500, Ser502, Ser506, Ser510), homologous desensitization seems to involve the phosphorylation of GC-A at Ser487, a newly identified site of phosphorylation. The identification and further characterization of the specific mechanisms involved in the downregulation of GC-A responsiveness to ANP may have important pathophysiological implications. Structured digital abstract ,,MINT-7713870, MINT-7713887: PMCA (uniprotkb:P20020) and GC-A (uniprotkb:P18910) colocalize (MI:0403) by fluorescence microscopy (MI:0416) [source] Atrial natriuretic peptide-dependent photolabeling of a regulatory ATP-binding site on the natriuretic peptide receptor-AFEBS JOURNAL, Issue 21 2005Simon Joubert The natriuretic peptide receptor-A (NPR-A) is composed of an extracellular ligand-binding domain, a transmembrane-spanning domain, a kinase homology domain (KHD) and a guanylyl cyclase domain. Because the presence of ATP or adenylylimidodiphosphate reduces atrial natriuretic peptide (ANP) binding and is required for maximal guanylyl cyclase activity, a direct interaction of ATP with the receptor KHD domain is plausible. Therefore, we investigated whether ATP interacts directly with a binding site on the receptor by analyzing the binding of a photoaffinity analog of ATP to membranes from human embryonic kidney 293 cells expressing the NPR-A receptor lacking the guanylyl cyclase moiety (,GC). We demonstrate that this receptor (NPR-A-,GC) can be directly labeled by 8-azido-3,-biotinyl-ATP and that labeling is highly increased following ANP treatment. The mutant receptor ,KC, which does not contain the KHD, is not labeled. Photoaffinity labeling of the NPR-A-,GC is reduced by 50% in the presence of 550 µm ATP, and competition curve fitting studies indicate a Hill slope of 2.2, suggestive of cooperative binding. This approach demonstrates directly that the interaction of ANP with its receptor modulates the binding of ATP to the KHD, probably through a conformational change in the KHD. In turn, this conformational change is essential for maximal activity. In addition, the ATP analog, 8-azido-adenylylimidodiphosphate, inhibits guanylyl cyclase activity but increases ANP binding to the extracellular domain. These results suggest that the KHD regulates ANP binding and guanylyl cyclase activity independently. [source] Vascular and renal actions of brain natriuretic peptide in man: physiology and pharmacologyFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2005Alphons J.H.M. Houben Abstract During the last decade brain natriuretic peptide (BNP) has received increasing attention as a potential marker of cardiovascular disease. BNP may act as a compensating mechanism in cardiovascular diseases in order to reduce preload. However, the increase in endogenous BNP is often not sufficient to compensate for volume overload in diseases like established hypertension and heart failure. The reported hemodynamic and renal effects of BNP in man differ largely between studies, because of differences in design and doses of BNP employed. In the pharmacological range, BNP has clear blood pressure and afterload lowering effects, and in the kidney blood flow and filtration is increased with concomitant natriuresis and diuresis. While in the physiological range BNP does not affect blood pressure and reduces preload only, and induces natriuresis/diuresis without changes in renal blood flow and filtration. There is increasing evidence from vascular studies that BNP preferentially acts on the venous system resulting in preload reduction, in contrast to atrial natriuretic peptide which acts preferentially on the arterial system to reduce afterload. This review summarizes our current understanding of BNP, and discuss its regulation and mechanisms of action on the vasculature and the kidneys. [source] Impulse conduction and gap junctional remodelling by endothelin-1 in cultured neonatal rat ventricular myocytesJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 3 2009Y. Reisner Abstract Endothelin-1 (ET-1) is an important contributor to ventricular hypertrophy and failure, which are associated with arrhythmogenesis and sudden death. To elucidate the mechanism(s) underlying the arrhythmogenic effects of ET-1 we tested the hypothesis that long-term (24 hrs) exposure to ET-1 impairs impulse conduction in cultures of neonatal rat ventricular myocytes (NRVM). NRVM were seeded on micro-electrode-arrays (MEAs, Multi Channel Systems, Reutlingen, Germany) and exposed to 50 nM ET-1 for 24 hrs. Hypertrophy was assessed by morphological and molecular methods. Consecutive recordings of paced activation times from the same cultures were conducted at baseline and after 3, 6 and 24 hrs, and activation maps for each time period constructed. Gap junctional Cx43 expression was assessed using Western blot and confocal microscopy of immunofluorescence staining using anti-Cx43 antibodies. ET-1 caused hypertrophy as indicated by a 70% increase in mRNA for atrial natriuretic peptide (P < 0.05), and increased cell areas (P < 0.05) compared to control. ET-1 also caused a time-dependent decrease in conduction velocity that was evident after 3 hrs of exposure to ET-1, and was augmented at 24 hrs, compared to controls (P < 0.01). ET-1 increased total Cx43 protein by ,40% (P < 0.05) without affecting non- phosphorylated Cx43 (NP-Cx43) protein expression. Quantitative confocal microscopy showed a ,30% decrease in the Cx43 immunofluorescence per field in the ET-1 group (P < 0.05) and a reduced field stain intensity (P < 0.05), compared to controls. ET-1-induced hypertrophy was accompanied by reduction in conduction velocity and gap junctional remodelling. The reduction in conduction velocity may play a role in ET-1 induced susceptibility to arrhythmogenesis. [source] N-terminal atrial natriuretic peptide and left ventricular geometry and function in a population sample of elderly malesJOURNAL OF INTERNAL MEDICINE, Issue 6 2000J. Ärnlöv Abstract. Ärnlöv J, Lind L, Stridsberg M, Andrén B, Lithell H (University of Uppsala, Sweden). N-terminal atrial natriuretic peptide and left ventricular geometry and function in a population sample of elderly males. J Intern Med 2000; 247: 699,708. Objectives. To investigate the relationships between N-terminal atrial natriuretic peptide (N-ANP) and left ventricular geometry and function. Design. A cross-sectional study of a population-based cohort. Setting. Follow-up of a health survey in Uppsala county, Sweden. Subjects., Two hundred and five men aged 70. Main outcome measures. A Delfia sandwich immunoassay was used to measure the plasma levels of N-ANP. M-mode and Doppler echocardiographic examinations were used to measure left ventricular dimensions, mass, geometry and systolic function and to classify the subjects into four groups (normal geometry, concentric remodelling, concentric hypertrophy or eccentric hypertrophy). Left ventricular systolic dysfunction was defined as a left ventricular ejection fraction , 0.40. Results. Plasma levels of N-ANP were significantly increased in subjects with left ventricular dysfunction compared to healthy subjects (702 ± 486, n = 14 vs. 277 ± 201 pmol L,1, n = 118, P < 0.0001), but there was a great overlap between the groups. N-ANP differed significantly between the four different left ventricular geometric groups (P = 0.02) with the highest N-ANP levels in the subjects with left ventricular eccentric hypertrophy (n = 40). However, N-ANP levels were no longer significantly associated with left ventricular geometry when taking the ejection fraction into account. Conclusions. This study showed that N-ANP levels were significantly elevated in subjects with left ventricular dysfunction, as well as in subjects with left ventricular hypertrophy. However, the increase in N-ANP seen in the eccentric hypertrophy group was mainly due to a decreased ejection fraction. [source] The cyclic GMP-protein kinase G pathway regulates cytoskeleton dynamics and motility in astrocytesJOURNAL OF NEUROCHEMISTRY, Issue 1 2007Mariela Susana Borįn Abstract We have previously demonstrated that inflammatory compounds that increase nitric oxide (NO) synthase expression have a biphasic effect on the level of the NO messenger cGMP in astrocytes. In this work, we demonstrate that NO-dependent cGMP formation is involved in the morphological change induced by lipopolysaccharide (LPS) in cultured rat cerebellar astroglia. In agreement with this, dibutyryl-cGMP, a permeable cGMP analogue, and atrial natriuretic peptide, a ligand for particulate guanylyl cyclase, are both able to induce process elongation and branching in astrocytes resulting from a rapid, reversible and concentration-dependent redistribution of glial fibrillary acidic protein (GFAP) and actin filaments without significant change in protein levels. These effects are also observed in astrocytes co-cultured with neurons. The cytoskeleton rearrangement induced by cGMP is prevented by the specific protein kinase G inhibitor Rp-8Br-PET-cGMPS and involves downstream inhibition of RhoA GTPase since is not observed in cells transfected with constitutively active RhoA. Furthermore, dibutyryl-cGMP prevents RhoA-membrane association, a step necessary for its interaction with effectors. Stimulation of the cGMP-protein kinase G pathway also leads to increased astrocyte migration in an in vitro scratch-wound assay resulting in accelerated wound closure, as seen in reactive gliosis following brain injury. These results indicate that cGMP-mediated pathways may regulate physio-pathologically relevant responses in astroglial cells. [source] Expression of brain natriuretic peptide in the rat heart studies during heart growth and in relation to sympathectomyMICROSCOPY RESEARCH AND TECHNIQUE, Issue 1 2004Magnus Hansson Abstract Brain natriuretic peptide (BNP) might be of importance during heart development and is described to be increasingly expressed in congestive heart failure and to affect the progress of this condition. However, details in the normal expression of BNP are still unclear in various parts of the adult and growing heart, including the conduction system. In this study, we investigated the expression of BNP in relation to that of atrial natriuretic peptide (ANP) in the growing as well as in the adult rat heart. The effects of chemical sympathectomy in adult rats were also examined. Contrary to previous BNP immunohistochemical studies, the BNP antiserum was preabsorbed with an excess of ANP before staining to abolish the crossreactivity with ANP. There was a pronounced BNP immunoreaction in the auricles, the trabeculated ventricular walls, and the peripheral parts of the conduction system at 0,1 days postnatally. The degree of immunoreaction gradually decreased with increasing age. A similar developmental pattern was seen concerning ANP expression, but the magnitude of the latter clearly exceeded that for BNP. Immunoreaction for BNP was never detected in the atrioventricular (AV) node and AV bundle at any stage. In contrast to the situation for ANP previously observed, no obvious changes in BNP immunoreaction patterns were observed in response to sympathectomy. This is the first study to thoroughly demonstrate the expression of BNP in the various regions of the rat heart during growth and in the normal and sympathectomized adult stage. The observations are related to possible functions of natriuretic peptides in the growing and adult heart. Microsc. Res. Tech. 64:30,42, 2004. © 2004 Wiley-Liss, Inc. [source] Natriuretic peptides in relation to the cardiac innervation and conduction systemMICROSCOPY RESEARCH AND TECHNIQUE, Issue 5 2002Magnus HanssonArticle first published online: 10 SEP 200 Abstract During the past two decades, the heart has been known to undergo endocrine action, harbouring peptides with hormonal activities. These, termed "atrial natriuretic peptide (ANP)," "brain natriuretic peptide (BNP)," and "C-type natriuretic peptide (CNP)," are polypeptides mainly produced in the cardiac myocardium, where they are released into the circulation, producing profound hypotensive effects due to their diuretic, natriuretic, and vascular dilatory properties. It is, furthermore, well established that cardiac disorders such as congestive heart failure and different forms of cardiomyopathy are combined with increased expression of ANP and BNP, leading to elevated levels of these peptides in the plasma. Besides the occurrence of natriuretic peptides (NPs) in the ordinary myocardium, the presence of ANP in the cardiac conduction system has been described. There is also evidence of ANP gene expression in nervous tissue such as the nodose ganglion and the superior cervical ganglion of the rat, ganglia known to be involved in the neuronal regulation of the heart. Furthermore, in the mammalian heart, ANP appears to affect the cardiac autonomic nervous system by sympathoinhibitory and vagoexcitatory actions. This article provides an overview of the relationship between the cardiac conduction system, the cardiac innervation and NPs in the mammalian heart and provides data for the concept that ANP is also involved in neuronal cardiac regulation. Microsc. Res. Tech. 58:378,386, 2002. © 2002 Wiley-Liss, Inc. [source] The Influence of Left Ventricle Diastolic Function on Natriuretic Peptides Levels in Patients with Atrial FibrillationPACING AND CLINICAL ELECTROPHYSIOLOGY, Issue 6 2009DAWID BAKOWSKI M.D., Ph.D. Background:The diagnosis of the impaired left ventricle (LV) diastolic function during atrial fibrillation (AF) using traditional methods is very difficult. Natriuretic peptides seem to be useful for assessment of diastolic function in patients with AF. Aim:To evaluate the influence of LV diastolic dysfunction on natriuretic peptides concentrations and to assess the diagnostic value of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in patients with AF and impaired LV diastolic function. Methods:The study included 42 patients (23 males, 19 females), aged 58.6 ± 8.2 years with nonvalvular persistent AF with preserved LV systolic function who were converted into sinus rhythm by DC cardioversion (CV) and maintained sinus rhythm for at least 30 days. Echocardiography (ECG), ANP, and BNP level measurements were taken at baseline 24 hours before CV and 24 hours and 30 days after CV. On the 30th day following CV in patients with sinus rhythm, Doppler ECG was performed to assess LV diastolic function. Results:Thirty days after CV, normal LV diastolic function in 15 patients and impaired diastolic function in 27 patients was diagnosed: 20 with impaired LV relaxation and seven with impaired LV compliance. During AF and 24 hours, and 30 days after sinus rhythm restoration, significantly higher ANP and BNP levels were observed in patients with LV diastolic dysfunction as compared to the subgroup with normal LV diastolic function. The average values of ANP during AF in patients with normal and impaired diastolic function were 167.3 ± 70.1 pg/mL and 298.7 ± 83.6 pg/mL, respectively (P < 0.001), and the average values of BNP in the above mentioned subgroups were 49.5 ± 14.7 pg/mL and 145.6 ± 49.6 pg/mL respectively (P < 0.001). While comparing the diagnostic value of both natriuretic peptides it was noted that BNP was a more specific and sensitive marker of impaired LV diastolic function. ANP value >220.7 pg/mL measured during AF identified patients with impaired LV diastolic function with 85% sensitivity and 90% specificity. BNP value >74.7 pg/mL proved 95% sensitive and 100% specific in the diagnosing of such a group. Conclusions:The increase of ANP/BNP concentration in patients with AF results not only from the presence of AF, but also reflects the impaired LV diastolic function. Natriuretic peptides, especially BNP, may be useful in diagnosing LV diastolic dysfunction in patients with AF. [source] Vascular amyloid of unknown origin and senile transthyretin amyloid in the lung and gastrointestinal tract of old age: Histological and immunohistochemical studiesPATHOLOGY INTERNATIONAL, Issue 5 2001Hironobu Matsutani The histological and immunohistochemical characteristics and the incidence of amyloid deposits in the tissues of the lung and gastrointestinal tract were investigated in 64 autopsied individuals who were 80 years and older (age range: 80,92 years; mean: 83.3 years). Immunohistochemical examination was performed with antibodies against amyloid A, transthyretin, immunoglobulin , and , light chain amyloid fibril proteins, ,2 -microglobulin, , protein, apolipoprotein AI, apolipoprotein AII, atrial natriuretic peptide, apolipoprotein E, and amyloid P component. Transthyretin amyloid fibril protein (ATTR) deposits were observed in five cases (7.8%). Gastrointestinal amyloid deposits of unknown origin were observed in the veins of the gastrointestinal tract in 26 cases (40.6%). This amyloid was regarded as portal amyloid with respect to distribution pattern. Pulmonary vascular amyloid deposits of unknown origin were observed in 12 cases (18.8%). These amyloid deposits were found mainly in medium-sized veins in the lungs and did not react with any antibodies against amyloid fibril proteins except apolipoprotein E and amyloid P component. Eleven of the 26 cases (42.3%) showing portal amyloid also showed pulmonary vascular amyloid of unknown origin. The pulmonary vascular amyloid deposits were similar to the portal amyloid deposits with respect to their morphological features and their relation to elastic fibers in the vessels. Further morphological investigation and biochemical analysis of the pulmonary vascular amyloid and portal amyloid will resolve questions of their origins and relation. [source] Effects of atrial natriuretic peptide on the extrasplenic microvasculature and lymphatics in the rat in vivoTHE JOURNAL OF PHYSIOLOGY, Issue 1 2005Zoė L. S. Brookes We developed a novel model using fluorescent intravital microscopy to study the effect of atrial natriuretic peptide (ANP) on the extrasplenic microcirculation. Continuous infusion of ANP into the splenic artery (10 ng min,1 for 60 min) of male Long,Evans rats (220,250 g, n= 24) induced constriction of the splenic arterioles after 15 min (,7.2 ± 6.6% from baseline diameter of 96 ± 18.3 ,m, mean ±s.e.m.) and venules (,14.4 ± 4.0% from 249 ± 25.8 ,m; P < 0.05). At the same time flow did not change in the arterioles (from 1.58 ± 0.34 to 1.27 ± 0.27 ml min,1), although it decreased in venules (from 1.67 ± 0.23 to 1.15 ± 0.20 ml min,1) and increased in the lymphatics (from 0.007 ± 0.001 to 0.034 ± 0.008 ml min,1; P < 0.05). There was no significant change in mean arterial pressure (from 118 ± 5 to 112 ± 5 mmHg). After continuous ANP infusion for 60 min, the arterioles were dilated (108 ± 16 ,m, P < 0.05) but the venules remained constricted (223 ± 24 ,m). Blood flow decreased in both arterioles (0.76 ± 0.12 ml min,1) and venules (1.03 ± 0.18 ml min,1; P < 0.05), but was now unchanged from baseline in the lymphatics (0.01 ± 0.001 ml min,1). This was accompanied by a significant decrease in MAP (104 ± 5 mmHg; P < 0.05). At 60 min, there was macromolecular leak from the lymphatics, as indicated by increased interstitial fluorescein isothiocyanate,bovine serum albumin fluorescence (grey level: 0 = black; 255 = white; from 55.8 ± 7.6 to 71.8 ± 5.9, P < 0.05). This study confirms our previous proposition that, in the extrasplenic microcirculation, ANP causes greater increases in post- than precapillary resistance, thus increasing intrasplenic capillary hydrostatic pressure (Pc) and fluid efflux into the lymphatic system. Longer-term infusion of ANP also increases Pc, but this is accompanied by increased ,permeability' of the extrasplenic lymphatics, such that fluid is lost to perivascular third spaces. [source] Effects of Natriuretic Peptides on Intracavernous Pressure and Blood Pressure in Conscious RatsTHE JOURNAL OF SEXUAL MEDICINE, Issue 10 2008Naoki Aizawa PhD ABSTRACT Introduction., Natriuretic peptides activate particulate guanylyl cyclases and have been shown to induce penile erection in rats, rabbits, and humans. Aim., We investigated the effects of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) on intracavernous pressure (ICP) and systemic blood pressure (BP) in conscious, free-moving rats. Methods., ICP and BP were measured in male Sprague,Dawley rats after catheters were inserted into the crus corpus cavernosum and carotid artery, respectively. Natriuretic peptides were given by intravenous bolus (3, 10, and 30 nmol/kg) or continuous (0.1 and 1 nmol/kg/minute) administration. Main Outcome Measures., The number of animals with increases in ICP were determined. Amplitudes and durations of ICP responses and changes in BP were also evaluated. Results., More animals had multiple transient increases of ICP in response to ANP and BNP than to CNP. The increases in ICP were transient and appeared to be an "all or none" response. ANP and BNP decreased BP more than CNP, especially with bolus administration. Conclusions., These findings show that in rats, erectile responses can be initiated by ANP, BNP, and less effectively, by CNP. ANP and BNP have a high affinity for the natriuretic peptide receptor-A, suggesting that this receptor is involved in the responses. Aizawa N, Ishizuka O, Ogawa T, Mizusawa H, Igawa Y, Nishizawa O, and Andersson K-E. Effects of natriuretic peptides on intracavernous pressure and blood pressure in conscious rats. J Sex Med 2008;5:2312,2317. [source] Biological Activity of Endogenous Atrial Natriuretic Peptide During Cardiopulmonary BypassARTIFICIAL ORGANS, Issue 10 2000Nobuhiko Hayashida Abstract: To evaluate the effect of cardiopulmonary bypass (CPB) on atrial natriuretic peptide (ANP) biological activity in patients undergoing cardiac operations, we conducted a prospective study. Ten patients undergoing mitral valve surgery were enrolled. Plasma levels of ANP and cyclic guanosine monophosphate (cGMP), hemodynamic variables, and renal function parameters were assessed perioperatively. The molar ratio of cGMP to ANP (as a marker for ANP biological activity) decreased significantly (p < 0.05) during CPB despite similar plasma ANP levels. The ratio correlated inversely with the duration of CPB (r = ,0.85, p = 0.002). The ratio also correlated with fractional sodium excretion (r = 0.65, p = 0.04) and correlated inversely with pulmonary vascular resistance (r = ,0.79, p = 0.009) and atrial filling pressure (r = ,0.84, p = 0.003) postoperatively. CPB decreased the molar ratio of cGMP to ANP, which may represent ANP biological activity, such as vasodilation and natriuresis. The phenomenon may contribute to water,sodium retention and pulmonary hypertension after cardiac surgery. [source] Mast cells, peptides and cardioprotection , an unlikely marriage?AUTONOMIC & AUTACOID PHARMACOLOGY, Issue 3 2009S. K. Walsh Summary 1,Mast cells have classically been regarded as the ,bad guys' in the setting of acute myocardial ischaemia, where their released contents are believed to contribute both to tissue injury and electrical disturbances resulting from ischaemia. Recent evidence suggests, however, that if mast cell degranulation occurs in advance of ischaemia onset, this may be cardioprotective by virtue of the depletion of mast cell contents that can no longer act as instruments of injury when the tissue becomes ischaemic. 2,Many peptides, such as ET-1, adrenomedullin, relaxin and atrial natriuretic peptide, have been demonstrated to be cardioprotective when given prior to the onset of myocardial ischaemia, although their physiological functions are varied and the mechanisms of their cardioprotective actions appear to be diverse and often ill defined. However, one common denominator that is emerging is the ability of these peptides to modulate mast cell degranulation, raising the possibility that peptide-induced mast cell degranulation or stabilization may hold the key to a common mechanism of their cardioprotection. 3,The aim of this review was to consolidate the evidence implying that mast cell degranulation could play both a detrimental and protective role in myocardial ischaemia, depending upon when it occurs, and that this may underlie the cardioprotective effects of a range of diverse peptides that exerts physiological effects within the cardiovascular system. [source] Metoprolol Treatment Lowers Thrombospondin-4 Expression in Rats with Myocardial Infarction and Left Ventricular HypertrophyBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 3 2010Erja Mustonen In this study, we characterised left ventricular thrombospondin-1 and -4 expression in rats treated with a beta-blocker metoprolol during the remodelling process in response to pressure overload and acute myocardial infarction. Left ventricular thrombospondin-1 and thrombospondin-4 mRNA levels increased 8.4-fold (p < 0.001) and 7.3-fold (p < 0.001) post-infarction, respectively. Metoprolol infusion by osmotic minipumps (1.5 mg/kg/hr) for 2 weeks after myocardial infarction decreased thrombospondin-1 and thrombospondin-4 mRNA levels (55% and 50%, respectively), improved left ventricular function, and attenuated left ventricular remodelling with reduction of left ventricular atrial natriuretic peptide and brain natriuretic peptide gene expression. Thrombospondin-1 and -4 mRNA levels correlated positively with echocardiographic parameters of left ventricular remodelling as well as with atrial natriuretic peptide and brain natriuretic peptide gene expression. Moreover, there was a negative correlation between left ventricular ejection fraction and thrombospondin-1 mRNA levels. In 12-month-old spontaneously hypertensive rats with left ventricular hypertrophy, metoprolol decreased left ventricular thrombospondin-4 levels and attenuated remodelling while thrombospondin-1, atrial natriuretic peptide and brain natriuretic peptide mRNA levels as well as left ventricular function remained unchanged. In metoprolol-treated spontaneously hypertensive rats, thrombospondin-4 gene expression correlated with parameters of left ventricular remodelling, while no correlations between thrombospondins and natriuretic peptides were observed. These results indicate that thrombospondin-1 expression is linked exclusively to left ventricular remodelling process post-infarction while thrombospondin-4 associates with myocardial remodelling both after myocardial infarction and in hypertensive heart disease suggesting that thrombospondins may have unique roles in extracellular matrix remodelling process. [source] Maternal pseudo primary hyperaldosteronism in twin-to-twin transfusion syndromeBJOG : AN INTERNATIONAL JOURNAL OF OBSTETRICS & GYNAECOLOGY, Issue 1 2007IL Gussi Objective, To monitor changes in the maternal renin,angiotensin,aldosterone system following laser therapy and amnioreduction in severe twin-to-twin transfusion syndrome (TTTS). Design, Observational prospective study. Setting, Single university hospital in Poissy, France. Population, Sixty cases of TTTS at 16,26 weeks of gestation. Method, Maternal blood sampling before, 6 and 24 hours following the procedure. Main outcome measures, Plasma levels of aldosterone, renin, angiotensin II (AII), atrial natriuretic peptide (ANP), vasopressin, sodium, potassium and plasma proteins together with full blood count were measured before, 6 and 24 hours following the procedure. Results, TTTS is associated with maternal hyperaldosteronism dissociated from renin,angiotensin changes. Correcting TTTS by placental surgery and amnioreduction triggers incomplete correction of hyperaldosteronism, as early as 6 hours following the procedure, without changes in AII but an increase in the levels of ANP in plasma. Electrolyte concentrations remained stable despite haemodilution, while vasoactive hormone levels such as that of vasopressin remained unchanged. Conclusion, Mechanisms involved in marked fluid retention in TTTS are rapidly corrected by laser therapy followed by amnioreduction while maintaining electrolyte homeostasis. [source] Reciprocal regulation of human soluble and particulate guanylate cyclases in vivoBRITISH JOURNAL OF PHARMACOLOGY, Issue 6 2006M Madhani Background & purpose: We demonstrated previously that reciprocal regulation of soluble (sGC) and particulate (pGC) guanylate cyclases by NO and natriuretic peptides coordinates cyclic cGMP-mediated vasodilatation in vitro. Herein, we investigated whether such an interaction contributes to vascular homeostasis in mice and humans in vivo. Experimental approach: Mean arterial blood pressure (MABP) changes in anaesthetized mice were monitored in response to i.v. administration of cGMP- and cAMP-dependent vasodilators in wild-type (WT), endothelial NO synthase (eNOS) and natriuretic peptide receptor (NPR)-A knockout mice. Forearm blood flow (FBF) in response to intra-brachial infusion of ANP (25, 50, 100, 200 pmol min -1) in the absence and presence of the NOS inhibitor NG -methyl-L-arginine (L-NMA; 4 ,mol min -1) and the control constrictor noradrenaline (240 pmol min -1) was assessed in healthy volunteers. Key results: Sodium nitroprusside (SNP; NO-donor) and atrial natriuretic peptide (ANP) produced dose-dependent reductions in MABP in WT animals that were significantly enhanced in eNOS KO mice. In NPR-A K mice, SNP produced a dose-dependent reduction in MABP that was significantly greater than that in WT mice. Responsiveness to the cAMP-dependent vasodilator epoprostenol was similar in WT, eNOS KO and NPR-A KO animals. ANP caused vasodilatation of the forearm resistance vasculature that was significantly greater in individuals lacking endothelium-derived NO (i.e. L-NMA treated). Conclusions & implications: These data demonstrate that crosstalk occurs between the NO-sGC and ANP-pGC pathways to regulate cGMP-dependent vasodilatation in vivo in both mice and humans. These findings have implications for understanding the link between natriuretic peptide activity and cardiovascular risk. British Journal of Pharmacology (2006) 149, 797,801. doi:10.1038/sj.bjp.0706920 [source] Notable effects of angiotensin II receptor blocker, valsartan, on acute cardiotoxic changes after standard chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisoloneCANCER, Issue 11 2005Hirohisa Nakamae M.D. Abstract BACKGROUND There are three distinct types of doxorubicin-induced cardiotoxicity (acute, chronic, and late-onset). Although previous studies with animal models suggest that angiotensin II plays a key role in the process of the doxorubicin-induced cardiotoxicity, there has been no such observation in humans. This randomized study investigated whether valsartan, a new class of angiotensin II receptor blocker (ARB), can inhibit acute cardiotoxicity after doxorubicin-based chemotherapy. METHODS Forty consecutive patients with untreated non-Hodgkin lymphoma who were scheduled to undergo standard chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) (mean age, 56 yrs; range, 24,70 yrs) were randomized with minimization methods to receive CHOP with or without 80 mg/day of valsartan. Acute cardiotoxicity was comprehensively evaluated with neurohumoral, echocardiographic, and electrocardiographic markers before and on Days 3, 5, and 7 after the initiation of CHOP. RESULTS CHOP induced transient increases in the left ventricular end-diastolic diameter in an echocardiogram, the QTc interval and QTc dispersion in an electrocardiogram, and in the plasma brain and atrial natriuretic peptides. All these changes returned to nearly normal levels within a week after CHOP (P < 0.001). Notably, valsartan significantly prevented all these changes except for the elevation in atrial natriuretic peptide (P < 0.05). No significant change was observed in blood pressure or heart rate between the valsartan and control groups. CONCLUSIONS The results indicate that angiotensin II may play an essential role in acute CHOP-induced cardiotoxicity in humans. Future long-term studies are necessary to judge whether ARBs have a potential to prevent the chronic or late-onset types of doxorubicin-induced cardiotoxicity. Cancer 2005. © 2005 American Cancer Society. [source] Downregulation of survival signalling pathways and increased apoptosis in the transition of pressure overload-induced cardiac hypertrophy to heart failureCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 11 2009Xiao-Mei Li Summary 1.,Transition from compensated left ventricular (LV) hypertrophy to decompensated heart failure was characterized using a pressure-overload induced model to elucidate the temporal relationship between cardiomyocyte apoptosis and survival signalling in this transition. 2.,Mice were subjected to transverse aortic constriction (TAC) or sham operation for 1,16 weeks and were studied by echocardiography, catheterization and histology. Relevant gene expression and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, Akt and glycogen synthase kinase (GSK)-3, were determined. 3.,Transverse aortic constriction resulted in myocyte hypertrophy and fibrosis from Week 4 and a progressive increase in left ventricular (LV) dimensions and wall thicknesses with maintained contractile function by Week 12. However, a sharp decline in contractile function and elevated LV end-diastolic pressure from 12 to 16 weeks were observed after TAC, indicating functional decompensation. 4.,Following TAC, mRNA levels of atrial natriuretic peptide, B-type natriuretic peptide, ,-myosin heavy chain (MHC) and transforming growth factor-,1 were increased time dependently, whereas mRNA expression of ,-MHC, sarcoplasmic/endoplasmic reticulum calcium ATPase 2a and Bcl-2 were decreased. The ratio of Bcl-2/Bax was decreased and this was consistent with progressively increased myocyte apoptosis demonstrated by terminal deoxyribonucleotidyl transferase-mediated dUTP,digoxigenin nick end-labelling staining. Phosphorylation of ERK1/2 was increased by Week 4, but decreased thereafter. Levels of phosphorylated Akt declined from Week 8, whereas GSK3, phosphorylation increased from 1 to 8 weeks, then decreased from Week 12 after TAC. 5.,In conclusion, TAC resulted in early concentric and late eccentric hypertrophy with eventual development of LV dysfunction. This transition was temporally associated with a progressive increase in cell size, fibrosis and myocyte apoptosis. Downregulation of ERK1/2, Akt and GSK3, and enhanced cardiomyocyte apoptosis are implicated as important mechanisms in the transition from compensated hypertrophy to heart failure. [source] | |||||||||||||||||||||||||||||||