UMLS:C0018801 - FACTA Search

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Query: UMLS:C0018801 (heart failure)
72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The myocardial Na(+)/H(+) exchanger isoform 1 (NHE-1) represents a major H(+) extrusion mechanism for intracellular pH (pH(i)) regulation especially during ischaemia and early reperfusion. Paradoxically, however, its activation contributes to induction of cell injury because Na(+)/H(+) exchange is coupled closely to elevations in intracellular [Ca(2+)] through the Na(+)/Ca(2+) exchanger. NHE-1 is exquisitely sensitive to intracellular acidosis but other factors may have also stimulatory effects via phosphorylation-dependent processes, like autocrine and paracrine agents as well as hormonal factors such as endothelin-1, angiotensin II and alpha-1-adrenoceptor agonists. In addition, phosphorylation-independent NHE-1 activation mechanisms are known, e.g. cell shrinkage. To date at least 8 NHE isoforms have been identified and designated as NHE-1-8. All, except NHE-6 and NHE-7, which are located intracellularly, are restricted to the sarcolemmal membrane. The NHE-1 subtype is the predominant isoform in the heart, but NHE-6 is also expressed in the heart. Newly developed, selective NHE-1 inhibitors possess potent cardioprotective properties. The efficacy of NHE-1 inhibitors in experimental studies with ischaemia/reperfusion has led to clinical trials for the evaluation of these agents in high-risk patients with coronary artery disease (GUARDIAN Trial) and acute myocardial infarction (ESCAMI Trial). The GUARDIAN trial demonstrated only for the coronary artery by-pass graft (CABG) patient population a reduction in the primary cardiovascular endpoint (death and reoccurring myocardial infarction). However, recent evidence also suggests that NHE-1 inhibition may be conducive to attenuation of remodelling processes after myocardial infarction, independently of infarct size reduction and blood pressure. In addition, in separate preclinical studies, the NHE-1 inhibitor cariporide also prevented and/or caused regression of age-related and hypertension-induced myocardial fibrosis and hypertrophy. NHE-1 inhibitors thus offer substantial promise for clinical development for attenuation of both a) acute responses to myocardial injury, b) chronic post-infarct and hypertension- and age-related responses resulting in the development of heart failure.
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PMID:NHE-1 inhibition: from protection during acute ischaemia/reperfusion to prevention/reversal of myocardial remodelling. 1450 89

Sodium/hydrogen exchange (NHE) inhibitors show promise as potential therapeutic agents for the treatment of heart failure, but it is not known whether they can reverse the maladaptive remodeling that results in heart failure. We sought to determine the effect of the NHE-1-specific inhibitor EMD-87580 (EMD) on heart failure produced by myocardial infarction in the rat and to assess whether up to 4 wk of treatment delay results in beneficial effects. Male Sprague-Dawley rats were subjected to coronary artery ligation (or a sham procedure) and followed for up to 3 mo, at which time hypertrophy and hemodynamics were determined. EMD was provided in the diet, and treatment commenced immediately or 2-4 wk after ligation. EMD significantly reduced hemodynamic abnormalities, including the elevation in left ventricular end-diastolic pressure, and diminished the loss of systolic function with all treatment protocols. Left ventricular dilatation and hypertrophy, as assessed by heart weight, cell size, and atrial natriuretic peptide (ANP) expression, were similarly reversed to sham or near-sham levels. In addition, the increased plasma ANP and pro-ANP values were reversed to levels not significantly different from sham. Surprisingly, virtually all beneficial effects were identical with all treatment protocols. These effects were observed in the absence of infarct size reduction or blood pressure-lowering effects. Our results suggest that NHE-1 inhibition attenuates and reverses postinfarction remodeling and heart failure with a treatment delay of up to 4 wk after infarction. The effect is independent of infarct size or afterload reduction, indicating a direct effect on the myocardium.
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PMID:Inhibition and reversal of myocardial infarction-induced hypertrophy and heart failure by NHE-1 inhibition. 1468 66

The mechanism by which Na+-H+ exchange (NHE) inhibition results in attenuation and reversal of postinfarction remodelling and heart failure remains controversial. In this study, we investigated the possible contribution of mitochondrial involvement by determining the effect of the NHE-1-specific inhibitor EMD-87580 (EMD) on mitochondrial permeability transition (MPT) and respiratory function during the postinfarction remodelling process. Male Sprague-Dawley rats were subjected to either 12 or 18 weeks of coronary artery ligation (CAL) or sham procedure. EMD was provided in the diet immediately after ligation. MPT pore opening was determined by perfusing hearts with 2-deoxy-[3H]-glucose ([3H]-DOG) and measurement of mitochondrial [3H]-DOG entrapment. The respiratory function of isolated mitochondria was measured using Clark-type oxygen electrode. Remodelling was associated with significant hypertrophy and there was an increase in MPT pore opening in hearts both 12 and 18 weeks following CAL. Mitochondrial respiratory function, especially state 2 and state 3 rates were significantly decreased in hearts subjected to CAL. EMD suppressed MPT pore opening by 40% (P <0.01) and 35% (P <0.01) 12 and 18 weeks after ligation, respectively. Mitochondria isolated from EMD treated hearts exhibited increased respiratory chain activity for oxidation of substrates at complex I and II. These beneficial effects of EMD were associated with decreased mitochondrial vulnerability to exogenous Ca2+. We conclude that NHE-1 inhibition has a protective effect on mitochondrial function, attenuating MPT pore opening and improving the respiratory function, which may contribute to the salutary effect of NHE-1 inhibitors in heart failure.
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PMID:NHE-1 inhibition improves impaired mitochondrial permeability transition and respiratory function during postinfarction remodelling in the rat. 1562 30

The major mechanism by which the heart cell regulates intracellular pH is the Na(+)-H(+) exchanger (NHE) with the NHE-1 isoform as the primary cardiac subtype. Although NHE-1 has been implicated in mediating ischemic injury, more recent evidence implicates the antiporter as a key mediator of hypertrophy, which is produced by various autocrine, paracrine and hormonal factors such as endothelin-1, angiotensin II, and alpha(1) adrenoceptor agonists. These agonists activate the antiporter via phosphorylation-dependent processes. NHE-1 inhibition is likely conducive to attenuating the remodelling process after myocardial infarction. These effects probably occur independently of infarct size reduction and involve attenuation of subsequent postinfarction heart failure. As such, inhibitors of NHE offer substantial promise for clinical development that will attenuate acute responses to myocardial postinfarction and chronic pos t infarction, which evolve toward heart failure. The regulation of NHE-1 is discussed as is its potential role in mediating cardiomyocyte hypertrophy.
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PMID:The cardiac Na-H exchanger: a key downstream mediator for the cellular hypertrophic effects of paracrine, autocrine and hormonal factors. 1567 30

1 We investigated the single vs the combined long-term inhibition of Na(+)-H(+) exchanger-1 (NHE-1) and ACE in rats with congestive heart failure induced by myocardial infarction (MI). 2 Rats with MI were randomized to receive either placebo, cariporide (3000 p.p.m. via chow), ramipril (1 mg kg(-1) day(-1) via drinking water) or their combination for 18 weeks starting on day 3 after surgery. 3 Cardiac morphology and function was assessed by echocardiography and by means of a 2.0 F conductance catheter to determine left ventricular (LV) pressure volume relationships. 4 MI for 18 weeks resulted in an increase in LV end-diastolic diameter (LVDed) in the placebo-treated group when compared to sham (placebo: 1.1+/-0.04 cm; sham: 0.86+/-0.01; P<0.05). Combined inhibition of NHE-1 and ACE, but not the monotherapies, significantly reduced LVDed (1.02+/-0.02 cm). 5 Preload recruitable stroke work (PRSW), dp/dt(max) (parameter of systolic function) and end-diastolic pressure volume relationship (EDPVR, diastolic function) were significantly impaired in placebo-treated MI group (PRSW: 39+/-7 mmHg; dp/dt(max): 5185+/-363 mmHg s(-1); EDPVR: 0.042+/-0.001 mmHg microl(-1); all P<0.05). Cariporide treatment significantly improved PRSW (64+/-7 mmHg), dp/dt(max) (8077+/-525 mmHg s(-1)) and EDPVR (0.026+/-0.014 mmHg microl(-1)), and reduced cardiac hypertrophy in rats with MI. Combined inhibition of NHE-1 and ACE had even a more pronounced effect on PRSW (72+/-5 mmHg) and EDPVR (0.026+/-0.014 mmHg microl(-1)), as well as cardiac hypertrophy that, however, did not reach statistical significance compared to cariporide treatment alone. 6 The NHE-1 inhibitor cariporide significantly improved LV remodeling and function in rats with congestive heart failure induced by MI. The effect of cariporide was comparable or tended to be stronger (e.g. systolic function) compared to ramipril. Combined treatment with cariporide and ramipril tended to be more effective on LV remodeling in rats with heart failure than the single treatments. Thus, inhibition of the NHE-1 may be a promising novel therapeutic approach for the treatment of congestive heart failure.
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PMID:Effects of combined inhibition of the Na+-H+ exchanger and angiotensin-converting enzyme in rats with congestive heart failure after myocardial infarction. 1615 39

The incidence and prevalence of heart failure (HF) has increased over the last decades. The main reasons for this increase are the ageing population and an increase in survival rate after myocardial infarction and other cardiovascular diseases. Although, pharmacotherapy has significantly improved survival, the prognosis of HF is still rather poor. Total mortality is high and approximately half of the deaths are sudden and unexpected. Angiotensin-converting-enzyme (ACE)-inhibitors generally given with diuretic and digoxin are the standard treatment for patients with HF. Despite the established benefits of ACE-inhibitors there is a need for new pharmacological tools for the treatment of HF. Recent experimental evidence has shown that activity of the Na(+)/H(+)-exchanger in the heart (NHE-1) is increased in HF. Because NHE-1 exchanges intracellular H(+) for extracellular Na(+) in a one by one stoichiometry, the intracellular ionic changes resulting from increased activity, will be a increased pH(i) and intracellular sodium ([Na(+)](i)). Activation of NHE-1 results only in a small increase in pH(i), under physiological conditions where bicarbonate-dependent mechanisms are active. However, a considerable increase in [Na(+)](i) was always present. The elevation of [Na(+)](i) might be responsible for the increase of intracellular calcium ([Ca(2+)](i)) levels mediated by the Na(+)/Ca(2+)-exchanger (NCX). Increases in [Na(+)](i), pH(i) and [Ca(2+)](i), features of cardiac myocytes isolated from failing hearts, are recognized as a cell growth signal And thus may play a role in the hypertrophic response, cellular remodeling and finally the development of HF. Acute application of cariporide, an inhibitor of NHE-1, on failing myocytes not only normalized [Na(+)](i) but also cytoplasmic and sarcoplasmic reticulum calcium handling and the propensity to develop delayed after depolarizations (DAD's). In several animal models of HF it has been shown the chronic inhibition of NHE-1 attenuates the development of hypertrophy and whole heart remodeling. Recently, in a volume and pressure overload model of HF in rabbits it has been demonstrated that chronic treatment also prevents the development of HF and cellular ionic and electrophysiological remodeling. Therefore, chronic treatment with an inhibitor of NHE-1 might prove beneficial in patients at risk of developing HF, especially when given at an early stage.
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PMID:Chronic inhibition of na(+)/h(+)-exchanger in the heart. 1647 74

Hypertrophic cardiomyocyte growth contributes substantially to the progression of heart failure. Activation of the plasma membrane Na+-H+ exchanger (NHE1) and Cl- -HCO3- exchanger (AE3) has emerged as a central point in the hypertrophic cascade. Both NHE1 and AE3 bind carbonic anhydrase (CA), which activates their transport flux, by providing H+ and HCO3-, their respective transport substrates. We examined the contribution of CA activity to the hypertrophic response of cultured neonatal and adult rodent cardiomyocytes. Phenylephrine (PE) increased cell size by 37 +/- 2% and increased expression of the hypertrophic marker, atrial natriuretic factor mRNA, twofold in cultured neonatal rat cardiomyocytes. Cell size was also increased in adult cardiomyocytes subjected to angiotensin II or PE treatment. These effects were associated with increased expression of cytosolic CAII protein and the membrane-anchored isoform, CAIV. The membrane-permeant CA inhibitor, 6-ethoxyzolamide (ETZ), both prevented and reversed PE-induced hypertrophy in a concentration-dependent manner in neonate cardiomyocytes (IC50=18 microm). ETZ and the related CA inhibitor methazolamide prevented hypertrophy in adult cardiomyocytes. In addition, ETZ inhibited transport activity of NHE1 and the AE isoform, AE3, with respective EC50 values of 1.2 +/- 0.3 microm and 2.7 +/- 0.3 microm. PE significantly increased neonatal cardiomyocyte Ca2+ transient frequency from 0.33 +/- 0.4 Hz to 0.77 +/- 0.04 Hz following 24 h treatment; these Ca2+ -handling abnormalities were completely prevented by ETZ (0.28 +/- 0.07 Hz). Our study demonstrates a novel role for CA in mediating the hypertrophic response of cardiac myocytes to PE and suggests that CA inhibition represents an effective therapeutic approach towards mitigation of the hypertrophic phenotype.
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PMID:Carbonic anhydrase inhibition prevents and reverts cardiomyocyte hypertrophy. 1712 62

In acute myocardial ischemia and in chronic heart failure, sympathetic activation with excessive norepinephrine (NE) release from and reduced NE reuptake into sympathetic nerve endings is a prominent cause of arrhythmias and cardiac dysfunction. The Na(+)/H(+) exchanger NHE1 is the predominant isoform in the heart. It contributes to cellular acid-base balance, and electrolyte, and volume homeostasis, and is activated in response to intracellular acidosis and/or activation of guanine nucleotide binding (G) protein-coupled receptors. NHE1 mediates its signaling via protein kinases A (PKA) or C (PKC). In cardiomyocytes, NHE1 is restricted to specialized membrane domains, where it regulates the activity of pH-sensitive proteins and modulates the driving force of the Na(+)/Ca(2+) exchanger. During acute ischemia/reperfusion and in heart failure the activity/amount of NHE1 is increased, leading to intracellular Ca(2+) overload and promoting structural (apoptosis, hypertrophy) and functional (arrhythmias, hypercontraction) myocardial damage. In sympathetic nerve endings, increased NHE1 activity results in the accumulation of axoplasmic Na(+) that diminishes the inward and/or favors the outward transport of NE via the neuronal norepinephrine transporter (NET). The increased NE levels within the nerve-muscle junction facilitate the sustained stimulation of myocardial alpha- and beta-adrenoceptors (ARs), which in turn aggravate the increases in myocardial NHE1 activity and the associated deleterious effects. Furthermore, the responsiveness of the beta-AR declines overtime, which results in further release of NE, initiating a vicious cycle. Accordingly, NHE1 is a potential candidate for targeted intervention to suppress this feedback loop.
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PMID:Regulation and role of the presynaptic and myocardial Na+/H+ exchanger NHE1: effects on the sympathetic nervous system in heart failure. 1761 35

Na-H exchange (NHE) is the primary process by which the cardiac cell extrudes protons particularly under conditions of intracellular acidosis. Nine isoforms of NHE have now been identified. Although these antiporters are expressed in virtually all tissues, cardiac cells posses primarily the ubiquitous NHE-1 subtype. It has been well established that NHE-1 is a major contributor to acute ischemic and reperfusion injury although it is now emerging that NHE-1 contributes to chronic maladaptive myocardial responses to injury such as post-infarction myocardial remodelling and likely contributes to the development of heart failure. Experimental studies using both in vitro approaches as well as animal models of heart failure have consistently demonstrated a beneficial effect of NHE-1 inhibitors in attenuating hypertrophy in response to various stimuli as well as inhibiting heart failure in a variety of animal models representing experimentally-induced or genetic models of heart failure. The beneficial effects of NHE-1 inhibitors occur independently of infarct size reduction or on any direct effects on afterload thus implicating a direct antiremodelling influence of these agents. It is proposed that NHE-1 inhibition represents a potentially effective new therapeutic approach for the treatment of heart failure.
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PMID:The role of NHE-1 in myocardial hypertrophy and remodelling. 1832 39

Connexin 43, the major connexin isoform in gap junctions of cardiac ventricular myocytes, undergoes changes in distribution and expression in cardiac diseases. The Na(+)-H(+) exchanger (NHE-1), a key mediator of hypertrophy and heart failure, has been shown to be localized in the cardiomyocyte gap junctional regions; however, whether NHE-1 regulates gap junction proteins in the hypertrophied cardiomyocyte is not known. To address this question, neonatal rat ventricular myocytes were treated with phenylephrine (PE) for 24 h to induce hypertrophy. Increased Cx43 expression observed with PE treatment (132.4 +/- 6.3% compared to control; P < 0.05) was further significantly augmented by the specific NHE-1 inhibitor EMD87580 [N-[2-methyl-4,5-bis(methylsulfonyl)-benzoyl]-guanidine hydrochloride] (173.2 +/- 8.7% increase compared to control; P < 0.05 versus PE), an effect that was mimicked by another NHE-1 inhibitor cariporide [4-isopropyl-3-(methylsulfonyl)benzoyl-guanidine methanesulfonate]. PE-induced hypertrophy was associated with mitogen-activated protein kinase c-Jun NH(2)-terminal kinase (JNK) 1/2 activation, whereas inhibition of JNK1/2 with either SP600125 [anthra(1,9-cd)pyrazol-6(2H)-one 1,9-pyrazoloanthrone] or small interfering RNA significantly increased PE-induced up-regulation of Cx43 protein levels. Inhibition of reverse mode Na(+)-Ca(2+) exchange (NCX) with KB-R7943 [2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea mesylate] partially reversed JNK1/2 activation (195.2 +/- 21.4 versus 143.7 +/- 14.4% with KB-R7943; P < 0.05) and augmented up-regulation of Cx43 protein (121.1 +/- 8.3 versus 215.9 +/- 25.6% with KB-R7943; P < 0.05) in the presence of PE. Our results demonstrate that NHE-1 negatively regulates Cx43 protein expression in PE-induced cardiomyocyte hypertrophy via a JNK1/2-dependent pathway, which is probably activated by reverse mode NCX activity.
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PMID:Sodium hydrogen exchange 1 (NHE-1) regulates connexin 43 expression in cardiomyocytes via reverse mode sodium calcium exchange and c-Jun NH2-terminal kinase-dependent pathways. 1865 Feb 45

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