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)

A major mechanism by which the heart adapts to intracellular acidosis during ischemia and recovers from the acidosis after reperfusion is through the sodium-hydrogen exchanger (NHE). There are at least 5 NHE isoforms thus-far identified with the NHE-1 subtype representing the major one found in the mammalian myocardium. This 110 kDa glycoprotein extrudes protons concomitantly with Na influx in a 1:1 stoichiometric relationship rendering the process electroneutral. Although NHE is critical for the maintenance of intracellular pH during acid loading conditions such as ischemia, there is convincing evidence that it also plays a pivotal role in mediating tissue injury during ischemia and reperfusion. The mechanism for this paradoxical deleterious role of NHE reflects the fact that under conditions of tissue stress, including ischemia, Na-K adenosine triphosphate (ATP)ase is inhibited thereby limiting Na extrusion resulting in an elevation in intracellular Na concentrations. The latter effect, in turn, will increase intracellular Ca concentrations via Na-Ca exchange. In addition, NHE-1 expression in the diseased myocardium is increased suggesting that elevated production of the antiporter represents a long-term adaptive process in an attempt by the cardiac cell to regulate intracellular pH which, paradoxically, contributes to cardiac pathology. Extensive studies using NHE inhibitors such as amiloride or its analogs, or more specific compounds including 3-methylsulphonyl-4-piperidinoloenzoyl-guanidine methanesulphonate (HOE 694) or 4-isopropyl-3-methylsulphonylbenzcyl-guanidine methane sulphonate (HOE 642) have consistently shown protective effects against ischemic and reperfusion injury in a large variety of experimental models and animal species particularly in terms of attenuating contractile dysfunction. Such studies have contributed greatly to the overwhelming evidence that NHE activation mediates ischemic and reperfusion injury. Indeed, HOE 642 (Cariporide) is currently undergoing clinical evaluation in high risk cardiac patients. Moreover, there is now emerging evidence that NHE may be involved in mediating cardiotoxicity directly produced by various ischemic metabolites such as lipid amphiphiles or reactive oxygen species. In this regard, we have demonstrated that NHE inhibitors can effectively attenuate the cardiac injury produced by lysophosphatidylcholine and hydrogen peroxide. In addition, it now appears that NHE inhibition reduces apoptosis in the ischemic myocardium, a process which may be of importance in the subsequent development of postinfarction heart failure. In conclusion, NHE represents an important adaptive process in response to intracellular acidosis resulting in a paradoxical contribution to cardiac tissue injury.
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PMID:The myocardial sodium-hydrogen exchanger (NHE) and its role in mediating ischemic and reperfusion injury. 965 15

The Na(+)-H(+) exchange (NHE) is a major mechanism by which the heart adapts to intracellular acidosis during ischemia and recovers from the acidosis after reperfusion. There are at least 6 NHE isoforms thus far identified with the NHE1 subtype representing the major one found in the mammalian myocardium. This 110-kDa glycoprotein extrudes protons concomitantly with Na(+) influx in a 1:1 stoichiometric relationship rendering the process electroneutral, and its activity is regulated by numerous factors, including phosphorylation-dependent processes. There is convincing evidence that NHE mediates tissue injury during ischemia and reperfusion, which probably reflects the fact that under conditions of tissue stress, including ischemia, Na(+)-K(+) ATPase is inhibited, thereby limiting Na(+) extrusion, resulting in an elevation in [Na(+)](i). The latter effect, in turn, will increase [Ca(2+)](i) via Na(+)-Ca(2+) exchange. In addition, NHE1 mRNA expression is elevated in response to injury, which may further contribute to the deleterious consequence of pathological insult. Extensive studies using NHE inhibitors have consistently shown protective effects against ischemic and reperfusion injury in a large variety of experimental models and has led to clinical evaluation of NHE inhibition in patients with coronary artery disease. Emerging evidence also implicates NHE1 in other cardiac disease states, and the exchanger may be particularly critical to postinfarction remodeling responses resulting in development of hypertrophy and heart failure.
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PMID:The myocardial Na(+)-H(+) exchange: structure, regulation, and its role in heart disease. 1053 45

We investigated the effect of sodium/hydrogen exchange inhibition (NHE-1) on hypertrophy and heart failure after coronary artery ligation (CAL) in the rat. Animals were subjected to occlusion (or sham) of the left main coronary artery and immediately administered a control diet or one consisting of the NHE-1 inhibitor cariporide for 13-15 wk. Hearts were separated by small [</=30% of left ventricle (LV)] and large (>30% of LV) infarcts. CAL depressed change in left ventricular increase in pressure over time (LV +dP/dt) in small and large infarct groups by 18.8% (P < 0.05) and 34% (P < 0.01), respectively, whereas comparative values for the cariporide groups were 8.7% (not significant) and 23.1% (P < 0.01), respectively. LV end-diastolic pressure was increased by 1,225% in the control large infarct group but was significantly reduced to 447% with cariporide. Cariporide also significantly reduced the degree of LV dilation in animals with large infarcts. Hypertrophy, defined by tissue weights and cell size, was reduced by cariporide, and shortening of surviving myocytes was preserved. Infarct sizes were unaffected by cariporide, and the drug had no influence on either blood pressure or the depressed inotropic response of infarcted hearts to dobutamine. These results suggest an important role for NHE-1 in the progression of heart failure after myocardial infarction.
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PMID:Na(+)/H(+) exchange inhibition reduces hypertrophy and heart failure after myocardial infarction in rats. 1115 73

The myocardial Na+/H+ exchange (NHE) represents a major mechanism for pH regulation during normal physiological processes but especially during ischaemia and early reperfusion. However, there is now very compelling evidence that its activation contributes to paradoxical induction of cell injury. The mechanism for this most probably reflects the fact that activation of the exchanger is closely coupled to Na+ influx and therefore to elevation in intracellular Ca2+ concentrations through the Na+/Ca2+ exchange. The NHE is exquisitely sensitive to intracellular acidosis; however, other factors can also exhibit stimulatory effects via phosphorylation-dependent processes. These generally represent various autocrine and paracrine as well as hormonal factors such as endothelin-1, angiotensin II and alpha1-adrenoceptor agonists, which probably act through receptor-signal transduction processes. Thus far, 6 NHE isoforms have been identified and designated as NHE1 through NHE6. All except NHE6, which is located intracellularly, are restricted to the sarcolemmal membrane. In the mammalian myocardium the NHE1 subtype is the predominant isoform, although NHE6 has also been identified in the heart. The predominance of NHE1 in the myocardium is of some importance since, as discussed in this review, pharmacological development of NHE inhibitors for cardiac therapeutics has concentrated specifically on those agents which are selective for NHE1. These agents, as well as the earlier nonspecific amiloride derivatives have now been extensively demonstrated to possess excellent cardioprotective properties, which appear to be superior to other strategies, including the extensively studied phenomenon of ischaemic preconditioning. Moreover, the salutary effects of NHE inhibitors have been demonstrated using a variety of experimental models as well as animal species suggesting that the role of the NHE in mediating injury is not species specific. The success of NHE inhibitors in experimental studies has led to clinical trials for the evaluation of these agents in high risk patients with coronary artery disease as well as in patients with acute myocardial infarction (MI). Recent evidence also suggests that NHE inhibition may be conducive to attenuating the remodelling process after MI, independently of infarct size reduction, and attenuation of subsequent postinfarction heart failure. As such, inhibitors of NHE offer substantial promise for clinical development for attenuation of both acute responses to myocardial as well as chronic postinfarction responses resulting in the evolution to heart failure.
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PMID:The myocardial Na+/H+ exchanger: a potential therapeutic target for the prevention of myocardial ischaemic and reperfusion injury and attenuation of postinfarction heart failure. 1129 48

The Na-H exchanger (NHE) represents a family of transporters which regulate intracellular pH by removing protons in exchange for sodium influx in an electroneutral 1:1 stoichiometric relationship. Six isoforms have thus far been identified with the NHE-1 subtype representing the primary isoform in the cardiac cell. It is well-established that NHE-1 contributes to cardiac injury produced by ischaemia and reperfusion and inhibitors of the antiporter exert excellent cardioprotection. More recent evidence suggests that NHE-1 may also be important for cell growth and may contribute to the maladaptive remodelling which contributes to heart failure particularly the early hypertrophic responses. Evidence from in vitro studies suggest that NHE-1 inhibitors attenuate cardiomyocyte hypertrophy in response to various stimuli whereas in vivo studies report substantial attenuation of both hypertrophy and heart failure by these agents, especially after myocardial infarction. Accordingly, NHE-1 inhibitors could emerge as important therapeutic tools for the attenuation and treatment of heart failure.
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PMID:Therapeutic potential of Na-H exchange inhibitors for the treatment of heart failure. 1132 61

The myocardial sodium-hydrogen exchanger (NHE), and more specifically the NHE-1 isoform is now well-recognized to be a major contributor to ischemic and reperfusion injury. Recent evidence suggests that NHE-1 is also potential candidate for targeted intervention in terms of attenuation of the remodelling and hypertrophic processes which contributes to heart failure. Experimental studies have shown that NHE-1 inhibitors attenuate cardiomyocyte hypertrophy induced by various factors and reduce heart failure in vivo, independently of infarct size reduction. Although the precise cellular mechanisms for NHE-1 involvement remain to be elucidated, current data suggest a potentially effective new therapeutic approach for the treatment of heart failure via NHE-1 inhibition.
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PMID:Role of sodium-hydrogen exchange in cardiac hypertrophy and heart failure: a novel and promising therapeutic target. 1151 88

Chronic stimulation of the beta(1)-adrenergic receptor leads to hypertrophy and heart failure in beta(1)-adrenergic receptor transgenic mice and contributes to disease progression in heart failure patients. The cellular mechanisms underlying these detrimental effects are largely unknown. In this study, we have identified the cardiac Na(+)-H(+) exchanger (NHE1) as a novel mediator of adrenergically induced heart failure. beta(1)-Adrenergic receptor transgenic mice showed upregulation of both NHE1 mRNA (+140+/-6%) and protein (+42+/-19%). In order to test whether increased NHE1 is causally related to beta(1)-adrenergic-induced hypertrophy, fibrosis, and heart failure, beta(1)-adrenergic receptor transgenic (TG) and wild-type (WT) littermates were treated with a diet containing 6000 ppm of the NHE1 inhibitor cariporide or control chow for 8 months. There was significant hypertrophy of cardiac myocytes in beta(1)-adrenergic receptor transgenic mice (2.3-fold increase in myocyte cross-sectional area), which was virtually absent in cariporide-fed animals. Interstitial fibrosis was prominent throughout the left ventricular wall in nontreated beta(1)-adrenergic receptor transgenic mice (4.8-fold increase in collagen volume fraction); cariporide treatment completely prevented this development of fibrosis. Left ventricular catheterization showed that cariporide also prevented the loss of contractile function in beta(1)-adrenergic receptor transgenic mice: whereas untreated transgenic mice showed a significant decrease in left ventricular contractility (5250+/-570 mm Hg/s TG versus 7360+/-540 mm Hg/s WT, dp/dt(max)), this decrease was completely prevented by cariporide (8150+/-520 mm Hg/s TG cariporide). Inhibition of NHE1 prevented the development of heart failure in beta(1)-receptor transgenic mice. We conclude that the cardiac Na(+)-H(+) exchanger 1 is essential for the detrimental cardiac effects of chronic beta(1)-receptor stimulation in the heart.
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PMID:Inhibition of Na(+)-H(+) exchange prevents hypertrophy, fibrosis, and heart failure in beta(1)-adrenergic receptor transgenic mice. 1196 65

Although the past number of years have seen a substantial improvement in the therapeutic approaches for the treatment of heart failure, mortality rates continue to be high. Moreover, the incidence of heart failure is expanding rapidly. Sodium-hydrogen exchange (NHE) is a key target for the treatment of heart failure. NHE is a major mechanism for intracellular pH regulation in most cell types, including the cardiac cell. Seven isoforms of NHE have been identified so far although cardiac cells possess primarily the ubiquitous NHE-1 subtype. NHE-1 is a major contributor to ischaemic and reperfusion injury and NHE-1 inhibitors exert marked cardioprotective effects, particularly when administered before ischaemia, findings which have now been extended to clinical trials. It is emerging that NHE-1 also contributes to chronic maladaptive myocardial responses to injury (myocardial remodelling) and may contribute 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 terms of inhibition of hypertrophy in response to various stimuli as well as inhibiting heart failure after coronary artery ligation. These effects occurred independently of any infarct size reducing effects of NHE-1 inhibitors or on any direct effects on afterload thus indicating a direct effect on the myocardial remodelling process. In fact, it appears that NHE-1 may represent a common downstream mediator for various hypertropic factors such as angiotensin II, endothelin-1 and beta(1) adrenergic receptor activation. NHE-1 inhibition, therefore, represents a potentially effective new therapeutic approach for the treatment of heart failure.
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PMID:Targeting the myocardial sodium-hydrogen exchange for treatment of heart failure. 1222 70

Sodium ion (Na(+)) transporters have roles in the modulation of cardiomyocyte pH and Na(+) and Ca(2+) handling. Activation of the cardiac Na(+)-H(+) exchanger 1 (NHE1) during ischaemia induces arrhythmias, myocardial stunning and irreversible cell injury. As the benefits of NHE1 inhibitors (e.g., amiloride, cariporide) in models of myocardial infarction are usually much greater when used as pretreatment, rather than during or after ischaemia, it is probably not surprising that clinical trials with cariporide in ischaemia have shown little shortterm benefit. NHE1 inhibitors have been shown to be beneficial in animal models of ventricular fibrillation and resuscitation, cardioplegia, hypertrophy and heart failure, and their therapeutic potential in these conditions should be further developed. The Na(+)-HCO(3)(-) cotransporter (NBC) is also stimulated by intracellular acidification, and part of the benefit of angiotensin-converting enzyme inhibitors after myocardial infarction may be due to inhibition of the NBC. Selective inhibitors of the NBC are required to determine the therapeutic potential of this mechanism. The Na(+)-Ca(2+) exchanger (NCX) has a major role in cardiac Na(+) and Ca(2+) homeostasis and influences cardiac electrical activity. The NCX also has a role in ischaemia/infarction, arrhythmias, hypertrophy and heart failure. NCX inhibitors may have beneficial effects in animal models of ischaemia and reperfusion injury and the therapeutic benefit of these should be further studied in animal models.
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PMID:Is timing everything? Therapeutic potential of modulators of cardiac Na(+) transporters. 1283 48

The first part of this report on the Australian Health and Medical Research Congress, held November 25-29, 2002, in Melbourne, Australia, considers some of the symposia and three plenary lectures: Neurosteroids: Nature's Valium, G-Protein-Coupled Receptors and the Mike Rand Memorial Lecture. In the new era in relaxin research symposium, we learned that relaxin is a general antifibrotic agent rather than just a hormone of pregnancy. The drugs discussed in the drug discovery symposium included drugs from natural products, allosteric modulators, antibodies to cytokines and AM-336, an N-type Ca(2+) channel blocker. In the matrix proteases symposium, we learned of the importance of these enzymes in bone, endometrial remodeling and cardiovascular disease. The emphasis of the cytokine antagonist symposium was the involvement of cytokines in rheumatoid arthritis and how these effects could be inhibited with cytokine antagonists. The second part of this report is on the cardiovascular components of the meeting. One of the major strengths of Australian research is the cardiovascular area. Thus, it was not surprising that there were three major symposia with a cardiovascular theme this congress. Although the clinical trials of the NHE1 inhibitors in ischemia and reperfusion have been disappointing to date, evidence was presented in the sodium-hydrogen exchanger symposium that these agents might be beneficial in hypertrophy and heart failure. The discussion in the vessel wall biology in diabetes symposium ranged from molecular aspects to clinical trials. In this, and the NAD(P)H oxidases symposium, many new potential drug targets were discussed. The plenary lecture of the High Blood Pressure Research Council concerned the pathophysiology and management of obesity hypertension, and included a discussion of the drugs for weight reduction.
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PMID:Health and medical research down under in 2002. 1294 54

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