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)

Ca(2+) overload in myocardial cells is responsible for arrhythmia. Sodium-calcium exchanger (NCX) inhibitors are more effective than sodium-hydrogen exchanger (NHE) inhibitors with regard to modulation of Ca(2+) overload, because NCX inhibitors can directly inhibit the influx of Ca(2+) into cells. NCX is an attractive target for the treatment of heart failure and ischemia-reperfusion. We have designed and synthesized a series of N-(2-aminopyridin-4-ylmethyl)nicotinamide derivatives, based on compound 5. We have discovered a novel NCX inhibitor (23 h) with an IC(50) value of 0.12 microM against reverse NCX. The inhibitory activities of our NCX inhibitors against cytochrome P450 were also evaluated. The effects on heart failure and the pharmacokinetic profile of compound 23 h are discussed.
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PMID:Discovery of an N-(2-aminopyridin-4-ylmethyl)nicotinamide derivative: a potent and orally bioavailable NCX inhibitor. 1591 15

Sodium transport in epithelial tissues is regulated by the physiological mineralocorticoid aldosterone. The response to aldosterone is mediated by the mineralocorticoid receptor (MR), for which the crystal structure of the ligand-binding domain has recently been established. The classical mode of action for this receptor involves the regulation of gene transcription. Several genes have now been shown to be regulated by aldosterone in epithelial tissues. Of these, the best characterized is serum- and glucocorticoid-regulated kinase, which increases sodium influx through the epithelial sodium channel. Turnover of these channels in the cell membrane is mediated by Nedd4-2, a ubiquitin protein ligase; serum- and glucocorticoid-regulated kinase interacts with and phosphorylates Nedd4-2, thereby rendering it unable to bind the sodium channels. In nonepithelial tissues, particularly the cardiovascular system, aldosterone also has direct effects, activating an inflammatory cascade, leading to cardiac fibrosis. A critical role for the MR in cardiovascular disease has now been demonstrated by the beneficial response to MR blockade in 2 large clinical trials in patients with cardiac failure. It is these nonepithelial actions of MR activation that need to be exploited for the development of antagonists that target the cardiovascular system while avoiding the undesirable side effects of renal MR blockade.
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PMID:Mechanisms of mineralocorticoid action. 1628 65

The pathophysiology of sodium and water retention in heart failure is characterized by a complex interplay of hemodynamic and neurohumoral factors. Relative arterial underfilling is an important signal that triggers heart failure-related sodium and water retention. The response to perceived arterial underfilling is modulated by the level of neurohormonal activation, the degree of renal vasoconstriction, and the extent to which renal perfusion pressure is reduced. Sodium retention can also be exceeded by water retention, with the result being dilutional hyponatremia. Sodium and water retention in heart failure also function to dampen the natriuretic response to diuretic therapy. The attenuated response to diuretics in heart failure is both disease-specific and separately influenced by the rate and extent of diuretic absorption, the rapidity of diuretic tubular delivery, and diuretic-related hypertrophic structural changes that surface in the distal tubule.
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PMID:Sodium and water retention in heart failure and diuretic therapy: basic mechanisms. 1678 6

Sodium current I(Na) plays an important role in the pacemaker activity of the sinoatrial node (SAN). However, expression profiles of corresponding sodium channel subunits in normal SAN remain unclear. And little is known about expression alteration of sodium channel in SAN under heart failure (HF) condition. We assessed SAN function and expression of Nav1.1, Nav1.2, Nav1.3, Nav1.5, Nav1.6, and Nav1.7 in sham-operated rats and rats subjected to abdominal arteriovenous shunt (volume overload)-induced HF. Immunohistochemistry, Western blot, and quantitative real-time reverse transcriptase PCR analysis were used to quantify sodium channel subunit protein and mRNA expression in the SAN. Intrinsic heart rate declined and sinus node recovery time was prolonged in HF rats, indicating suppressed SAN pacemaker function. In rat SAN, Nav1.1 and Nav1.6 were the primary subunits, Nav1.5 and Nav1.7 were weakly expressed, and Nav1.2 and Nav1.3 were not found to be present. HF significantly decreased SAN sodium channel expression at both the protein and mRNA levels (Nav1.1 by 61 and 71%, Nav1.6 by 49 and 46%, respectively). In conclusion, Nav1.1 and Nav1.6 are the dominant subunits in rat SAN, and downregulation of Nav1.1 and Nav1.6 expression contributes to HF-induced SAN dysfunction. These findings provide additional information about molecular basis of disease-related impairment of SAN function.
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PMID:Downregulation of neuronal sodium channel subunits Nav1.1 and Nav1.6 in the sinoatrial node from volume-overloaded heart failure rat. 1727 63

Sodium appetite, the behavioural drive to ingest salt, is stimulated by prolonged physiological sodium deficiency in many animal species. The same neural mechanisms that are responsible for sodium appetite in laboratory animals may influence human behaviour as well, with particular relevance to the dietary salt intake of patients with diseases such as heart failure, renal failure, liver failure and salt-sensitive hypertension. Since the original experimental work of Curt Richter in the 1930s, much has been learned about the regulation of salt-ingestive behaviour. Here, we review data from physiology, pharmacology, neuroanatomy and neurobehavioural investigations into the stimulatory and inhibitory signals that regulate sodium appetite. A rudimentary framework is proposed for the brain circuits that integrate peripheral information representing the need for sodium with neural signals for the gustatory detection of salt in order to drive a motivated ingestive response. Based on this model, areas of remaining uncertainty are highlighted where future information would allow a more detailed understanding of the neural circuitry responsible for sodium appetite.
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PMID:Central regulation of sodium appetite. 1798 30

Optimal care of patients with heart failure requires a multifaceted approach that includes guideline-driven, evidence-based therapies, intensive patient education, careful initial and follow-up assessment, and appropriately constructed nutrition prescriptions. Central to the construct of the nutrition prescription is advice regarding sodium consumption. It is intuitively and generally agreed upon that sodium restriction is appropriate for patients with heart failure, despite the lack of evidence-based research studies. Whereas limiting sodium is most appropriate for the hypertensive patient at risk for developing heart failure and the patient who is overtly volume overloaded, less certainty exists regarding the sodium prescription for patients with diagnosed heart failure that is well compensated. Sodium intake is only 1 component of medical nutrition therapy, and prescription must be individualized according to nutrition assessment and priority of needs. However, in the absence of new compelling data, sodium restriction remains the most appropriate dietary intervention in general for patients with heart failure.
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PMID:The heart failure and sodium restriction controversy: challenging conventional practice. 1884 52

Sodium ion transporters in sarcolemma are involved in numerous vital cell functions, such as excitability, excitation-contraction coupling, energy metabolism, pH and volume regulation, development and growth. In a number of cardiac pathologies, the intracellular sodium concentration ([Na+]i) is elevated. Since [Na+]i and intracellular Ca2+ concentration ([Ca2+]i are coupled through the Na+/Ca(2+)-exchanger, these cardiac pathologies display disturbed calcium handling. For instance, [Na+]i is increased in heart failure (HF) leading to Na+/Ca(2+)-exchanger mediated increase in [Ca2+]i, reduced contractility and increased propensity to arrhythmias. Several studies support the contention that an increase in [Na+]i and [Ca2+]i transduces a signal the nucleus, that triggers development of cardiac remodelling and hypertrophy. Pharmacological intervention, which favourably interferes with [Na+]i and [Ca2+]i homeostasis, might prevent hypertrophy, cardiac remodelling, arrhythmias and HF. The most important sodium transport mechanisms that may underlie increased [Na+]i are: Na+/H(+)-exchanger (NHE-1), Na+-HCO(3)(-) co-transporter (NBC), Na(+)-K(+)-Cl(-) co-transporter (NKCC), Na(+)-channel, Na+/K(+)-ATPase and Na+/Ca(2+)-exchanger (NCX). Preclinical studies showed that pharmacological interventions, targeted against sarcolemmal sodium ion transporters, proved effective in ameliorating heart failure. In this respect: 1) NHE-1 inhibition reduces cardiac remodelling, hypertrophy and HF, although, in the patients following coronary artery bypass graft surgery, it was associated with an increase of stroke. 2) The activity of NBC is up-regulated, during the development of hypertrophy and may be a therapeutic strategy to prevent the development of hypertrophy and HF. 3) NKCC is increased in post-infarction HF, and the inhibition of NKCC attenuated post-infarction remodelling. 4) Inactivation of sodium channels is impaired in HF, which may result, in increased Na+ influx and prolongation of the action potential. 5) Blockade of NCX may be useful as a part of a combined therapeutic approach. Inhibition of reversed mode, or activation of forward mode NCX reduce Ca2+ overload. 6) Inhibition of Na+/K(+)-ATPase (digoxin), is used to increase contractility, however, it enhances progression of HF. Oppositely, new drugs which increase activity of Na+/K(+)-ATPase may prevent the development of cardiac remodelling hypertrophy and HF.
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PMID:Sodium ion transporters as new therapeutic targets in heart failure. 1885 35

1. The kidneys are the key organs to maintain the balance of the different electrolytes in the body and the acid-base balance. Progressive loss of kidney function results in a number of adaptive and compensatory renal and extrarenal changes that allow homeostasis to be maintained with glomerular filtration rates in the range of 10-25 ml/min. With glomerular filtration rates below 10 ml/min, there are almost always abnormalites in the body's internal environment with clinical repercussions. 2. Water Balance Disorders: In advanced chronic kidney disease (CKD), the range of urine osmolality progressively approaches plasma osmolality and becomes isostenuric. This manifests clinically as symptoms of nocturia and polyuria, especially in tubulointerstitial kidney diseases. Water overload will result in hyponatremia and a decrease in water intake will lead to hypernatremia. Routine analyses of serum Na levels should be performed in all patients with advanced CKD (Strength of Recommendation C). Except in edematous states, a daily fluid intake of 1.5-2 liters should be recommended (Strength of Recommendation C). Hyponatremia does not usually occur with glomerular filtration rates above 10 ml/min (Strength of Recommendation B). If it occurs, an excessive intake of free water should be considered or nonosmotic release of vasopressin by stimuli such as pain, anesthetics, hypoxemia or hypovolemia, or the use of diuretics. Hypernatremia is less frequent than hyponatremia in CKD. It can occur because of the provision of hypertonic parenteral solutions, or more frequently as a consequence of osmotic diuresis due to inadequate water intake during intercurrent disease, or in some circumstance that limits access to water (obtundation, immobility). 3. Sodium Balance Disorders: In CKD, fractional excretion of sodium increases so that absolute sodium excretion is not modified until glomerular filtration rates below 15 ml/min (Strength of Recommendation B). Total body content of sodium is the main determinant of extracellular volume and therefore disturbances in sodium balance will lead to clinical situations of volume depletion or overload: Volume depletion due to renal sodium loss occurs in abrupt restrictions of salt intake in advanced CKD. It occurs more frequently in certain tubulointerstitial kidney diseases (salt losing nephropathies). Volume overload due to sodium retention can occur with glomerular filtration rates below 25 ml/min and leads to edema, arterial hypertension and heart failure. The use of diuretics in volume overload in CKD is useful to force natriuresis (Strength of Recommendation B). Thiazides have little effect in advanced CKD. Loop diuretics are effective and should be used in higher than normal doses (Strength of Recommendation B). The combination of thiazides and loop diuretics can be useful in refractory cases (Strength of Recommendation B). Weight and volume should be monitored regularly in the hospitalized patient with CKD (Strength of Recommendation C). 4. Potassium Balance Disorders: In CKD, the ability of the kidneys to excrete potassium decreases proportionally to the loss of glomerular filtration. Stimulation of aldosterone and the increase in intestinal excretion of potassium are the main adaptive mechanisms to maintain potassium homeostasis until glomerular filtration rates of 10 ml/min. The main causes of hyperkalemia in CKD are the following: Use of drugs that alter the ability of the kidneys to excrete potassium: ACEIs, ARBs, NSAIDs, aldosterone antagonists, nonselective beta-blockers, heparin, trimetoprim, calcineurin inhibitors. Determination of serum potassium two weeks after the initiation of treatment with ACEIs/ARBs is recommended (Strength of Recommendation C). Routine use of aldosterone antagonists in advanced CKD is not recommended (Strength of Recommendation C). Abrupt reduction in glomerular filtration rate: Constipation. Prolonged fasting. Metabolic acidosis. A low-potassium diet is recommended with GFR less than 20 ml/min, or GFR less than 50 ml/min if drugs that raise serum potassium are taken (Strength of Recommendation C). In the absence of symptoms or electrocardiographic abnormalities, review of medications, restriction of dietary potassium and use of oral ion exchange resins are usually sufficient therapeutic measures (Strength of Recommendation C). If symptoms and/or electrocardiographic abnormalities are present, the usual parenteral pharmacological measures should be used (10% calcium gluconate, insulin and glucose, salbutamol, resins, diuretics) (Strength of Recommendation A). Parenteral bicarbonate and ion exchange resins in enemas are not recommended as first-line treatment (Strength of Recommendation C). Hemodialysis should be considered in patients with glomerular filtration rates below 10 ml/min (Strength of Recommendation C). 5. Acid-Base Disorders in CKD: Moderate metabolic acidosis (Bic 16-20) mEq/L is common with glomerular filtration rates below 20 ml/min, and favors bone demineralization due to the release of calcium and phosphate from the bone, chronic hyperventilation, and muscular weakness and atrophy. Its treatment consists of administration of sodium bicarbonate, usually orally (0.5-1 mEq/kg/day), with the goal of achieving a serum bicarbonate level of 22-24 mmol/L (Strength of Recommendation C). Limitation of daily protein intake to less than 1 g/kg/day is also useful (Strength of Recommendation C). Use of sevelamer as a phosphate binder aggravates metabolic acidosis since it favors endogenous acid production and therefore acidosis should be monitored and corrected if it occurs (Strength of Recommendation C). Hypocalcemia should always be corrected before metabolic acidosis in CKD (Strength of Recommendation B). Metabolic acidosis is an infrequent disorder and requires exogenous alkali administration (bicarbonate, phosphate binders) or vomiting.
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PMID:[Electrolyte and acid-base balance disorders in advanced chronic kidney disease]. 1901 44

Sodium restriction is the primary nutritional strategy in heart failure; however, other diet-related concerns may also occur. We characterized dietary intake among stable patients with heart failure and a non-heart-failure cardiac control group to quantify and determine prevalence of inadequate micronutrient intake. Two 3-day food records were completed by 123 patients with heart failure and 58 controls. A subset of each group provided two 24-hour urine collections. Mean intake of sodium (2,540+/-1,122 vs 2,596+/-1,184 mg/day) and potassium (3,190+/-980 vs 3,114+/-828 mg/day) was similar between the heart failure and control groups. Prevalence of inadequate potassium intake was 94% among patients with heart failure and 91% among controls. More than 50% in each group had inadequate intakes of calcium, magnesium, folate, and vitamins D and E. In stable patients with heart failure, sodium intake was not excessive. However, we demonstrated widespread dietary inadequacies of other vitamins and minerals. These findings highlight the importance of diet beyond that of sodium restriction.
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PMID:Nutritional inadequacies in patients with stable heart failure. 1985 33

The cardiac action potential consists of the sequential activation of various ion channels in a precisely orchestrated manner. Pathologic alterations of ion channel currents disrupt this coordinated behavior and have been linked to arrhythmias, such as atrial fibrillation, as well as to heart failure. The late sodium current is increased in the ventricular myocytes in patients with heart failure and can result in contractile dysfunction. The most likely mechanism whereby elevated intracellular Na+ levels may lead to heart failure is through calcium overload. Sodium channel blockade is a proven strategy in the treatment of atrial fibrillation. Although all class I antiarrhythmic drugs inhibit the sodium current, ranolazine has been shown to be a more specific and potent blocker of the late sodium current. In clinical trials, ranolazine has significantly decreased episodes of nonsustained ventricular tachycardia and supraventricular tachycardia as compared with placebo.
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PMID:Potential application of late sodium current blockade in the treatment of heart failure and atrial fibrillation. 1989 88

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