Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ranolazine was previously shown to stimulate cardiac glucose oxidation. Dichloroacetate (DCA) also does and was shown to improve exercise capacity in animals, but it has long-term toxicity problems. To test the hypothesis that ranolazine would increase exercise performance in the chronic heart failure (CHF) condition, we compared the exercise endurance capacities of rats with a surgically induced myocardial infarction (MI) with those of noninfarcted sham-operated (Sham) controls both before and after 14 and 28 days of drug administration. Chronic administration of ranolazine, 50 mg/kg twice daily (b.i.d.) oral, significantly reduced the endurance capacities of both Sham and MI rats (measured after a 12-h fast to reduce liver glycogen stores), as indicated by the reductions in run times to fatigue during a progressive treadmill test. Ranolazine produced reductions in resting plasma lactate and glucose concentrations of animals fasted for 12 h (consistent with stimulating glucose oxidation); however, tissue glycogen concentrations measured in various locomotor muscles located in the animal's hindlimb were unaffected when measured 48 h after the last treadmill test and after 12 h of fasting. Chronic administration of ranolazine did not increase the endurance capacity of rats with CHF induced by MI at the dosage and with the protocol used. To the contrary, the chronic administration of ranolazine appears to reduce the work capacity of all rats, suggesting that this drug may not be useful therapeutically in the treatment of CHF. Whether the decrements in endurance capacity produced by ranolazine are related to the high plasma concentrations of the drug produced in this study as compared with previous studies in humans remains subject to further experimentation.
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PMID:Effects of ranolazine on the exercise capacity of rats with chronic heart failure induced by myocardial infarction. 887 80

The present study assesses whether ranolazine increases left ventricular (LV) function without an increase in myocardial oxygen consumption (MVO2) and thus improves LV mechanical efficiency in dogs with heart failure (HF). Ranolazine did not change MVO2 and LV mechanical efficiency increased (22.4+/-2.8% to 30.9+/-3.4% (P<0.05). In contrast, dobutamine significantly increased MVO2 and did not improve mechanical efficiency. Thus, short-term treatment with ranolazine improved LV function without an increase in MO2, resulting in an increased myocardial mechanical efficiency in dogs with HF.
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PMID:Short-term treatment with ranolazine improves mechanical efficiency in dogs with chronic heart failure. 1219 59

Ranolazine (Ranexa), a piperazine derivative, is a new antianginal agent approved for the treatment of chronic stable angina pectoris for use as combination therapy when angina is not adequately controlled with other antianginal agents. While the exact mechanism of action of ranolazine is not known, its antianginal and anti-ischaemic effects do not appear to depend upon changes in blood pressure or heart rate. An extended-release (ER) oral formulation of ranolazine has been developed to facilitate twice-daily administration whilst maintaining therapeutically effective plasma concentrations. In patients with chronic stable angina, ranolazine ER monotherapy was shown to improve exercise duration at trough plasma drug concentration in a dose-dependent manner compared with placebo. The drug was effective as adjunctive therapy in patients with chronic stable angina whose condition was not controlled adequately with conventional antianginal therapy. In randomised clinical trials, ranolazine ER was well tolerated, with no overt effects on cardiovascular haemodynamics or conduction, apart from a modest increase in corrected QT (QTc) interval (but no torsades de pointes). Importantly, the efficacy and tolerability of ranolazine ER were not affected by comorbid conditions, including old age, heart failure (HF) or diabetes mellitus. Comparative trials of ranolazine ER with other antianginal agents and trials examining its effects on long-term morbidity and mortality in patients with ischaemic heart disease are required to determine with greater certainty the place of the drug in current antianginal therapy. Nevertheless, ranolazine ER may well prove to be a useful alternative and adjunct to conventional haemodynamic antianginal therapy in the treatment of chronic stable angina.
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PMID:Ranolazine: a review of its use in chronic stable angina pectoris. 1662 Jan 47

Pathological conditions linked to imbalances in oxygen supply and demand (for example, ischaemia, hypoxia and heart failure) are associated with disruptions in intracellular sodium ([Na(+)](i)) and calcium ([Ca(2+)](i)) concentration homeostasis of myocardial cells. A decreased efflux or increased influx of sodium may cause cellular sodium overload. Sodium overload is followed by an increased influx of calcium through sodium-calcium exchange. Failure to maintain the homeostasis of [Na(+)](i) and [Ca(2+)](i) leads to electrical instability (arrhythmias), mechanical dysfunction (reduced contractility and increased diastolic tension) and mitochondrial dysfunction. These events increase ATP hydrolysis and decrease ATP formation and, if left uncorrected, they cause cell injury and death. The relative contributions of various pathways (sodium channels, exchangers and transporters) to the rise in [Na(+)](i) remain a matter of debate. Nevertheless, both the sodium-hydrogen exchanger and abnormal sodium channel conductance (that is, increased late sodium current (I(Na))) are likely to contribute to the rise in [Na(+)](i). The focus of this review is on the role of the late (sustained/persistent) I(Na) in the ionic disturbances associated with ischaemia/hypoxia and heart failure, the consequences of these ionic disturbances, and the cardioprotective effects of the antianginal and anti-ischaemic drug ranolazine. Ranolazine selectively inhibits late I(Na), reduces [Na(+)](i)-dependent calcium overload and attenuates the abnormalities of ventricular repolarisation and contractility that are associated with ischaemia/reperfusion and heart failure. Thus, inhibition of late I(Na) can reduce [Na(+)](i)-dependent calcium overload and its detrimental effects on myocardial function.
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PMID:Inhibition of the late sodium current as a potential cardioprotective principle: effects of the late sodium current inhibitor ranolazine. 1677 92

Ranolazine (Ranexa), a piperazine derivative, is a new antianginal agent approved for the treatment of chronic stable angina pectoris for use as combination therapy when angina is not adequately controlled with other antianginal agents. While the exact mechanism of action of ranolazine is not known, its antianginal and anti-ischemic effects do not appear to depend upon changes in BP or heart rate. An extended-release (ER) oral formulation of ranolazine has been developed to facilitate twice-daily administration whilst maintaining therapeutically effective plasma concentrations. In patients with chronic stable angina, ranolazine ER monotherapy was shown to improve exercise duration at trough plasma drug concentration in a dose-dependent manner compared with placebo. The drug was effective as adjunctive therapy in patients with chronic stable angina whose condition was not controlled adequately with conventional antianginal therapy. In randomized clinical trials, ranolazine ER was well tolerated, with no overt effects on cardiovascular hemodynamics or conduction, apart from a modest increase in corrected QT interval (but no torsades de pointes). Importantly, the efficacy and tolerability of ranolazine ER were not affected by old age and co-morbid conditions (heart failure or diabetes mellitus). Comparative trials of ranolazine ER with other antianginal agents and trials examining its effects on long-term morbidity and mortality in patients with ischemic heart disease are required to determine with greater certainty the place of the drug in current antianginal therapy. Nevertheless, ranolazine ER may well prove to be a useful alternative and adjunct to conventional hemodynamic antianginal therapy in the treatment of chronic stable angina.
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PMID:Spotlight on ranolazine in chronic stable angina pectoris. 1708 71

There is increasing evidence that the late sodium current of the sodium channel in myocytes plays a critical role in the pathophysiology of myocardial ischemia and thus is a potential therapeutic target in patients with ischemic heart disease. Ranolazine, an inhibitor of the late sodium current, reduces the frequency and severity of anginal attacks and ST-segment depression in humans, and unlike other antianginal drugs, ranolazine does not alter heart rate or blood pressure. In experimental animal models, ranolazine has been shown to reduce myocardial infarct size and to improve left ventricular function after acute ischemia and chronic heart failure. This article reviews published data describing the role of late sodium current and its inhibition by ranolazine in clinical and experimental studies of myocardial ischemia.
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PMID:Late sodium current inhibition as a new cardioprotective approach. 1846 46

Altered myocardial Ca(2+) and Na(+) handling in congestive heart failure (CHF) may be expected to decrease the tolerance to ischemia by augmenting reperfusion Ca(2+) overload. The aim of the present study was to investigate tolerance to hypoxia-reoxygenation by measuring enzyme release, cell death, ATP level, and cell Ca(2+) and Na(+) in cardiomyocytes from failing rat hearts. CHF was induced in Wistar rats by ligation of the left coronary artery during isoflurane anesthesia, after which cardiac failure developed within 6 wk. Isolated cardiomyocytes were cultured for 24 h and subsequently exposed to 4 h of hypoxia and 2 h of reoxygenation. Cell damage was measured as lactate dehydrogenase (LD) release, cell death as propidium iodide uptake, and ATP by firefly luciferase assay. Cell Ca(2+) and Na(+) were determined with radioactive isotopes, and free intracellular Ca(2+) concentration ([Ca(2+)](i)) with fluo-3 AM. CHF cells showed less increase in LD release and cell death after hypoxia-reoxygenation and had less relative reduction in ATP level after hypoxia than sham cells. CHF cells accumulated less Na(+) than sham cells during hypoxia (117 vs. 267 nmol/mg protein). CHF cells maintained much lower [Ca(2+)](i) than sham cells during hypoxia (423 vs. 1,766 arbitrary units at 4 h of hypoxia), and exchangeable Ca(2+) increased much less in CHF than in sham cells (1.4 vs. 6.7 nmol/mg protein) after 120 min of reoxygenation. Ranolazine, an inhibitor of late Na(+) current, significantly attenuated both the increase in exchangeable Ca(2+) and the increase in LD release in sham cells after reoxygenation. This supports the suggestion that differences in Na(+) accumulation during hypoxia cause the observed differences in Ca(2+) accumulation during reoxygenation. Tolerance to hypoxia and reoxygenation was surprisingly higher in CHF than in sham cardiomyocytes, probably explained by lower hypoxia-mediated Na(+) accumulation and subsequent lower Ca(2+) accumulation in CHF after reoxygenation.
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PMID:Cardiomyocytes from postinfarction failing rat hearts have improved ischemia tolerance. 1913 4

Inhibition of the persistent or late Na current (INa) using ranolazine (Ranexa) represents a novel mechanism of action that was approved in the United States in 2006 and only recently in the European Union for use in patients with stable angina pectoris. In general, myocardial ischemia is associated with reduced adenosine triphosphate fluxes and decreased energy supply, resulting in severe disturbances of intracellular ion homeostasis in cardiac myocytes. In the recent years, increased late INa was suggested to contribute to this phenomenon by elevating intracellular Na concentration with subsequent rise in diastolic Ca levels by means of the sarcolemmal Na-Ca exchange system. Ranolazine, a specific inhibitor of late INa, reduces Na influx and hence ameliorates disturbed Na and Ca homeostasis. This is associated with a symptomatic improvement of angina in patients unlike other antianginal drugs without affecting heart rate or systemic blood pressure as shown in placebo-controlled studies. Therefore, ranolazine is a useful new option for patients with chronic stable angina not only as an add-on therapy. New clinical and experimental studies even point to potential antiarrhythmic effects, beneficial effects in diastolic heart failure, and under hyperglycemic conditions. In the present article, the relevant pathophysiological concepts for the role of late INa inhibition are reviewed and the most recent data from basic studies and clinical trials are summarized.
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PMID:A novel mechanism for the treatment of angina, arrhythmias, and diastolic dysfunction: inhibition of late I(Na) using ranolazine. 1933 33

Pathological conditions, including ischemia and heart failure, are associated with altered sodium channel function and increased late sodium current (I(Na,L)), leading to prolonged action potential duration, increased intracellular sodium and calcium concentrations, and arrhythmias. We used anemone toxin (ATX)-II to study the effects of increasing I(Na,L) on intracellular calcium cycling in rat isolated hearts. Cardiac contraction was abolished using paralytic agents. Ranolazine (RAN) was used to inhibit late I(Na). Hearts were loaded with fluo-4-acetoxymethyl ester, and myocyte intracellular calcium transients (CaTs) were measured using laser scanning confocal microscopy. ATX (1 nM) prolonged CaT duration at 50% recovery in hearts paced at a basal rate of 2 Hz and increased the sensitivity of the heart to the development of calcium alternans caused by fast pacing. ATX increased the time required for recovery of CaT amplitude following a previous beat, and ATX induced spontaneous calcium release waves during rapid pacing of the heart. ATX prolonged the duration of repolarization from the initiation of the activation to terminal repolarization in the pseudo-electrocardiogram. All actions of ATX were both reversed and prevented by subsequent or prior exposure, respectively, of hearts to RAN (10 microM). Most importantly, the increased vulnerability of the heart to the development of calcium alternans during rapid pacing was reversed or prevented by 10 microM RAN. These results suggest that enhancement of I(Na,L) alters calcium cycling. Reduction by RAN of I(Na,L)-induced dysregulation of calcium cycling could contribute to the antiarrhythmic actions of this agent in both reentrant and triggered arrhythmias.
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PMID:Ranolazine antagonizes the effects of increased late sodium current on intracellular calcium cycling in rat isolated intact heart. 1967 98

The hypothesis proposed is that heart failure (HF) is associated with a reactive hyperadrenergic state that increases circulating plasma free fatty acids (FFAs), which leads to impaired glucose metabolism and insulin resistance. We propose that increased FFA-induced mitochondrial uncoupling and substantial oxygen wastage is closely associated with the generation of reactive oxygen species, inflammatory markers, and the development of insulin resistance. The therapeutic aims of metabolic therapy are as follows: 1) to decrease hyperadrenergic drive; 2) to inhibit lipotoxicity and glucotoxicity; and 3) to increase glucose uptake by muscle. These aims are achieved, respectively, by the following: 1) the use of beta-adrenergic blockade and all measures that relieve the mechanical load on the heart; 2) the use of drugs that inhibit fatty acid oxidation (trimetazidine, perhexiline), although without clinical evidence that the heart is their major site of action in HF; and 3) increase of the transport of glucose into the cells by exercise and metformin. Of these measures, only data concerning the reduction of mortality as the result of exercise are available. Of all the other measures, there are substantial positive data on the use of trimetazidine that demonstrate metabolic and clinical benefit with almost no side effects, but data from a large outcome trial are lacking. Our data suggest a major extracardiac site of trimetazidine action. Ranolazine, which inhibits the late sodium inward current, requires testing in human HF. Insulin to reduce hyperglycemia and FFAs is untested in HF, with incretins such as glucagon-like peptide-1 on the horizon. Other future therapies may include malonyl-coenzyme A regulators to inhibit fatty acid oxidation, fish oil omega-3, and activators of protein kinase C-epsilon.
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PMID:The adrenergic-fatty acid load in heart failure. 1985 Feb 4


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