Upregulation of the rat cardiac sodium channel by in vivo treatment with a class I antiarrhythmic drug.

Taouis, Mohammed; Sheldon, Robert S.; Duff, Henry J.

doi:10.1172/jci115313

Cited by 40 publications

(26 citation statements)

References 12 publications

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“…In contrast, we observed no proarrhythmic effects in ischemia/reperfusion after chronic pretreatment with troglitazone. This dichotomy is unexplained; however, precedent exists for compensatory upregulation of ion channels in response to chronic exposure to inhibitory ligands (29,30). The pro-arrhythmic response to acute troglitazone treatment was an unexpected finding of the present investigation, therefore limited electrophysiologic data were collected.…”

Section: Discussionmentioning

confidence: 78%

Deleterious Effects of Acute Treatment With a Peroxisome Proliferator–Activated Receptor-γ Activator in Myocardial Ischemia and Reperfusion in Pigs

Greyson

et al. 2003

Diabetes

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proliferator-activated receptors (PPARs) are a family of nuclear receptors that regulate gene transcription, particularly those affecting energy substrate metabolism and inflammation (1,2). Thiazolidinedione drugs activate PPAR-␥ and are used clinically to treat patients with type 2 diabetes (3). Currently, several million patients are treated with these agents worldwide. Although the clinical use of thiazolidinediones in type 2 diabetes is based on effects of these agents in adipose tissue, liver, and skeletal muscle to improve glycemic control, PPAR-␥ is also expressed in myocardium (4 -6). Considering the prevalence of coronary heart disease among diabetic patients, surprisingly little is known about the effects of PPAR-␥ activation in myocardium.In addition to activation of nuclear PPAR-␥ receptors, thiazolidinediones produce immediate (nontranscriptional) effects on ion channel conductances across the cell membrane of vascular smooth muscle cells (7-9). To date, however, cardiac electrophysiologic effects of thiazolidinediones have not been reported.Our laboratory previously studied the effects of 8 weeks' pretreatment with the thiazolidinedione compound, troglitazone, in low-flow myocardial ischemia and reperfusion in nondiabetic pigs. We found that pretreated pigs had significantly greater recovery of myocardial mechanical function and carbohydrate metabolism after ischemia and reperfusion than untreated pigs (10). There were no sustained ventricular arrhythmias among treated pigs. These findings indicated a beneficial effect of chronic pretreatment with troglitazone in experimental myocardial ischemia and reperfusion. In clinical practice, however, there are inherent limitations to a strategy of chronic, anticipatory pretreatment for episodes of myocardial ischemia that may occur sporadically and unpredictably. If acute treatment with a PPAR-␥ activator afforded similar benefits to chronic pretreatment, there might be clinical utility of acute treatment in situations where ischemia is known to occur, such as in acute coronary syndromes or cardiopulmonary bypass. Conversely, if salutary effects of PPAR-␥ activation require prolonged drug exposure to alter the expression of target genes (11), acute treatment may be futile. Recent studies using rat models of total coronary occlusion and reperfusion demonstrated reduction of infarct size with either chronic oral pretreatment or acute intravenous treatment with the thiazolidinedione compound, rosiglitazone (12,13). The present study was undertaken to determine whether acute treatment with a thiazolidinedione improves recovery of myocardial me- FFA, free fatty acid; LAD, left anterior descending coronary artery; LV, left ventricular; PPAR, peroxisome proliferator-activated receptor.

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Section: Discussionmentioning

confidence: 78%

Deleterious Effects of Acute Treatment With a Peroxisome Proliferator–Activated Receptor-γ Activator in Myocardial Ischemia and Reperfusion in Pigs

Greyson

et al. 2003

Diabetes

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“…The number of sodium channels in rat cardiomyocytes was quantified by measuring the specific binding of the sodium channel-specific toxin [ 3 H]BTXB to the cells. This has been shown to be a reliable method by a number of investigators (2,16,20,21). (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Sodium channel blockers have been previously shown to up-regulate sodium channel expression, as measured by Northern blot analysis and radioligand binding assay (2,3,22,23). Chronic in vivo treatment with mexiletine produced an increase in both sodium channel mRNA and protein in rat cardiac muscle (2,3).…”

Section: Discussionmentioning

confidence: 99%

“…Although the mechanisms responsible for these deleterious effects during chronic administration of the class I antiarrhythmic drugs are not fully understood, one possible explanation comes from the findings reported from the laboratories of Catterall and Duff (2,3). They found that chronic treatment in rats with the class I antiarrhythmic drug mexiletine resulted in upregulation of cardiac Na ϩ channel expression, as shown by increase in both the level of mRNA encoding sodium channel ␣-subunits and the number of sodium channels per cell.…”

mentioning

confidence: 99%

“…They found that chronic treatment in rats with the class I antiarrhythmic drug mexiletine resulted in upregulation of cardiac Na ϩ channel expression, as shown by increase in both the level of mRNA encoding sodium channel ␣-subunits and the number of sodium channels per cell. It was proposed that the increased number of sodium channels caused by chronic treatment with these drugs may itself cause arrhythmias as a secondary consequence of therapy (2,3). These previous observations indicate the importance of careful reevaluation of the safety of other forms of antiarrhythmic agents and the need of development of a safe and highly effective means of preventing lethal arrhythmias.…”

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confidence: 99%

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Regulation of sodium channel gene expression by class I antiarrhythmic drugs and n − 3 polyunsaturated fatty acids in cultured neonatal rat cardiac myocytes

Kang

Leaf

1997

Proc. Natl. Acad. Sci. U.S.A.

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Previous studies have shown that chronic administration of class I antiarrhythmic drugs, which have definite inhibitory action on the fast Na ؉ channel, result in up-regulation of cardiac Na ؉ channel expression, and suggest that this effect may contribute to their deleterious effects during chronic administration. Recent studies have shown that the antiarrhythmic effects of free n ؊ 3 polyunsaturated fatty acids (PUFA) are associated with an inhibition of the Na ؉ channel. Whether the PUFA when used chronically will mimic the effect of the class I drugs on the expression of the Na ؉ channel is not known. To answer this question, we determined the level of mRNA encoding cardiac Na ؉ channels and the number of the Na ؉ channels per cell in cultured neonatal rat cardiac myocytes after supplementation of the cells with the n ؊ 3 PUFA eicosapentaenoic acid (EPA), the class I drug mexiletine, or both EPA and mexiletine for 3-4 days. The number of sodium channels was assessed with a radioligand binding assay using the sodium channel-specific toxin 3 H]BTXB binding, compared with that seen with mexiletine alone. RNA isolated from cardiac myocytes was probed with a 2.5-kb cRNA transcribed with T7 RNA polymerase from the clone Na-8.4, which encodes nucleotides 3361-5868 of the ␣-subunit of the R IIA sodium channel subtype. The changes in the level of mRNA encoding sodium channel ␣-subunit were correlated with comparable changes in sodium channel number in the cultured myocytes, indicating that regulation of transcription of mRNA or its processing and stability is primarily responsible for the regulation of sodium channel number. These data demonstrate that chronic EPA treatment not only does not up-regulate the cardiac sodium channel expression but also reduces the mexiletineinduced increase in the cardiac sodium channel expression.

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Biochemical and biophysical studies of the interaction of class I antiarrhythmic drugs with the cardiac sodium channel

Zamponi

Duff

French

et al. 1994

Drug Development Research

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Class I antiarrhythmic drugs block the cardiac sodium channel and are now used widely for a variety ot cardiac arrhythmias. The nature of the interaction of the drugs with these channels, and their mechanism of action, have been areas of considerable recent interest. Here we review several aspects of drug action. tvidence that sodium channel blockade itself i s antiarrhythmic arises from experiments in which the sodium channel-specific toxin tetrodotoxin was shown to prevent ventricular fibrillation in rabbit hearts. A radioligand binding assay for the cardiac sodium channel was then developed using 13H]Batrachotoxin~n (BTX) Benzoate and freshly isolated rat cardiac myocytes Class I antiarrhythmic drug binding identified in this model fits conventional criteria for binding to a receptor. This receptor behaves like an allosteric protein, class I antiarrhythmic drugs appear to bind to and stabilize closed channels. The mechanism of drug binding and electrophysiologic consequences have been examined in a number of model systems by microelectrode studies, whole cell voltage clamping, and more recently voltage clamp studies of single isolated channels in lipid bilayers. Using the latter method, we have shown that lidocaine causes two distinct kinds of sodium channel blockade. The first i s a very slow block which can be demonstrated with simple aryl compounds. The second kind of block i s a very rapid block which can also be caused by simple alkyl amines. Thus, the two major structural moieties of lidocdinc each cause a specific form of block. The structure-activity relationships o i class I drugs were explored with homologs of Iidocaine in the radioligand binding assay. With this method the existence of a number of receptor subdomains ha5 been demonstrated, each of which recognizes specific structural moieties of class I drugs. Finally, we have explored both drug proarrhythmia and drug resistance. Drug proarrhythmia may be due to homogeneous slowing of conduction with little effect o n refractoriness. One form of drug resistance may be due to induction of synthesis of new cardiac sodium channels by exposure to animals with chronic class i drug administration. Mexiletine induces a three-fold increase in rat cardiac sodium channels within 3 days due to increased sodium channel mRNA synthesis. Thus drug resistance might be due to drug-induced increases in the numbers of cardiac sodium channels.

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Upregulation of the rat cardiac sodium channel by in vivo treatment with a class I antiarrhythmic drug.

Cited by 40 publications

References 12 publications

Deleterious Effects of Acute Treatment With a Peroxisome Proliferator–Activated Receptor-γ Activator in Myocardial Ischemia and Reperfusion in Pigs

Deleterious Effects of Acute Treatment With a Peroxisome Proliferator–Activated Receptor-γ Activator in Myocardial Ischemia and Reperfusion in Pigs

Regulation of sodium channel gene expression by class I antiarrhythmic drugs and n − 3 polyunsaturated fatty acids in cultured neonatal rat cardiac myocytes

Biochemical and biophysical studies of the interaction of class I antiarrhythmic drugs with the cardiac sodium channel

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