Metabolites of the glycolytic pathway modulate the activity of single cardiac Na
            <sup>+</sup>
            channels

Kohlhardt, M.; Fichtner, H.; Fröbe, U.

doi:10.1096/fasebj.3.8.2542113

Cited by 33 publications

(14 citation statements)

References 17 publications

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“…As likewise found in cell-free conditions, several intermediate products of glycolysis including glyceroaldehyde phosphate and 2,3-diphosphoglycerate may also exert an influence thereby activating Na + channels and causing them to enhanced burst-like activity (Kohlhardt et al, 1989a). Apparently the same effect appears when lysophosphatidylcholine is present at the cytoplasmic surface of inside-out patches (Burnashev et al, 1989) which represents a degradation product of the membrane constituent phosphatidylcholine.…”

Section: Discussionmentioning

confidence: 74%

Na+ channel blockade by cyclic AMP and other 6-aminopurines in neonatal rat heart

Herzig

Kohlhardt

1991

J. Membrain Biol.

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Elementary Na+ currents were recorded at 19 degrees C in cell attached and inside-out patches from cultured neonatal rat cardiocytes in order to study the effect of cAMP and other 6-aminopurines. The treatment of the cardiocytes with db-cAMP (1 x 10(-3) mol/liter) led to a decline of reconstructed macroscopic peak INa to 62 +/- 7.6% of the initial control value. This reduction in NPo was mostly accompanied by a decrease in burst activity. Open-state kinetics were preserved even in DPI-modified, noninactivating Na+ channels. Since the stimulator of the adenylate cyclase, forskolin (1 x 10(-6) mol/liter), evoked a similar pattern of response, the NPo decrease can be considered as the functional correlate of Na+ channel phosphorylation brought about by cAMP-dependent protein kinase. As found in inside-out patches, cAMP (1 x 10(-3) mol/liter) remained effective under cell-free conditions and reduced reconstructed macroscopic peak INa to about 50% of the initial control value when the absence of Mg-ATP at the cytoplasmic membrane surface prevents phosphorylation reactions. A very similar response developed in the cytoplasmic presence of other 6-aminopurines including ATP (1 x 10(3) mol/liter), adenosine (1 x 10(-4) mol/liter), adenine (1 x 10(-5) mol/liter) and hypoxanthine (1 x 10(-5) mol/liter). This susceptibility to adenine suggests that cardiac Na+ channels in situ could sense intracellular fluctuations of adenine nucleotides, most likely of ATP.

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Section: Discussionmentioning

confidence: 74%

Na+ channel blockade by cyclic AMP and other 6-aminopurines in neonatal rat heart

Herzig

Kohlhardt

1991

J. Membrain Biol.

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“…The accumulation during ischemia of glycolytic metabolites (Kohlhardt et al, 1989) and the amphipathic lipids lysophosphatidylcholine and long-chain acyl carnitines (Sobel et al, 1978;DaTorre et al, 1991) appears to be at least partly responsible for causing the increase of late I Na during ischemia. There are several studies (see Gautier et al, 2008, and references therein) demonstrating the effect of lysophosphatidylcholine to increase late I Na and cause cardiac electrical and mechanical dysfunction.…”

Section: Discussionmentioning

confidence: 99%

The Late Na⁺ Current (I_Na) Inhibitor Ranolazine Attenuates Effects of Palmitoyl-L-Carnitine to Increase Late I_Na and Cause Ventricular Diastolic Dysfunction

Wu¹,

Song²,

Belardinelli³

et al. 2009

J Pharmacol Exp Ther

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Palmitoyl-L-carnitine (PC), an ischemic metabolite, causes cellular Na ϩ and Ca 2ϩ overload and cardiac dysfunction. This study determined whether ranolazine [(Ϯ)-1-piperazineacetamide, N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]Ϫ] attenuates PC-induced Na ϩ current and ventricular contractile dysfunction of the isolated heart. PC (4 M, 30 min) increased late Na ϩ current by 1034 Ϯ 349% in guinea pig isolated ventricular myocytes; ranolazine (10 M) and tetrodotoxin (TTX, 3 M) significantly attenuated this effect of PC. PC increased left ventricular end-diastolic pressure (LVEDP), coronary perfusion pressure (CPP), wall stiffness, and cardiac lactate and adenosine release from the isolated heart. Ranolazine (10 M) significantly reduced the PC-induced increase in LVEDP by 72 Ϯ 6% (n ϭ 6, p Ͻ 0.001), reduced left ventricular wall stiffness, and attenuated the PC-induced increase of CPP by 53 Ϯ 10% (n ϭ 6 -7, p Ͻ 0.05). Ranolazine (10 M) reduced the PC-induced increases of lactate and adenosine release by 70 Ϯ 8 and 81 Ϯ 5%, respectively (n ϭ 6, p Յ 0.05 for both). TTX (2 M) significantly (p Ͻ 0.05) reduced PC-induced increases of CPP and LVEDP. Pretreatment of isolated myocytes or hearts with the free radical scavenger tiron (4,5-dihydroxy-1,3-benzenedisulfonic acid, disodium salt) (1 mM) significantly reduced the effects of PC to cause increases of late Na ϩ current and LVEDP, respectively, but unlike ranolazine or TTX, tiron did not reverse increases of late Na ϩ current and LVEDP caused by PC. In summary, ranolazine and TTX, inhibitors of the late Na ϩ current, attenuated the PC-induced ventricular contractile dysfunction and increase of coronary resistance in the guinea pig isolated heart. Long-chain acyl carnitines, including palmitoyl-L-carnitine (PC), are intermediates of fatty acid metabolism that accumulate rapidly during brief ischemia (Sobel et al., 1978;DaTorre et al., 1991), secondary to a reduction of tissue oxygenation and mitochondrial lipid oxidation. Hypoxia of 1-h duration was shown to increase the content of long-chain acylcarnitines in sarcolemmal membranes of cultured neonatal rat cardiac myocytes by 70-fold (Knabb et al., 1986). PC has been shown to cause metabolic, electrical, and mechanical cardiac malfunction (Corr et al

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“…Regarding the nature of the glucose-derived metabolite(s) sensed by glomus cells, there are several candidates. For instance, TRP and various subtypes of voltage-gated channels can be modulated by NAD/NADH, ADP-ribose, 2,3 diphosphoglycerate, or glyceraldehyde phosphate (41)(42)(43)(44). Another possibility is that glucopenia leads to an increase in the AMP/ATP ratio in glomus cells and to activation of AMP kinase, which in turn activates the Na ϩ -permeable channels.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Low-Glucose Sensitivity in Carotid Body Glomus Cells

et al. 2007

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OBJECTIVE—Glucose sensing is essential for the adaptive counterregulatory responses to hypoglycemia. We investigated the mechanisms underlying carotid body (CB) glomus cells activation by low glucose. RESEARCH DESIGN/METHODS AND RESULTS—Removal of extracellular glucose elicited a cell secretory response, abolished by blockade of plasma membrane Ca2+ channels, and a reversible increase in cytosolic Ca2+ concentration. These data indicated that glucopenia induces transmembrane Ca2+ influx and transmitter secretion. In patch-clamped glomus cells, exposure to low glucose resulted in inhibition of macroscopic outward K+ currents and in the generation of a depolarizing receptor potential (DRP). The DRP was abolished upon removal of extracellular Na+. The membrane-permeable 1-oleoyl-2-acetyl-sn-glycerol induced inward currents of similar characteristics as the current triggered by glucose deficiency. The functional and pharmacological analyses suggest that low glucose activates background cationic Na+-permeant channels, possibly of the transient receptor potential C subtype. Rotenone, a drug that occludes glomus cell sensitivity to hypoxia, did not abolish responsiveness to low glucose. The association of Glut2 and glucokinase, characteristic of some high glucose–sensing cells, did not seem to be needed for low glucose detection. CONCLUSIONS—Altogether, these data support the view that the CB is a multimodal chemoreceptor with a physiological role in glucose homeostasis.

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Metabolites of the glycolytic pathway modulate the activity of single cardiac Na ⁺ channels

Cited by 33 publications

References 17 publications

Na+ channel blockade by cyclic AMP and other 6-aminopurines in neonatal rat heart

Na+ channel blockade by cyclic AMP and other 6-aminopurines in neonatal rat heart

The Late Na⁺ Current (I_Na) Inhibitor Ranolazine Attenuates Effects of Palmitoyl-L-Carnitine to Increase Late I_Na and Cause Ventricular Diastolic Dysfunction

Mechanisms of Low-Glucose Sensitivity in Carotid Body Glomus Cells

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Metabolites of the glycolytic pathway modulate the activity of single cardiac Na + channels

Cited by 33 publications

References 17 publications

Na+ channel blockade by cyclic AMP and other 6-aminopurines in neonatal rat heart

Na+ channel blockade by cyclic AMP and other 6-aminopurines in neonatal rat heart

The Late Na+ Current (INa) Inhibitor Ranolazine Attenuates Effects of Palmitoyl-L-Carnitine to Increase Late INa and Cause Ventricular Diastolic Dysfunction

Mechanisms of Low-Glucose Sensitivity in Carotid Body Glomus Cells

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Metabolites of the glycolytic pathway modulate the activity of single cardiac Na ⁺ channels

The Late Na⁺ Current (I_Na) Inhibitor Ranolazine Attenuates Effects of Palmitoyl-L-Carnitine to Increase Late I_Na and Cause Ventricular Diastolic Dysfunction