Beneficial Effects of Dilazep on the Palmitoyl-L-carnitine-Induced Derangements in Isolated, Perfused Rat Heart: Comparison with Tetrodotoxin.

Hara, Akiyoshi; Arakawa, Johji; Hashizume, Hiroko; Abiko, Yasushi

doi:10.1254/jjp.74.147

Cited by 10 publications

(13 citation statements)

References 21 publications

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“…This result indicates that the prolongation of APD caused by H 2 O 2 can be mainly attributed to an increase of late I Na . Consistent with the findings of the present study, TTX has been shown to markedly attenuate the deleterious effects (Ca 2ϩ overload, diastolic dysfunction, and so on) caused by ROS and palmitoyl-L-carnitine, known to increase late I Na (Ver Donck and Borgers, 1991;Hara et al, 1997). Ranolazine has also been reported to be a rather selective (38-fold) inhibitor of late relative to peak I Na (Undrovinas et al, 2006).…”

Section: Attenuation Of Arrhythmogenic Actions Of Ros 219supporting

confidence: 90%

Blocking Late Sodium Current Reduces Hydrogen Peroxide-Induced Arrhythmogenic Activity and Contractile Dysfunction

Song¹,

Shryock²,

Wagner³

et al. 2006

J Pharmacol Exp Ther

252

242

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Reactive oxygen species (ROS), including H 2 O 2 , cause intracellular calcium overload and ischemia-reperfusion damage. The objective of this study was to examine the hypothesis that H 2 O 2 -induced arrhythmic activity and contractile dysfunction are the results of an effect of H 2 O 2 to increase the magnitude of the late sodium current (late I Na ). Guinea pig and rabbit isolated ventricular myocytes were exposed to 200 M H 2 O 2 . Transmembrane voltages and currents and twitch shortening were measured using the whole-cell patch-clamp technique and video edge detection, respectively.

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Section: Attenuation Of Arrhythmogenic Actions Of Ros 219supporting

confidence: 90%

Blocking Late Sodium Current Reduces Hydrogen Peroxide-Induced Arrhythmogenic Activity and Contractile Dysfunction

Song¹,

Shryock²,

Wagner³

et al. 2006

J Pharmacol Exp Ther

252

242

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“…Long-chain acylcarnitines are regarded as one of the important factors in producing irreversible damage in the ischemic heart [6,7], and therefore several studies have addressed the actions of substances that protect the myocardium from damage induced by long-chain acylcarnitine [10,[15][16][17][18]. We have shown that lidocaine [15], dilazep [16,17] and diltiazem [10] attenuate the PALCAR-induced mechanical and metabolic derangements in the isolated perfused heart.…”

Section: Discussionmentioning

confidence: 99%

“…We have shown that lidocaine [15], dilazep [16,17] and diltiazem [10] attenuate the PALCAR-induced mechanical and metabolic derangements in the isolated perfused heart. Kang and Leaf [18] have reported that free polyunsaturated fatty acids attenuate arrhythmia induced by PAL- CAR in cardiac myocytes.…”

Section: Discussionmentioning

confidence: 99%

“…Second, administration of 5 Ìmol/l PALCAR may inflict damage to the heart to an extent similar to that induced by ischemia in terms of tissue accumulation of long-chain acylcarnitines [19]. Last, 5 Ìmol/l PALCAR produces not only mechanical dysfunction and energy deficiency [10,15,16] but also membrane damage [10,19], and induces electrophysiological alterations [11,12,20] in the heart.…”

Section: Discussionmentioning

confidence: 99%

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Effect of 5-(N,N-Dimethyl)-Amiloride, a Specific Inhibitor of Na+/H+ Exchanger, on the Palmitoyl-L-Carnitine-Induced Mechanical and Metabolic Derangements in the Isolated Perfused Rat Heart

Arakawa

Hara

1999

Pharmacology

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The present study was carried out to determine the effect of 5-(N,N-dimethyl)-amiloride (DMA), a specific inhibitor of the Na⁺/H⁺ exchanger, on the cardiac mechanical and metabolic derangements induced by palmitoyl-L-carnitine (PALCAR). Rat hearts were perfused aerobically at a constant flow according to the Langendorff technique, while being paced electrically. PALCAR (5 μmol/l) increased the left-ventricular end-diastolic pressure, decreased the left ventricular developed pressure (i.e. mechanical dysfunction), decreased the tissue level of ATP and increased the tissue level of AMP (i.e. metabolic change). DMA (10 or 20 μmol/l) attenuated the mechanical and metabolic alterations induced by PALCAR in a concentration-dependent way. Nevertheless, DMA (10 or 20 μmol/l) did not affect the mechanical function or energy metabolism in the normal (PALCAR-untreated) heart. These results suggest that inhibition of the Na⁺/H⁺ exchanger with DMA is effective in attenuating the PALCAR-induced mechanical and metabolic derangements in the heart.

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“…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, 1979;Sakata et al, 1989;Sato et al, 1992Sato et al, , 1993Tanaka et al, 1992;Wu and Corr, 1992Allely et al, 1993;Shen and Pappano, 1995;Hara et al, 1997;Netticadan et al, 1999;Maruyama et al, 2000). PC alters ion channel function and has been reported to decrease I Ca,L (Wu and Corr, 1992), reduce the open probability of the inward rectifier K ϩ current I K1 (Sato et al, 1993), inhibit I KATP (Haruna et al, 2000), and reduce peak I Na (Sato et al, 1992).…”

mentioning

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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Beneficial Effects of Dilazep on the Palmitoyl-L-carnitine-Induced Derangements in Isolated, Perfused Rat Heart: Comparison with Tetrodotoxin.

Cited by 10 publications

References 21 publications

Blocking Late Sodium Current Reduces Hydrogen Peroxide-Induced Arrhythmogenic Activity and Contractile Dysfunction

Blocking Late Sodium Current Reduces Hydrogen Peroxide-Induced Arrhythmogenic Activity and Contractile Dysfunction

Effect of 5-(N,N-Dimethyl)-Amiloride, a Specific Inhibitor of Na<sup>+</sup>/H<sup>+</sup> Exchanger, on the Palmitoyl-<i>L</i>-Carnitine-Induced Mechanical and Metabolic Derangements in the Isolated Perfused 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

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Beneficial Effects of Dilazep on the Palmitoyl-L-carnitine-Induced Derangements in Isolated, Perfused Rat Heart: Comparison with Tetrodotoxin.

Cited by 10 publications

References 21 publications

Blocking Late Sodium Current Reduces Hydrogen Peroxide-Induced Arrhythmogenic Activity and Contractile Dysfunction

Blocking Late Sodium Current Reduces Hydrogen Peroxide-Induced Arrhythmogenic Activity and Contractile Dysfunction

Effect of 5-(N,N-Dimethyl)-Amiloride, a Specific Inhibitor of Na<sup>+</sup>/H<sup>+</sup> Exchanger, on the Palmitoyl-<i>L</i>-Carnitine-Induced Mechanical and Metabolic Derangements in the Isolated Perfused Rat Heart

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

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