Effects of a Selective Inhibitor of Na+/Ca2+ Exchange, KB-R7943, on Reoxygenation-Induced Injuries in Guinea Pig Papillary Muscles

Mukai, Makoto; Terada, Hajime; Sugiyama, Shiho; Satoh, Hiroshi; Hayashi, Hideharu

doi:10.1097/00005344-200001000-00016

Cited by 55 publications

(27 citation statements)

References 28 publications

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“…38 KB-R7943 has been shown to prevent digitalis-induced calcium overload of cardiomyocytes 21 and was also effective in preventing reoxygenationinduced injury in cardiomyocytes 39 and isolated papillary muscles. 40 The data from the present study show that KB-R7943 could prevent hydroxyl radical-induced acute diastolic dysfunction. KB-R7943 was not administered until after hydroxyl radical exposure was finished, so that potential scavenger properties of the KB-R7943 molecule can be excluded to cause the protective effect of the compound.…”

Section: Hydroxyl Radicals and Calcium Overloadsupporting

confidence: 49%

Hydroxyl Radical-Induced Acute Diastolic Dysfunction Is Due to Calcium Overload via Reverse-Mode Na ⁺ -Ca ²⁺ Exchange

Zeitz

Maass²,

Nguyen³

et al. 2002

Circulation Research

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Abstract-Hydroxyl radicals (OH) are involved in the development of reperfusion injury and myocardial failure. In the acute phase of the OH-mediated diastolic dysfunction, increased intracellular Ca 2ϩ levels and alterations of myofilaments may play a role, but the relative contribution of these systems to myocardial dysfunction is unknown. Intact contracting cardiac trabeculae from rabbits were exposed to OH, resulting in an increase in diastolic force (F dia ) by 540%. Skinned fiber experiments revealed that OH-exposed preparations were sensitized for Ca 2ϩ (EC 50 : 3.27Ϯ0.24ϫ10Ϫ6 versus 2.69Ϯ0.15ϫ10 Ϫ6 mol/L; PϽ0.05), whereas maximal force development was unaltered. Western blots showed a proteolytic degradation of troponin T (TnT) with intact troponin I (TnI). Blocking of calpain I by MDL-28.170 inhibited both TnT-proteolysis and Ca 2ϩ sensitization, but failed to prevent the acute diastolic dysfunction in the intact preparation. The OH-induced diastolic dysfunction was similar in preparations with intact (540Ϯ93%) and pharmacologically blocked sarcoplasmic reticulum (539Ϯ77%), and was also similar in presence of the L-type Ca 2ϩ -channel antagonist verapamil. In sharp contrast, inhibition of the reverse-mode sodium-calcium exchange by KB-R7943 preserved diastolic function completely. Additional experiments were performed in rat myocardium; the rise in diastolic force was comparable to rabbit myocardium, but Ca 2ϩ sensitivity was unchanged and maximal force development was reduced. This was associated with a degradation of TnI, but not TnT. Electron microscopic analysis revealed that OH did not cause irreversible membrane damage. We conclude that OH-induced acute diastolic dysfunction is caused by Ca 2ϩ influx via reverse mode of the sodium-calcium exchanger. Degradation of troponins appears to be species-dependent but does not contribute to the acute diastolic dysfunction.

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Section: Hydroxyl Radicals and Calcium Overloadsupporting

confidence: 49%

Hydroxyl Radical-Induced Acute Diastolic Dysfunction Is Due to Calcium Overload via Reverse-Mode Na ⁺ -Ca ²⁺ Exchange

Zeitz

Maass²,

Nguyen³

et al. 2002

Circulation Research

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“…Our results affirmed the opinion of some authors about the antiarrhythmogenic effect of reoxygenation [56,57]. However, some reports describe serious injury to the heart by the reoxygenation [58,59].…”

Section: Discussionsupporting

confidence: 91%

Light-dark dependence of electrocardiographic changes during asphyxia and reoxygenation in a rat model

et al. 2010

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AbstractThe aim of this study was to evaluate the effect of ventilation on electrocardiographic time intervals as a function of the light-dark (LD) cycle in an in vivo rat model. RR, PQ, QT and QTc intervals were measured in female Wistar rats anaesthetized with both ketamine and xylazine (100 mg/15 mg/kg, i.m., open chest experiments) after adaptation to the LD cycle (12:12h) for 4 weeks. Electrocardiograms (ECG) were recorded before surgical interventions; after tracheotomy, and thoracotomy, and 5 minutes of stabilization with artificial ventilation; 30, 60, 90 and 120 seconds after the onset of apnoea; and after 5, 10, 15, and 20 minutes of artificial reoxygenation. Time intervals in intact animals showed significant LD differences, except in the QT interval. The initial significant (p<0,001) LD differences in PQ interval and loss of dependence on LD cycle in the QT interval were preserved during short-term apnoea-induced asphyxia (30–60 sec) In contrast, long-term asphyxia (90–120 sec) eliminated LD dependence in the PQ interval, but significant LD differences were shown in the QT interval. Apnoea completely abolished LD differences in the RR interval. Reoxygenation restored the PQ and QT intervals to the pre-asphyxic LD differences, but with the RR intervals, the LD differences were eliminated. We have concluded that myocardial vulnerability is dependent on the LD cycle and on changes of pulmonary ventilation.

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“…This blocker selectively inhibited the reverse mode of Na + /Ca 2+ exchange, attenuated reoxygenation-induced arrhythmic activity and prevented contractile dysfunction in guinea pig papillary muscles. These results suggest that Ca 2+ influx by Na + /Ca 2+ exchange may play a key role in reoxygenation injury (Mukai et al, 2000). It is well established that hypoxia followed by reperfusion may be fatal and result in generation of reactive oxygen species (ROS) and subsequent tissue damage (Danielsson et al, 2007) and is associated with additional damage to the myocardium by oxidation of cellular components and activation of the inflammatory cascade (Cerniway et al, 2002).…”

Section: Wwwintechopencom Chronobiological Aspects Of the Heart Rhymentioning

confidence: 98%

Chronobiological Aspects of the Heart Rhythm Disorders at the Change of Pulmonary Ventilation in Rat Model

Švorc¹,

Marossy²,

Grešová³

et al. 2012

Cardiac Arrhythmias - New Considerations

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Effects of a Selective Inhibitor of Na+/Ca2+ Exchange, KB-R7943, on Reoxygenation-Induced Injuries in Guinea Pig Papillary Muscles

Cited by 55 publications

References 28 publications

Hydroxyl Radical-Induced Acute Diastolic Dysfunction Is Due to Calcium Overload via Reverse-Mode Na ⁺ -Ca ²⁺ Exchange

Hydroxyl Radical-Induced Acute Diastolic Dysfunction Is Due to Calcium Overload via Reverse-Mode Na ⁺ -Ca ²⁺ Exchange

Light-dark dependence of electrocardiographic changes during asphyxia and reoxygenation in a rat model

Chronobiological Aspects of the Heart Rhythm Disorders at the Change of Pulmonary Ventilation in Rat Model

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Effects of a Selective Inhibitor of Na+/Ca2+ Exchange, KB-R7943, on Reoxygenation-Induced Injuries in Guinea Pig Papillary Muscles

Cited by 55 publications

References 28 publications

Hydroxyl Radical-Induced Acute Diastolic Dysfunction Is Due to Calcium Overload via Reverse-Mode Na + -Ca 2+ Exchange

Hydroxyl Radical-Induced Acute Diastolic Dysfunction Is Due to Calcium Overload via Reverse-Mode Na + -Ca 2+ Exchange

Light-dark dependence of electrocardiographic changes during asphyxia and reoxygenation in a rat model

Chronobiological Aspects of the Heart Rhythm Disorders at the Change of Pulmonary Ventilation in Rat Model

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Hydroxyl Radical-Induced Acute Diastolic Dysfunction Is Due to Calcium Overload via Reverse-Mode Na ⁺ -Ca ²⁺ Exchange

Hydroxyl Radical-Induced Acute Diastolic Dysfunction Is Due to Calcium Overload via Reverse-Mode Na ⁺ -Ca ²⁺ Exchange