Role of intracellular sodium in the regulation of intracellular calcium and contractility. Effects of DPI 201-106 on excitation-contraction coupling in human ventricular myocardium.

Gwathmey, Judith K.; Slawsky, Mara; Briggs, George M.; Morgan, James P.

doi:10.1172/jci113771

Cited by 43 publications

(13 citation statements)

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“…It is only at higher stimulus frequencies that depressed myocardial contractility is observed and peak intracellular calcium concentration is reduced in the presence of elevated diastolic calcium concentrations (Schmidt et al 1998). We have also shown that at higher stimulus frequencies with failing human myocardium, there is progressive abbreviation in APD as opposed to the abbreviation seen in non-failing myocardium that stabilizes at a set frequency and APD (Gwathmey et al 1988). Similarly, we found that APD was dynamically changed in response to stimulus frequency perturbation in failed avian myocardium, such that APD did not reach steady-state at higher frequencies.…”

Section: Discussionmentioning

confidence: 55%

Intracellular calcium and the relationship to contractility in an avian model of heart failure

Kim

Davidoff

Mäki

et al. 2000

Journal of Comparative Physiology B: Biochemical, Systemic, and

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Global contractile heart failure was induced in turkey poults by furazolidone feeding (700 ppm).Abnormal calcium regulation appears to be a key factor in the pathophysiology of heart failure, but the cellular mechanisms contributing to changes in calcium fluxes have not been clearly defined. Isolated ventricular myocytes from non-failing and failing hearts were therefore used to determine whether the whole heart and ventricular muscle contractile dysfunctions were realized at the single cell level. Whole cell current-and voltage-clamp techniques were used to evaluate action potential configurations and L-type calcium currents, respectively. Intracellular calcium transients were evaluated in isolated myocytes with fura-2 and in isolated left ventricular muscles using aequorin. Action potential durations were prolonged in failing myocytes, which correspond to slowed cytosolic calcium clearing. Calcium current-voltage relationships were normal in failing myocytes; preliminary evidence suggests that depressed transient outward potassium currents contribute to prolonged action potential durations. The number of calcium channels (as measured by radioligand binding) were also similar in non-failing and failing hearts. Isolated ventricular muscles from failing hearts had enhanced inotropic responses, in a dose-dependent fashion, to a calcium channel agonist (Bay K 8644). These data suggest that changes in intracellular calcium mobilization kinetics and longer calcium-myofilament interaction may be able to compensate for contractile failure. We conclude that the relationship between calcium current density and sarcoplasmic reticulum calcium release is a dynamic process that may be altered in the setting of heart failure at higher contraction rates. Keywords

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Section: Discussionmentioning

confidence: 55%

Intracellular calcium and the relationship to contractility in an avian model of heart failure

Kim

Davidoff

Mäki

et al. 2000

Journal of Comparative Physiology B: Biochemical, Systemic, and

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“…However, this pathway can also promote Ca 2 + influx. Ca 2 + influx would continue during the plateau phase of the action potential until membrane potential repolarizes to −40 mV, the calculated reversal potential for Na + -Ca 2 + exchange [43]. At that point Ca 2 + efflux would begin, resulting in relaxation.…”

Section: Discussionmentioning

confidence: 99%

“…The contribution of the Na +-Ca 2 + exchanger to Ca 2 + handling could be more efficient in HF if one takes into account that messenger RNA (mRNA) as well as protein levels are significantly increased in the failing human heart [9,44]. Another potential source of Ca 2 + entry during action potential plateau, the L-type Ca 2 + ''window'' current [45], was shown to have a limited contribution to overall Ca 2 + entry into the cell in human HF [43]. The data on L-type Ca 2 + -channel expression in HF are still controversial.…”

Section: Discussionmentioning

confidence: 99%

Relationship between action potential, contraction-relaxation pattern, and intracellular Ca 2+ transient in cardiomyocytes of dogs with chronic heart failure

Maltsev¹,

Sabbah²,

Tanimura³

et al. 1998

Cellular and Molecular Life Sciences (CMLS)

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Abnormalities of contractile function have been identified in cardiomyocytes isolated from failed human hearts and from hearts of animals with experimentally induced heart failure (HF). The mechanism(s) responsible for these functional abnormalities are not fully understood. In the present study, we examined the relationship between action potential duration, pattern of contraction and relaxation, and associated intracellular Ca2+ transients in single cardiomyocytes isolated from the left ventricle (LV) of dogs (n = 7) with HF produced by multiple sequential intracoronary microembolizations. Comparisons were made with LV cardiomyocytes isolated from normal dogs. Action potentials were measured in isolated LV cardiomyocytes by perforated patch clamp, Ca2+ transients by fluo 3 probe fluorescence, and cardiomyocyte contraction and relaxation by edge movement detector. HF cardiomyocytes exhibited an abnormal pattern of contraction and relaxation characterized by an attenuated initial twitch (spike) followed by a sustained contracture ('dome') of 1 to 8 s in duration and subsequent delayed relaxation. This pattern was more prominent at low stimulation rates (58% at 0.2 Hz, n = 211, 21% at 0.5 Hz, n = 185). Measurements of Ca2+ transients in HF cardiomyocytes at 0.2 Hz manifested a similar spike and dome configuration. The dome phase of both the contraction/relaxation pattern and Ca2+ transients seen in HF cardiomyocytes coincided with a sustained plateau of the action potential. Shortening of the action potential duration by administration of saxitoxin (100 nM) or lidocaine (30 microM) reduced the duration of the dome phase of both the contraction/relaxation profile as well as that of the Ca2+ transient profile. An increase of stimulation rate up to 1 Hz caused shortening of the action potential and disappearance of the spike-dome profile in the majority of HF cardiomyocytes. In HF cardiomyocytes, the action potential and Ca2+ transient duration were not significantly different from those measured in normal cells. However, the contraction-relaxation cycle was significantly longer in HF cells (314 +/- 67 ms, n = 21, vs. 221 +/- 38 ms, n = 46, mean +/- SD), indicating impaired excitation-contraction uncoupling in HF cardiomyocytes. The results show that, in cardiomyocytes isolated from dogs with HF, contractile abnormalities and abnormalities of intracellular Ca2+ transients at low stimulation rates are characterized by a spike-dome configuration. This abnormal pattern appears to result from prolongation of the action potential.

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“…1 (top (12). The action potential was also prolonged ( 14,15 ). The addition of 1 X lo-5 M ryanodine significantly depressed the peak levels of tension and Ca?'.…”

Section: Resultsmentioning

confidence: 95%

“…The (12,14,15). With this combination of drugs, Ca2" release from the sarcoplasmic reticulum (SR), which predominantly regulates the Ca?'…”

Section: Methodsmentioning

confidence: 99%

Sodium/calcium exchange modulates intracellular calcium overload during posthypoxic reoxygenation in mammalian working myocardium. Evidence from aequorin-loaded ferret ventricular muscles.

Kihara¹,

Sasayama²,

Inoko³

et al. 1994

J. Clin. Invest.

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We tested the hypothesis that the intracellular Ca2" overload of ventricular myocardium during the period of posthypoxic reoxygenation is mediated by transsarcolemmal Ca2" influx via Na + /Ca2+ exchange. In aequorin-loaded, ferret right ventricular papillary muscles, blockers of the sarcolemmal and the sarcoplasmic reticulum Ca2" channels, slowed the Ca?' transient, producing a convex ascent during membrane depolarization, followed by a concave descent during repolarization. The magnitude of the Ca, transient was affected by changes in the membrane potential, Nat, Na4, and Ca2+, and was blocked by Ni2+, or dichlorbenzamil. The calculated Na+/Ca2' exchange current was in the reverse mode (Ca2+ influx) during the ascending phase of the Ca2+ transient, and was abruptly switched to the forward mode (Ca2+ efflux) at repolarization, matching the time course of the CaF+ transient. During hypoxic superfusion, the Ca transient was abbreviated, which was associated with a shorter action potential duration. In contrast, immediately after reoxygenation, the Ca?' transient increased to a level greater than that of the control, even though the action potential remained abbreviated. This is the first demonstration on a beat-to-beat basis that, during reoxygenation, Ca2+ influx via Na+/Ca2+ exchange is augmented and transports a significant amount of Ca2+ into the ventricular myocardial cell. The activation of the exchanger at the time of reoxygenation appears to be mediated by Na+ accumulation, which occurs during hypoxia. (J. Clin. Invest. 1994.93:1275-1284

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Role of intracellular sodium in the regulation of intracellular calcium and contractility. Effects of DPI 201-106 on excitation-contraction coupling in human ventricular myocardium.

Cited by 43 publications

References 50 publications

Intracellular calcium and the relationship to contractility in an avian model of heart failure

Intracellular calcium and the relationship to contractility in an avian model of heart failure

Relationship between action potential, contraction-relaxation pattern, and intracellular Ca 2+ transient in cardiomyocytes of dogs with chronic heart failure

Sodium/calcium exchange modulates intracellular calcium overload during posthypoxic reoxygenation in mammalian working myocardium. Evidence from aequorin-loaded ferret ventricular muscles.

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