Na/Ca Exchange and the Sarcolemmal Ca-Pump

Bers, Donald M.

doi:10.1007/978-94-010-0658-3_6

Cited by 9 publications

(12 citation statements)

References 133 publications

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“…These results confirm the observation by Wang et al [37] in isolated ventricular papillary muscles preparations and in ventricular myocytes. Bers [5] proposed that the rate of extrusion of intracellular Ca 2+ via the Na + -Ca 2+ exchange system plays an important role in the rate of muscle relaxation. Inhibition of this exchange system, and an ensuing delay in the Ca 2+ extrusion from the cells, causes the prolongation of action potential duration, prolongation of the time to the peak of twitch tension, and an increase in developed tension [5].…”

Section: Discussionmentioning

confidence: 99%

“…Bers [5] proposed that the rate of extrusion of intracellular Ca 2+ via the Na + -Ca 2+ exchange system plays an important role in the rate of muscle relaxation. Inhibition of this exchange system, and an ensuing delay in the Ca 2+ extrusion from the cells, causes the prolongation of action potential duration, prolongation of the time to the peak of twitch tension, and an increase in developed tension [5]. Wang et al 2+ concentrationcontraction curves observed in skinned fiber preparations.…”

Section: Discussionmentioning

confidence: 99%

“…These effects are expected because an inhibition of the Na + -Ca 2+ exchange system would elevate intracellular Ca 2+ concentrations more at higher stimulation frequencies when greater amounts of Ca 2+ enter the cells through the slow Ca 2+ channels [5,34]. Therefore, an inhibition of the Na + -Ca 2+ exchange system is unlikely to be the main mechanism responsible for the delay of muscle relaxation and the positive inotropic effects observed with mitoxantrone.…”

Section: Discussionmentioning

confidence: 99%

“…In fact, Ca 2+ removal by the Ca 2+ uptake mechanism accounts for approximately 70% of the total removal [5]. Thus, such a mechanism is thought to be the most important one, and the inhibition of the rate of Ca 2+ uptake is inferred to be the greatest cause of the delay in muscle relaxation [5].…”

Section: Discussionmentioning

confidence: 99%

“…The results show that doxorubicin causes an irreversible myocardial dysfunction. The impairment of the Ca 2+ handling mechanism of the sarcoplasmic reticulum is apparently the cause of myocardial dysfunction and hence the doxorubicin-induced late (chronic) cardiotoxicity.It has been reported that the time to the peak of twitch tension depends primarily on the rate of Ca 2+ -uptake by the sarcoplasmic reticulum [5], whereas the size of muscle contractions observed at lower stimulation frequencies [1,17,21,24,25,27] or the postrest contraction [4,27] depends on the Ca 2+ release from the sarcoplasmic reticulum. Consistent with these concepts, we observed that doxorubicintreatment of the rat results in a significant reduction of the caffeine-induced contraction in skinned muscle fiber preparations, although Ca 2+ sensitivity was unchanged [7].…”

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confidence: 99%

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Mechanisms Responsible for Reduced Cardiotoxicity of Mitoxantrone Compared to Doxorubicin Examined in Isolated Guinea-Pig Heart Preparations

et al. 2008

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ABSTRACT. We reported previously that doxorubicin, an anticancer agent that has an anthracycline structure, alters Ca 2+ releasing and uptake mechanisms in the sarcoplasmic reticulum of myocardial cells. These effects of doxorubicin are apparently related to its cardiotoxicity. Mitoxantrone is a similar anticancer agent with an anthracenedion structure that has been shown to be significantly less cardiotoxic. In the present study, the effects of mitoxantrone on the functions of the sarcoplasmic reticulum were examined in isolated muscle preparations obtained from the guinea-pig heart. In electrically-stimulated left atrial muscle preparations, incubation in vitro for 4 hr with 30 or 100 µM mitoxantrone significantly prolonged the time to the peak of twitch tension, markedly increased the developed tension observed at lower stimulation frequencies, thereby attenuating the slope of positive force-frequency relationships, and increased the postrest contraction observed after a 60-sec quiescent period. In myocytes isolated from ventricular muscles, 30 µM mitoxantrone increased the peak and the size of intracellular Ca 2+ concentrations ([Ca 2+ ]i), and prolonged the time to peak [Ca 2+ ]i. In skinned muscle fiber preparations obtained from the left ventricular muscle, 30 µM mitoxantrone significantly increased the caffeine-induced contraction without affecting the Ca 2+ sensitivity of contractile proteins. These results suggest that mitoxantrone enhances Ca 2+ release from the sarcoplasmic reticulum in isolated atrial muscle preparations obtained from the guinea-pig heart. Apparent enhancement of the sarcoplasmic reticulum functions, in contrast to anthracyclines that has been shown to suppress these functions, seems to explain the relative lack of marked cardiotoxicity of mitoxantrone. KEY WORDS: caffeine-induced contraction, Ca 2+ release and uptake by sarcoplasmic reticulum, inotropic effects, intracellular Ca 2+ concentration, mitoxantrone.J. Vet. Med. Sci. 70(3): 255-264, 2008 Anthracyclines are efficacious anti-tumor agents; however, their clinical usefulness is limited by serious cardiotoxic effects. Mitoxantrone, an anthracenedion derivative, has been synthesized in an attempt to develop an agent that has a reliable anticancer activity without the compromising cardiotoxic effects [9,35].Human as well as animal studies demonstrated that the cardiotoxic effects of mitoxantrone are significantly less severe at clinically equivalent anticancer doses compared to those observed with anthracyclines [2,9,11,13,20,22,33].We reported previously [7] that in vivo treatment of rats with doxorubicin results in a prolongation of the time to the peak of twitch tension, a reduction of the developed tension observed at lower stimulation frequencies and an attenuation of the postrest contraction (contraction that is evoked by the first stimulus after a brief quiescent period) observed in electrically-stimulated heart muscle preparations obtained from the drug-treated animals. These changes developed slowly with time aft...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Mechanisms Responsible for Reduced Cardiotoxicity of Mitoxantrone Compared to Doxorubicin Examined in Isolated Guinea-Pig Heart Preparations

et al. 2008

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Manganese ions as intracellular contrast agents: proton relaxation and calcium interactions in rat myocardium

et al. 2003

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Paramagnetic manganese (Mn) ions (Mn(2+)) are taken up into cardiomyocytes where they are retained for hours. Mn content and relaxation parameters, T(1) and T(2), were measured in right plus left ventricular myocardium excised from isolated perfused rat hearts. In the experiments 5 min wash-in of MnCl(2) were followed by 15 min wash-out to remove extracellular (ec) Mn(2+) MnCl(2), 25 and 100 micro M, elevated tissue Mn content to six and 12 times the level of control (0 micro M MnCl(2)). Variations in perfusate calcium (Ca(2+)) during wash-in of MnCl(2) and experiments including nifedipine showed that myocardial slow Ca(2+) channels are the main pathway for Mn(2+) uptake and that Mn(2+) acts as a pure Ca(2+) competitor and a preferred substrate for slow Ca(2+) channel entry. Inversion recovery analysis at 20 MHz revealed two components for longitudinal relaxation: a short T(1 - 1) and a longer T(1 - 2). Approximate values for control and Mn-treated hearts were in the range 600-125 ms for T(1 - 1) and 2200-750 ms for T(1 - 2). The population fractions were about 59 and 41% for the short and the long component, respectively. The intracellular (ic) R(1 - 1) and R(2 - 1) correlated best with tissue Mn content. Applying two-site exchange analyses on the obtained T(1) data yielded results in parallel to, but also differing from, results reported with an ec contrast agent. The calculated lifetime of ic water (tau(ic)) of about 10 s is compatible with a slow water exchange in the present excised cardiac tissue. The longitudinal relaxivity of Mn ions in ic water [60 (s mM)(-1)] was about one order of magnitude higher than that of MnCl(2) in water in vitro [6.9 (s mM)(-1)], indicating that ic Mn-protein binding is an important potentiating factor in relaxation enhancement.

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Na⁺/Ca²⁺ exchanger inhibition exerts a positive inotropic effect in the rat heart, but fails to influence the contractility of the rabbit heart

Farkas

Acsai

Nagy

et al. 2008

British J Pharmacology

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Background and purpose: The Na þ /Ca 2 þ exchanger (NCX) may play a key role in myocardial contractility. The operation of the NCX is affected by the action potential (AP) configuration and the intracellular Na þ concentration. This study examined the effect of selective NCX inhibition by 0.1, 0.3 and 1.0 mM SEA0400 on the myocardial contractility in the setting of different AP configurations and different intracellular Na þ concentrations in rabbit and rat hearts. Experimental approach: The concentration-dependent effects of SEA0400 on I Na/Ca were studied in rat and rabbit ventricular cardiomyocytes using a patch clamp technique. Starling curves were constructed for isolated, Langendorff-perfused rat and rabbit hearts. The cardiac sarcolemmal NCX protein densities of both species were compared by immunohistochemistry. Key results: SEA0400 inhibited I Na/Ca with similar efficacy in the two species; there was no difference between the inhibitions of the forward or reverse mode of the NCX in either species. SEA0400 increased the systolic and the developed pressure in the rat heart in a concentration-dependent manner, for example, 1.0 mM SEA0400 increased the maximum systolic pressures by 12% relative to the control, whereas it failed to alter the contractility in the rabbit heart. No interspecies difference was found in the cardiac sarcolemmal NCX protein densities. Conclusions and implications: NCX inhibition exerted a positive inotropic effect in the rat heart, but it did not influence the contractility of the rabbit heart. This implies that the AP configuration and the intracellular Na þ concentration may play an important role in the contractility response to NCX inhibition.

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Na/Ca Exchange and the Sarcolemmal Ca-Pump

Cited by 9 publications

References 133 publications

Mechanisms Responsible for Reduced Cardiotoxicity of Mitoxantrone Compared to Doxorubicin Examined in Isolated Guinea-Pig Heart Preparations

Mechanisms Responsible for Reduced Cardiotoxicity of Mitoxantrone Compared to Doxorubicin Examined in Isolated Guinea-Pig Heart Preparations

Manganese ions as intracellular contrast agents: proton relaxation and calcium interactions in rat myocardium

Na⁺/Ca²⁺ exchanger inhibition exerts a positive inotropic effect in the rat heart, but fails to influence the contractility of the rabbit heart

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Na/Ca Exchange and the Sarcolemmal Ca-Pump

Cited by 9 publications

References 133 publications

Mechanisms Responsible for Reduced Cardiotoxicity of Mitoxantrone Compared to Doxorubicin Examined in Isolated Guinea-Pig Heart Preparations

Mechanisms Responsible for Reduced Cardiotoxicity of Mitoxantrone Compared to Doxorubicin Examined in Isolated Guinea-Pig Heart Preparations

Manganese ions as intracellular contrast agents: proton relaxation and calcium interactions in rat myocardium

Na+/Ca2+ exchanger inhibition exerts a positive inotropic effect in the rat heart, but fails to influence the contractility of the rabbit heart

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Na⁺/Ca²⁺ exchanger inhibition exerts a positive inotropic effect in the rat heart, but fails to influence the contractility of the rabbit heart