Mechanisms contributing to the cardiac inotropic effect of Na pump inhibition and reduction of extracellular Na.

Bers, Donald M.

doi:10.1085/jgp.90.4.479

Cited by 98 publications

(70 citation statements)

References 64 publications

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“…outward. 10 That amount of calcium entering through voltage-dependent calcium channels is removed by the exchanger. However, when a' N , is raised, as it is during high atrial contraction frequency, the net movement of calcium through the exchanger becomes inward.…”

Section: Discussionmentioning

confidence: 99%

Calcium dependency of frequency-stimulated atrial natriuretic peptide secretion.

Schiebinger

Cragoe

1994

Hypertension

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In this study we examined the mechanism whereby atrial natriuretic peptide secretion is increased when the frequency of contraction is raised from 2 to 5 Hz. We tested the hypothesis that calcium plays a significant role in the frequency-stimulated response. Using superfused rat left atria, we found that lowering the superfusate calcium concentration from 1.8 to 0.2 mmol/L abolished the frequency-stimulated atrial natriuretic peptide secretory response. Superfusion with ryanodine (1 /xmol/L), an inhibitor of sarcoplasmic reticulum calcium release, resulted in a minimal inhibitory effect. Superfusion with 50 junol/L nitrendipine or 10 junol/L diltiazem inhibited the frequency-stimulated response by 46% to 48%. The lack of total inhibition suggested that an additional mechanism of calcium influx was involved, namely, inward calcium movement carried by Na + -Ca 2+ exchange. As intracellular sodium has been reported to rise with an increase in beat frequency, a fall in the sodium gradient would favor inward calcium movement by Na + -Ca 2+ exchange. Because we could not directly assess the role of Na + -Ca 2+ exchange in this experimental paradigm, we examined the effect of lowering the transmembrane sodium gradient on atrial natriuretic peptide secretion by superfusion with the sodium channel activator A trial tachycardias are associated with a rise in / \ plasma atrial natriuretic peptide (ANP) lev-A.JL els. 15 Using an isolated superfused rat atrial preparation, we have found that increasing the frequency of atrial contraction directly increases ANP secretion 6 ; this observation has been confirmed. 7 In the present study, we examined the mechanisms whereby an increase in the frequency of contraction enhances ANP secretion.It has been reported that raising the contraction frequency increases intracellular sodium activity (a' N> ) in rat atrial muscle. 8 In cardiac tissue, a rise in a' N , results in an increase in cytosolic calcium via Na + -Ca 2+exchange. 910 We therefore tested the hypothesis that calcium plays a significant role in the frequency-stimulated ANP secretory response because we and others have noted that calcium appears to play an important role in stimulated ANP secretion. 1115In addition, we attempted to determine the source of the rise in a' Nt , speculating that an increase in Na + -H + antiporter activity may contribute.

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Section: Discussionmentioning

confidence: 99%

Calcium dependency of frequency-stimulated atrial natriuretic peptide secretion.

Schiebinger

Cragoe

1994

Hypertension

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“…7,21) This effect is mediated by the Na,Ca-exchanger, since the reduction of the concentration gradient for Na + across the sarcolemma leads to a reduced Ca 2+ -extrusion by the Na,Ca-exchanger. 7) These data suggest that contracting failing human myocardium is more sensitive to a reduction of the Na,Ca-exchanger mediated Ca 2+ -extrusion. To assess whether this can be attributed to alterations of the Na,Ca-exchanger itself, direct measurements of the Na,Ca-exchanger activity were performed in vesicular preparations from failing and nonfailing hearts.…”

Section: Discussionmentioning

confidence: 99%

“…5,7) However, a study by Dipla and coworkers suggests that the Na,Ca-exchanger contributes significantly to the systolic Ca 2+ -influx (in reverse mode) of cardiomyocytes from failing human hearts indicating that at least in the failing heart an enhanced Ca 2+ -influx is part of the observed effect.…”

Section: Discussionmentioning

confidence: 99%

Increased Functional Importance of the Na,Ca-Exchanger in Contracting Failing Human Myocardium but Unchanged Activity in Isolated Vesicles

et al. 2007

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SUMMARYThe present study aimed to investigate the hypothesis that the function of the Na,Caexchanger (NCX) is of higher importance for contractility and Ca 2+-homeostasis in left ventricle from terminally failing than from nonfailing human hearts.The effect of decreasing extracellular [Na] e (140 to 25 mmol/L) on force of contraction in isolated left ventricular papillary muscle strips was studied as a reflection of NCX function in multicellular preparations (terminally failing, DCM, dilated cardiomyopathy, NYHA IV, n = 13; nonfailing, NF, donor hearts, n = 10). Decreasing [Na] e has previously been shown to increase contractility in vitro secondary to a decreased Ca 2+ -extrusion by the NCX. In addition, the NCX activity was measured as Na + -dependent 45 Ca 2+ -uptake into isolated myocardial vesicles as a function of time and Ca 2+ -concentration (DCM n = 8, NF n = 8). Decreasing [Na] e enhanced the contractility of papillary muscle strips in both DCM and NF, but the contractility of DCM was increased at smaller reductions of [Na] e than NF. The NCX activity in isolated myocardial vesicles was unchanged as a function of time (T 1/2 : DCM 2.4 ± 0.3 s versus NF 2.5 ± 0.3 s) and as a function of Ca These results demonstrate a higher sensitivity of the failing human myocardium towards Na,Ca-exchanger mediated positive inotropic effects, suggesting a higher significance of the Na,Ca-exchanger for the extrusion of Ca 2+ -ions in intact failing versus nonfailing human myocardium. Since the activity and the Ca 2+ -affinity of the Na,Caexchanger in isolated vesicles was unchanged, we propose that alterations in Ca 2+ -and Na + -homeostasis (due to impaired function of the sarcoplasmic reticulum and the Na + , K + -ATPase) or the prolonged action potential are the reason for this observation. (Int Heart J 2007; 48: 755-766)

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“…3). Reduced time for restitution of steady state force of contraction at higher frequencies [9,17,18] [6,9,20] perfusions or ischemia-reperfusion [20][21][22][23]. As the muscle becomes Ca 2+ overloaded, oscillatory release of Ca 2+ from SR occurs during the prolonged rest intervals.…”

Section: Discussionmentioning

confidence: 99%

Effect of ischemia‐reperfusion on the post‐rest inotropy of isolated perfused rat heart

Juggi

2002

J Cellular Molecular Medi

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This paper aims to study of the effects of ischemia‐reperfusion on the post‐rest inotropy and to characterize post‐rest B1:B2 ratio as an index of intracellular Ca2+ overload. When the rest interval between the cardiac beats is increased, the magnitude of the post‐rest beats is increased. First beat (B1) is maximally potentiated with exponental decline of the second (B2) and subsequent beats, thereby establishing a normal B1:B2 ratio of post‐ rest inotropy of the cardiac muscle. The rest potentiation of B1 and subsequent decay in the magnitude B2 is thought to develop from the time‐dependent changes in the Ca2+‐uptake and release from the sarcoplasmic reticulum (SR). Ca2+‐kinetics of SR can be modulated by a variety of interventions which produce Ca2+ loading of the SR. Methods: Isolated perfused (K‐H buffer, 34°C) rat hearts were paced at 1 Hz (steady state frequency). Interbeat intervals between 1s and 10s were introduced and the recovery in the left ventricular contractile force (Pmax) of post‐rest B1 and B2 for each interval was recorded. Their relative relationship was computed and compared under control and experimental conditions. Results: High extracellular Ca2+ (2.50 to 7.0 mM) or low extracellular Na+ (50% of control), and ischemia (60 min, 34°C) ‐ reperfusion (30 min, 34°C) caused the reversal of the control relationship of the B1 to B2, with B2 being more potentiated than B1, accompanied by the appearance of after‐contractions during the rest intervals of 4s or more. The mean (± SE) control B1:B2 ratio (at 4s interval) of 1.12 ± 0.05 was significantly (P<0.001) reduced to 0.93 ± 0.07; 0.89 ± 0.01; and 0.96 ± 0.02 after high Ca2+ (6 mM) perfusion, low Na+(50%) perfusion and ischemia‐reperfusion respectively. Simultaneous perfusion with ryanodine (1 μM) abolished the after‐contractions and significantly increased the reduced ratios. The time course of changes in B1:B2 ratio after graded ischemia‐reperfusion showed a significant fall in the ratio between 30 and 60 min of ischemia. A parallel change in Pmax and a significant rise in the left ventricular end‐diastolic pressure, indicating an irreversible phase of the injury was recorded. No significant changes in B1:B2 ratio were detected during the reversible phase (<30 min) of the ischemia‐reperfusion injury. Conclusions: Ischemia‐reperfusion induces significant alterations in the relative ratio of the post‐rest contractions of the left ventricle in isolated perfused rat heart. The altered ratios were characterized to predict the irreversibility of the reperfusion injury and to index the extent of Ca2+‐loading of the sarcoplasmic reticulum.

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Mechanisms contributing to the cardiac inotropic effect of Na pump inhibition and reduction of extracellular Na.

Cited by 98 publications

References 64 publications

Calcium dependency of frequency-stimulated atrial natriuretic peptide secretion.

Calcium dependency of frequency-stimulated atrial natriuretic peptide secretion.

Increased Functional Importance of the Na,Ca-Exchanger in Contracting Failing Human Myocardium but Unchanged Activity in Isolated Vesicles

Effect of ischemia‐reperfusion on the post‐rest inotropy of isolated perfused rat heart

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