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(Circulation Research. 2003;93:592.)
© 2003 American Heart Association, Inc.

Report

Elevated Sarcoplasmic Reticulum Ca²⁺ Leak in Intact Ventricular Myocytes From Rabbits in Heart Failure

Thomas R. Shannon, Steven M. Pogwizd, Donald M. Bers

From the Department of Physiology and Biophysics (T.R.S.), Rush University, Chicago, Ill; the Department of Medicine (S.M.P.), University of Illinois–Chicago, Chicago, Ill; and the Department of Physiology (T.R.S., D.M.B.), Loyola University Chicago, Maywood, Ill.

Correspondence to Thomas R. Shannon, Department of Molecular Biophysics and Physiology, Rush University, 1750 W Harrison Ave, Chicago, IL 60612. E-mail tshannon{at}rush.edu

Abstract

Altered sarcoplasmic reticulum (SR) Ca²⁺-ATPase and Na⁺-Ca²⁺ exchange (NCX) function have been implicated in depressing SR Ca²⁺ content and contractile function in heart failure (HF). Enhanced diastolic ryanodine receptor (RyR) leak could also lower SR Ca²⁺ load in HF, but direct cellular measurements are lacking. In this study, we measure SR Ca²⁺ leak directly in intact isolated rabbit ventricular myocytes from a well-developed nonischemic HF model. Abrupt block of SR Ca²⁺ leak by tetracaine shifts Ca²⁺ from the cytosol to SR. The tetracaine-induced decline in [Ca²⁺]_i and increase total SR Ca²⁺ load ([Ca²⁺]_SRT) directly indicate the SR Ca²⁺ leak (before tetracaine). Diastolic SR Ca²⁺ leak increases with [Ca²⁺]_SRT, and for any [Ca²⁺]_SRT is greater in HF versus control. Mathematical modeling was used to compare the relative impact of alterations in SR Ca²⁺ leak, SR Ca²⁺-ATPase, and Na⁺-Ca²⁺ exchange on SR Ca²⁺ load in HF. We conclude that increased diastolic SR Ca²⁺ leak in HF may contribute to reductions in SR Ca²⁺ content, but changes in NCX in this HF model have more impact on [Ca²⁺]_SRT.

Key Words: sarcoplasmic reticulum • ryanodine receptors • Ca²⁺ pump • excitation-contraction coupling • heart failure

The two main pathways of diastolic Ca²⁺ removal from the cytosol are extrusion via Na⁺-Ca²⁺ exchange (NCX) and sarcoplasmic reticulum (SR) uptake via the SR Ca²⁺-pump.¹ In numerous heart failure (HF) models, evidence from mRNA, protein expression, and cellular Ca²⁺ transients, indicates depressed SR Ca²⁺-ATPase function, enhanced NCX function, or both, leading to reduced SR Ca²⁺ content ([Ca²⁺]_SRT).^2–8 Either of these effects can reduce total SR Ca²⁺ content ([Ca²⁺]_SRT) by allowing NCX to better compete with SR Ca²⁺-ATPase during relaxation. Reduced [Ca²⁺]_SRT decreases systolic SR Ca²⁺ release and contraction, due to both reduced Ca²⁺ available for release and a depressed ryanodine receptor (RyR) function at low [Ca²⁺]_SRT or free intra–SR-free [Ca²⁺] ([Ca²⁺]_SR).^9–12 We recently developed novel approaches to assess diastolic SR Ca²⁺ leak, and leak has a steep dependence on [Ca²⁺]_SRT or [Ca²⁺]_SR, similar to the effects of [Ca²⁺]_SRT on systolic release. This leak is primarily via ryanodine receptors.^13,14

Enhanced diastolic SR Ca²⁺ leak could also contribute to reduced [Ca²⁺]_SRT in HF. Indeed, Marx et al¹⁵ reported that in HF the RyR is hyperphosphorylated by PKA and that this increased overall RyR Ca²⁺ flux in single channel bilayer recordings. However, the situation may be more complex, because PKA-dependent phosphorylation of the RyR in control myocytes may not enhance Ca²⁺ spark frequency (at constant [Ca²⁺]_SRT).¹⁶ Direct assessment of diastolic SR Ca²⁺ leak in intact ventricular myocytes in HF is lacking.

In this study, we measured SR Ca²⁺ leak directly in intact rabbit ventricular myocytes from a well-characterized nonischemic HF model^5,6 using our recently developed approach.¹⁴ The SR Ca²⁺ leak at a given [Ca²⁺]_SRT is increased and this may contribute to contractile dysfunction in HF.

Materials and Methods

Experiments were conducted in accordance with the Guide for the Care and Use of Experimental Animals at Loyola University Medical Center and conformed to the Guide for the Care and Use of Laboratory Animalspublished by NIH (publication No. 85-23, revised 1985). Ventricular myocytes were isolated from New Zealand White rabbits (Myrtle’s Rabbitry, Inc, Thompson Station, Tenn) in which HF was induced by combined aortic insufficiency and stenosis^5,6 and diastolic SR Ca²⁺ leak was measured¹⁴ (see online data supplement available at http://www.circresaha.org). Briefly, cells were stimulated to steady state at different frequencies to vary load. Diastolic [Ca²⁺]_i was measured in 0 Na⁺, 0 Ca²⁺ normal Tyrode’s±tetracaine followed by caffeine to measure RyR-dependent changes in [Ca²⁺]_SRT (Figure 1A).

View larger version (19K): [in this window] [in a new window]   Figure 1. A, Experimental protocol for determination of SR Ca2+ leak. Tetracaine addition blocks the RyR at rest, and the shift downward in resting [Ca2+]i compared with control is proportional to SR Ca2+ leak. B, [Ca2+]SRT in control and HF myocytes. [Ca2+]SRT tended to be lower in HF at higher frequency. C, Shift of Ca2+ from the cytosol to the SR on tetracaine addition. [Ca2+]SRT increases and [Ca2+]i decreases with increasing leak. D, SR Ca2+ leak-[Ca2+]SRT relationship. Control data were taken from Shannon et al.14

Results and Discussion

Rabbit HF myocytes in this model have significantly reduced Ca²⁺ transients, [Ca²⁺]_SRT, and blunted force-frequency relationship.^5,6 Cells used in this study had similar characteristics (Figure 1B) with the pacing protocols used. Increasing [Ca²⁺]_SRT increases fractional SR Ca²⁺ release,^9–12 and fractional release (twitch [Ca²⁺]_i/[Ca²⁺]_SRT) increased in this study in control cells as [Ca²⁺]_SRT rose (2.7±0.1 at 0.25 Hz to 4.6±0.5 at 1 Hz, in nmol/L per µmol/L; P<0.05). However, in HF myocytes, fractional release was higher at 0.25 Hz (3.6±0.1) and failed to increase with [Ca²⁺]_SRT (4.2±0.3 at 1 Hz). Thus, HF may change how RyRs respond to [Ca²⁺]_SRT.

To assess SR Ca²⁺ leak, superfusate was abruptly switched to 0 Na⁺, 0 Ca²⁺ solution ±1 mmol/L tetracaine (after conditioning trains). Total cell [Ca²⁺] does not change under these conditions with NCX blocked.¹⁴ When tetracaine, a RyR blocker, is included, resting [Ca²⁺]_i declines and there is a complementary rise in [Ca²⁺]_SRT (assessed by caffeine addition and tetracaine removal). Tetracaine thus shifts Ca²⁺ from cytosol to SR. The magnitude of this tetracaine-dependent Ca²⁺ shift directly reflects the magnitude of diastolic RyR leak. The [Ca²⁺]_SRT and [Ca²⁺]_i indicate that SR Ca²⁺ leak increases with [Ca²⁺]_SRT (Figure 1C).¹⁴ The tetracaine-dependent shifts at each [Ca²⁺]_SRT were converted to SR Ca²⁺ leak rates.¹⁴ The leak-[Ca²⁺]_SRT relationship also shifted leftward in the HF (P<0.05) versus control data (Figure 1D), indicating increased SR Ca²⁺ leak at a given [Ca²⁺]_SRT in HF.

Our study is the first to show increased SR Ca²⁺ leak in intact HF cells and its [Ca²⁺]_SRT dependence. This is consistent with some RyR bilayer and SR vesicle findings in HF,^15,16 where Marx et al¹⁵ showed RyR hyperphosphorylation by protein kinase A, causing FK-506 binding protein (FKBP) dissociation, increased RyR Ca²⁺ sensitivity, and higher RyR channel Ca²⁺ flux. However, not all results agree that RyR is hyperphosphorylated in HF,¹⁷ or that RyR phosphorylation alone enhances SR Ca²⁺ leak.¹⁸ Cellular results show that excess FKBP can inhibit SR Ca²⁺ leak,¹⁹ and reduced FKBP-RyR association enhances SR Ca²⁺ leak.^20–22

Enhanced SR Ca²⁺ leak in HF could reduce SR [Ca²⁺]_SRT and contractile function. However, Eisner et al²³ showed that RyR sensitization with caffeine only transiently increased [Ca²⁺]_i with little or no steady-state effect. The lower [Ca²⁺]_SRT was counterbalanced at steady state by increased fractional SR Ca²⁺ release (because both systolic and diastolic RyR gating are enhanced). In HF, it is unclear whether diastolic SR Ca²⁺ leak is accompanied by enhanced fractional release. Most results show either unchanged or depressed fractional release in HF.

Three major factors may contribute to reduced [Ca²⁺]_SRT in HF: (1) reduced SR Ca²⁺-ATPase function, (2) enhanced NCX, and (3) increased diastolic SR Ca²⁺ leak.^1–8 Relative contributions may vary in different HF models (and human etiologies) and are difficult to assess quantitatively. We use computer modeling to assess how these factors may alter [Ca²⁺]_SRT (see online data supplement).²⁴

Figure 2A shows how reduced SR Ca²⁺-ATPase function alone (in the range reported for HF) would reduce steady-state [Ca²⁺]_SRT at 1 Hz stimulation for control conditions (open symbols) or with our HF values of NCX,⁶ and SR Ca²⁺ leak (filled symbols). Figures 2B and 2C show similar analyses for increased NCX and SR Ca²⁺ leak function alone. All three perturbations can independently reduce [Ca²⁺]_SRT. Twitch [Ca²⁺]_i generally parallels [Ca²⁺]_SRT, but if diastolic leak and systolic release are similarly enhanced, twitch [Ca²⁺]_i would be little affected by RyR alteration.²³

View larger version (33K): [in this window] [in a new window]   Figure 2. Mathematical modeling for steady state at 1 Hz. Decreases in [Ca2+]SRT and twitch [Ca2+]i due to decreasing SR Ca2+-ATPase function alone (with NCX, Na+ influx and leak at Ctl or HF levels) (A), enhanced NCX function alone (with SR Ca2+-ATPase and leak at Ctl or HF levels) (B), and increased SR Ca2+ leak (with NCX, Na+ influx and SR Ca2+-ATPase at Ctl or HF levels) (C). Large circles indicate [Ca2+]SRT under normal and HF conditions for the measured levels of each transporter. Arrows indicate changes seen in this rabbit HF model.5,6 D, Impact of reduced SERCA function and enhanced NCX function on expected [Ca2+]SRT (darker=higher). See online data supplement.

Moreover, these three pathways may work synergistically to reduce [Ca²⁺]_SRT, and the relative extents of this may vary in different HF models (Figure 2D). In our rabbit HF model,^5,6 enhanced NCX function appears dominant, whereas different balances of enhanced NCX and reduced SR Ca²⁺-ATPase could cause similar [Ca²⁺]_SRT reductions in other cases (where leak has not been assessed).^2,3,7 NCX changes seem most influential on [Ca²⁺]_SRT for the ranges in Figure 2, but further experimental tests may be required to further validate this. In addition, one would expect a diastolic SR Ca²⁺ leak to be more influential at low heart rate (due to the longer diastolic interval), but in HF twitch depression is more apparent at higher heart rate versus low. In conclusion, SR Ca²⁺ leak increases in HF, but it may be less influential than altered SR Ca²⁺-ATPase and NCX in causing the [Ca²⁺]_SRT reduction in HF, which reduces systolic function.

Acknowledgments

This work was supported by NIH-HL-30077 and -64098 (D.M.B.) and AHA-0030381Z (T.R.S.).

Footnotes

Original received July 18, 2003; resubmission received August 20, 2003; accepted August 20, 2003.

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