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Masonic Medical Research Laboratory, Utica, New York 13501-1787
Submitted 11 August 2003 ; accepted in final form 10 December 2003
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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L-type Ca2+ current; cell shortening; transients
Although a great deal of attention has focused on the electrical distinctions of the diverse ventricular cells types, little attention has been directed at the mechanical correlates. In ventricular myocardium, the Ca2+ transient that activates contraction appears to result from the summation of numerous local microscopic release events called Ca2+ sparks (6, 7). It is widely believed that the Ca2+ transient represents the spatial and temporal summation of many sparks (7). In ventricular myocardial cells, the opening of the L-type Ca2+ current (ICa,L) induces the release of Ca2+ from the sarcopalsmic reticulum (SR) via ryanodine receptors (RyRs), thus initiating contraction. Differences in the characteristics of phase 1 and phase 3 repolarization among the three principal ventricular cell types may affect the Ca2+ transient and other characteristics of excitation-contraction (E-C) coupling. Prolongation of action potential (AP) duration (APD) intensifies cell shortening secondary to elevation of intracellular Ca2+ concentration ([Ca2+]i) and increased SR Ca2+ release (4, 37). SR Ca2+ release can also be modulated by phase 1 repolarization of the AP. A rapid rate of repolarization has been shown to lead to synchronization of SR Ca2+ release events or sparks (33, 35). The presence of a prominent AP notch in epicardial and midmyocardial cells and the longer APD of the midmyocardial cells may contribute to differences in E-C coupling. However, the regional differences of E-C coupling in ventricular muscle are not well defined.
The present study examines the characteristics of cell shortening, Ca2+ transients, and inward calcium current in epicardial, endocardial, and midmyocardial cells isolated from the left ventricle of the canine heart. Some of the results have been presented in preliminary form (11, 13).
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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5 min. The wedge preparations were then subjected to enzyme digestion with the nominally Ca2+-free solution supplemented with 0.5 mg/ml collagenase (type II, Worthington) and 1 mg/ml BSA for 8–12 min. After perfusion, thin slices of tissue from the epicardium (<2 mm from the epicardial surface), midmyocardial region (5–7 mm from the epicardial surface), and endocardium (<2 mm from the endocardial surface) were shaved from the wedge using a dermatome. The tissue slices were then placed in separate beakers, minced, and incubated in fresh buffer containing 0.5 mg/ml collagenase, 1 mg/ml BSA, and agitated. The supernatant was filtered, centrifuged, and the pellet containing the myocytes was stored in Kraftbruhe (KB) solution at room temperature. All animal procedures were in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publication No. 85-23, Revised 1985). Solutions. All solutions were made with Milli-Q grade water. Nominally Ca2+-free dissecting buffer had the following composition (in mM): 129 NaCl, 5.4 KCl, 2.0 MgSO4, 0.9 NaH2PO4, 5.5 glucose, and 20 NaHCO3. This solution was bubbled with 95% O2-5% CO2. The modified KB storage solution (20) had the following composition (in mM): 100 K+ glutamate, 10 K+ aspartate, 25 KCl, 10 KH2PO4, 2 MgSO4, 20 taurine, 5 creatine, 0.5 EGTA, 20 glucose, and 5 HEPES and 0.2% BSA (pH was adjusted to 7.2 with KOH). Myocytes were superfused with a HEPES buffer of the following composition (in mM): 140 NaCl, 5.4 KCl, 1.0 MgCl2, 2.0 CaCl2, 10 HEPES, and 10 glucose (pH was adjusted to 7.4 with NaOH). In the case of AP recording using high-resistance microelectrodes, the HEPES buffer contained 4 mM KCl.
Recording techniques. AP recordings were obtained using high-resistance glass microelectrodes (18–25 M
) filled with 2.7 M KCl. Voltage- and current-clamp recordings were made using patch pipettes fabricated from borosilicate glass capillaries (1.5 mm OD, Fisher Scientific; Pittsburg, PA). The pipettes were pulled with the use of a gravity puller (Narashige) and filled with pipette solution of the following composition (in mM): 90 K+ aspartate, 30 KCl, 5.0 K2ATP, 5.0 HEPES, 1.0 MgCl2, and 10 NaCl (pH was adjusted to 7.2 with KOH). The pipette resistance ranged from 1 to 4 M when filled with the internal solution. Current and voltage signals were recorded using a MultiClamp 700A amplifier (Axon Instruments; Foster City, CA) and series resistance errors were reduced by 60–70% with electronic compensation. All signals (current, voltage, fluorescence, and unloaded cell shortening) were acquired at 5 kHz (Digidata 1322, Axon Instruments) and analyzed with the use of personal computer running pCLAMP version 8 software (Axon Instruments). All experiments were performed at 36°C.
Fluo-3 dye preparation and loading. The AM form of fluo-3 was used. A 100 µM stock solution was prepared by adding 1 mg of fluo-3 AM (dissolved in 0.86 ml DMSO) to 9 ml of fetal bovine serum (containing 225 µl of 20% F-127 pluronic in DMSO). The stock solution was then divided into 200-µl aliquots and stored at –70°C. When needed, 1.5 ml of cell suspension containing either epicardial, endocardial, or midmyocardial cells were added to the fluo-3 AM (final concentration 15 µM) for 30 min at room temperature (7, 12).
All experiments were performed on an inverted microscope with epifluorescence capabilities (Nikon Eclipse TE300). Fluo-3-loaded myocytes were placed in a perfusion bath mounted on the stage of the microscope and myocytes were excited at 488 nm using a 100-W mercury bulb. Fluorescence signals were collected with a x40 oilimmersion objective lens (1.3 numerical aperture) and the emission fluorescence was sent through a 520-nm band-pass filter to a photomultiplier tube (Photon Technologies International).
Cell shortening. Myocytes were monitored with a closed circuit video camera (Phillips) and monitor (Hitachi Denshi). Contractions were recorded as unloaded cell shortening using a video edge detector (Crescent Electronics) at a 120-Hz frame rate.
Statistics. Results from pooled data are presented as means ± SE. Statistical analysis was performed using an ANOVA test, followed by the Student-Newman-Keuls test or Student's t-test, as appropriate, using SigmaStat software. P < 0.05 was considered to indicate statistical significance.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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The distinctions in the kinetics of cell shortening observed in the three cell types may simply be due to differences in action potential waveform and duration. To eliminate these differences, we measured cell shortening during application of square pulses under voltage-clamp conditions. Figure 2 shows the representative ionic currents and corresponding cell shortening recorded from an epicardial, endocardial, and midmyocardial cell in response to a 300-ms pulse. Before application of the test pulse, five square prepulses were applied to maintain a uniform SR Ca2+ content (28) and no inhibitors were present in the pipette or bath solution. A large inward Na+ current was recorded in all three cell types in response to a 300 ms depolarization to +20 mV (INa truncated for clarity). In addition, a prominent Ito was observed in both the epicardial and midmyocardial cell (Fig. 2, top traces). ICa,L was masked by the presence of the larger currents. The corresponding normalized cell shortening traces (Fig. 2, bottom traces) display a faster time to peak in epicardial and midmyocardial cells versus endocardial cells. In addition, the onset of contraction was slower in the endocardial versus epicardial and midmyocardial cells under voltage-clamp conditions (Table 1). The rate of relaxation was fastest in epicardial cells and slowest in endocardial cells; midmyocardial cells displayed in intermediate rate of relaxation. Thus the data demonstrate that when the differences in AP waveform and APD are eliminated, some of the distinctions in cell shortening kinetics among the cell types remain. Endocardial cells exhibited a slower time to peak, slower relaxation rate, and a greater latency to onset of contraction compared with epicardial and midmyocardial cells.
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To obtain further insight into the mechanisms underlying the mechanical distinctions, we examined the characteristics of the Ca2+ transient in the three cell types. Cells loaded with fluo-3 were excited with an Hg lamp at 488 nm and the emission fluorescence was collected at 520 nm through a band-pass filter and photomultiplier tube. Figure 3 shows representative AP and normalized Ca2+ transients simultaneously recorded from cells stimulated at a cycle length of 2 s. The latency for the onset of the Ca2+ transient was not significantly different among the three cell types (Table 1). Time to peak of the Ca2+ transient was significantly faster in epicardial cells compared with midmyocardial and endocardial cells (Table 1). In addition, the decay of the Ca2+ transient was faster in epicardial cells compared with the other cell types. These distinctions in Ca2+ transient are similar to those recently reported (23). These results suggest that differences in cell shortening kinetics observed in the three cell types may be explained in part by differences in the kinetics of the Ca2+ transient.
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Cell shortening and Ca2+ transient distinctions among the three cell types could be due to variations in the magnitude of ICa,L or differences in the fluorescence-voltage relationship. To test these hypotheses, we recorded ICa,L and Ca2+ transients under voltage-clamp conditions. Ito was suppressed by addition of 2 mM 4-aminopyridine to the bath solution. Figure 4A shows representative ICa,L traces and corresponding Ca2+ transients recorded from an midmyocardial cell under voltage-clamp conditions. ICa,L activated at –30 mV and peaked at +10 mV (Fig. 4A, prepulses not shown). The current-voltage relationship was not significantly different among the three cell types (Fig. 4B). The corresponding fluorescence-voltage relation (normalized to peak fluorescence) was not significantly different among the three cell types (Fig. 4C). ICa,L density measured using square pulses is similar among the three cell types (Fig. 4B). Moreover, fluorescence was similar at all voltages measured, suggesting no difference in the efficiency of SR Ca2+ release (or gain) (42) among the three cell types. Thus differences in the density of calcium channels are unlikely to be responsible for the observed differences in cell shortening and Ca2+ transient activity in the three cell types.
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We next examined the hypothesis that differences in SR Ca2+ content contribute to the transmural heterogeneity of mechanical function (34). SR content was estimated by the application of caffeine for a period of 1 s under voltage-clamp conditions and integration of the area under the current deflection. Each cell represents the average of two caffeine applications. Refilling of the SR after depletion is enhanced by stimulation. Therefore, we increased the number of prepulses to 10 to achieve steady state as previously described (38). Figure 5 shows representative traces recorded from an endocardial (Fig. 5A) and epicardial cell (Fig. 5B) during application of 10 mM caffeine (prepulses not shown). Caffeine caused release of Ca2+ from the SR, leading to the appearance of a large inward current secondary to activation of the Na+/Ca2+ exchanger. When the inward current was integrated and normalized to cell size, epicardial cells were found to contain a significantly greater SR Ca2+ content compared with midmyocardial and endocardial cells (Table 1).
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Epicardial cells displayed the largest Ca2+ content and endocardial cells the smallest. Because epicardial cells show a more rapid Ca2+ release from the SR, a more rapid inactivation of ICa,L would be expected. We measured the time (
) of inactivation of ICa,L and found that epicardial cells tended to have faster inactivation time constants, although this difference was not significant (Table 1). Our values closely correspond to those recently reported by Wang and Cohen (40) in canine ventricular cells.
Our findings thus far show that the cell shortening time to peak measured with AP is 100 ms faster in epicardial versus endocardial cells (Fig. 1). Although the magnitude of ICa,L was equivalent in the three ventricular cell types when measured using a square-wave voltage-clamp pulse, we considered the hypothesis that a more prominent phase 1 in epicardial cells could increase the magnitude of ICa,L, leading to an increase in "trigger" Ca2+, a greater SR Ca2+ release, and consequently faster cell shortening kinetics. To test this hypothesis, we measured ICa,L using AP voltage-clamp techniques, in which epicardial and endocardial waveforms were used to activate the current. The waveforms were taken from previously recorded AP of comparable duration and amplitude. A series of five square-wave prepulses were applied to the cell. After the fifth prepulse, the postconditioning potential was returned to –50 mV to keep INa inactivated and the upstroke of the AP was modified so that takeoff potential was at –50 mV (Fig. 6A) (31). In addition, 5 mM EGTA was included in the pipette to suppress other Ca2+-activated currents. Figure 7A shows representative ICa,L measured as the nicardipine-sensitive difference current elicited in the same cell using the two different AP waveforms. Both peak current as well as total charge were greater when ICa,L was elicited with an epicardial AP waveform. On average, peak current and total charge were 26 ± 12 and 47 ± 10% (P < 0.05) larger (n = 5), respectively, with an epicardial versus endocardial AP clamp protocol (Fig. 6B).
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To determine whether the greater ICa,L observed using an epicardial waveform translates into greater cell shortening kinetics, both waveforms were applied to the same cell and unloaded cell shortening was recorded. Figure 7 shows the epicardial and endocardial waveforms applied (top trace) and corresponding contractions (bottom traces). In this set of experiments, the waveforms were not modified. Before application of the waveform, five square-wave prepulses were applied to the cell to maintain a constant SR load (28). The epicardial waveform resulted in a greater magnitude and faster time to peak of cell shortening. In five similar experiments, time to peak was 16.4 ± 7.9 ms earlier during activation with the epicardial versus endocardial waveform (P < 0.05). In addition, the magnitude of cell shortening was 19.7 ± 6.8% larger when the epicardial waveform was applied to the cells.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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The differences in cell shortening persisted when the three transmural cell types were uniformly activated using a square-wave voltage-clamp pulse, suggesting that factors other than AP morphology contribute to the mechanical distinctions. These observations suggest that there are intrinsic differences in E-C coupling between the three cell types. These variations may be due to differences in intracellular Ca2+ buffering or expression of Ca2+-handling proteins. For example, in canine ventricular myocardium, it has been shown that the expression of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) is much greater in the epicardium versus endocardium (23). In that study, the greater SERCA2a expression in epicardium resulted in a faster decline of the Ca2+ transient consistent with our observations. In addition, there may be regional differences in RyR2 expression or FK506 binding protein, which stabilizes RyR2. A differential expression in either of these proteins may affect SR Ca2+ release. The differences in cell shortening kinetics may also be due to the presence of different contractile protein isoforms between the cell types. For example, V1 isomyosin shows high ATPase and contractile activity compared with V3 isomyosin (32). Although species-dependent differences in cardiac myosin isoforms exist (21), it is possible that similar regional differences in myosin isoforms contribute to the mechanical distinctions that we describe (Fig. 2).
AP studies. All mammals exhibit regional differences in the morphology of the ventricular AP (2, 8, 15) that may contribute to differences in E-C coupling. A prolonged AP is known to augment cell shortening via elevation of [Ca2+]i (4, 17). Recent studies have shown that the rate of repolarization of the cardiac AP can profoundly affect SR Ca2+ release in rat ventricular myocytes. A fast rate of repolarization results in a much larger ICa,L and a greater increase in [Ca2+]i than a slow rate (33). Moreover, a faster rate of repolarization contributes to synchronization of Ca2+ sparks (5, 33, 35). The present study demonstrates the effect of a prominent phase 1 to increase not only peak ICa,L, but also the total charge carried by the current (Fig. 6) in canine ventricular myocytes. A recent report by Banyasz et al. (3) also noted that the presence of a spike and dome AP waveform in canine ventricular cells results in a greater magnitude of ICa,L (3). These observations suggest that cell types with a rapid phase 1 (and hence a large Ito) would exhibit a faster time to peak of cell shortening (Fig. 7). Consistent with these observations, our results show that during AP recordings, epicardial, and midmyocardial cells exhibit faster cell shortening kinetics and a shorter time to peak of the [Ca2+]i transient.
Cell shortening and the Ca2+ transient is a dynamic process that is controlled by Ca2+ influx and release as well as Ca2+ reuptake and extrusion. Laurita et al. (23) demonstrated that decay of the [Ca2+]i transient is slower in canine ventricular endocardium compared with epicardium due in part ot a lesser expression of SERCA2a in endocardial cells. These observations are concordant with our data showing slower [Ca2+]i transient and cell shortening kinetics in canine ventricular endocardial cells and more rapid kinetics in epicardium. On a steady-state basis, the faster rate Ca2+ reuptake may contribute to a greater SR Ca2+ content.
Voltage-clamp observations. When variations in AP waveform and duration are eliminated by replacing AP with square-wave voltage-clamp pulses, epicardial, and midmyocardial cells show no significant difference in cell shortening kinetics (latency to onset of contraction and time to peak), but endocardial cells continue to exhibit slower cell shortening kinetics. Similar observations in unloaded cell shortening kinetics were previously described in a preliminary report involving canine and ferret epicardial and endocardial cells studied under voltage-clamp conditions (44). Epicardial cells display a larger SR calcium content compared with endocardial cells (Fig. 5). The difference in cell shortening kinetics (time to peak and latency) between epicardial and endocardial cells when measured with square-wave voltage-clamp pulses (Fig. 2) cannot simply be explained by a larger SR Ca2+ content. These observations suggest that E-C coupling in endocardial cells is intrinsically different from that of the other ventricular cell types. These intrinsic differences may be related to a differential expression of Ca2+-buffering proteins, Ca2+-handling proteins (23), or myosin isoforms (21). Differences in the distribution of T-tubules may contribute as well (18); this hypothesis is currently under investigation in our laboratory.
We considered the hypothesis that differences in ICa,L contribute to variations in cell shortening kinetics. Under voltage-clamp conditions, ICa,L density and the corresponding fluorescence-voltage relationship were similar among the three cell types. The absence of transmural differences in ICa,L is consistent with two recent reports by other investigators (3, 26) but not with a third, in which endocardial cells from the canine left ventricle were found to have a larger ICa,L density and to express the T-type Ca2+ current (40). The disparate results may be related to differences in experimental conditions. The study by Wang and Cohen (40) recorded ICa,L with Na+ and K+ replaced by TEA-Cl and Cs+, respectively. We avoided the use of Cs+ in our study because of its ability to alter SR Ca2+ release, unloaded cell shortening, and E-C coupling (24).
We further evaluated ICa,L under AP clamp conditions and found that the spike-and-dome morphology of the epicardial AP significantly augments peak current and total charge of ICa in epicardial cells, providing support for the hypothesis that differences in ICa,L contribute to cellular distinctions in cell shortening kinetics. The ability of AP morphology to influence ICa was also recently demonstrated in canine (3) and mouse ventricular myocytes (5), and those from other species (35). In mouse ventricular myocytes, which has a very brief APD due to a prominent Ito, Bridge et al. (5) showed that much of the SR Ca2+ release is activated during the repolarization phase of the AP when the driving force for Ca2+ entry increases dramatically (5). Variations in phase 1 repolarization due to species-related and cell-related differences in Ito can affect Ca2+ influx, SR Ca2+ release, and contractility (35).
E-C coupling in cardiac cells can be affected by numerous other factors. Cardiac contractions can be influenced by activation of T-type Ca2+ current (36, 45), Na+/Ca2+ exchange operating in "reverse mode" (25, 28), and a voltage-sensitive release mechanism (16, 19). In the canine ventricle, previous studies have demonstrated a differential distribution of INa/Ca (Ref. 47, but see Ref. 23) and late INa (46). These distinctions contribute to electrical heterogeneity and likely contribute to differences in E-C coupling. Furthermore, the triggers of SR Ca2+ release do not operate in a simple additive fashion, but sum in a nonlinear manner (10). Thus differences in Na+/Ca2+ exchange can importantly potentiate ICa-mediated SR Ca2+ release (9, 39, 41).
Possible physiological implications. Our data point to important differences in calcium homeostasis and mechanical function among the three predominant ventricular cell types. Although these distinctions are conferred in part by differences in electrical characteristics of the three cell types, intrinsic differences in E-C coupling are evident.
Implications relative to the mechanical function of the heart in health and disease are many. Among them is the observation that transmural distinctions in onset of contraction may improve the contractile efficiency of the ventricular myocardium. The normal activation pattern of the ventricle is from endocardium to epicardium. Previous studies (43) have shown that transmural conduction delay is on the order of 20–30 ms in the canine left ventricle. The present study indicates that that the latency to onset of contraction in epicardial cells is 28 ms, whereas that of endocardial cells is 47 ms. The 20-ms differential allows the impulse to traverse the left ventricular wall and effect a coordinated contraction of the ventricular myocardium.
The greater SR Ca2+ content and Ca2+ current (when triggered by an AP) in epicardial cells may explain the greater INa/Ca measured in epicardial versus endocardial cells (47) as well as the greater propensity for these cells to develop early afterdepolarization in the presence of IKr and IKs block (14).
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ACKNOWLEDGMENTS |
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GRANTS
This study was supported by National Heart, Lung, and Blood Institute Grant HL-47678, the American Heart Association, New York State Affiliate (both to C. Antzelevitch), and the Masons of New York State and Florida.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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J.M. Cordeiro, R. Brugada, Y.S. Wu, K. Hong, and R. Dumaine Modulation of IKr inactivation by mutation N588K in KCNH2: A link to arrhythmogenesis in short QT syndrome Cardiovasc Res, August 15, 2005; 67(3): 498 - 509. [Abstract] [Full Text] [PDF]
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 W. Xiong, Y. Tian, D. DiSilvestre, and G. F. Tomaselli Transmural Heterogeneity of Na+-Ca2+ Exchange: Evidence for Differential Expression in Normal and Failing Hearts Circ. Res., August 5, 2005; 97(3): 207 - 209. [Abstract] [Full Text] [PDF]
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 G.-B. Nam, A. Burashnikov, and C. Antzelevitch Cellular Mechanisms Underlying the Development of Catecholaminergic Ventricular Tachycardia Circulation, May 31, 2005; 111(21): 2727 - 2733. [Abstract] [Full Text] [PDF]
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X. Sun and H.-S. Wang Role of the transient outward current (Ito) in shaping canine ventricular action potential - a dynamic clamp study J. Physiol., April 15, 2005; 564(2): 411 - 419. [Abstract] [Full Text] [PDF]
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A. Cheng, F. Langer, F. Rodriguez, J. C. Criscione, G. T. Daughters, D. C. Miller, and N. B. Ingels Jr. Transmural cardiac strains in the lateral wall of the ovine left ventricle Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1546 - H1556. [Abstract] [Full Text] [PDF]
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M. Rubart Two-Photon Microscopy of Cells and Tissue Circ. Res., December 10, 2004; 95(12): 1154 - 1166. [Abstract] [Full Text] [PDF]
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T. J. Hund and Y. Rudy Rate Dependence and Regulation of Action Potential and Calcium Transient in a Canine Cardiac Ventricular Cell Model Circulation, November 16, 2004; 110(20): 3168 - 3174. [Abstract] [Full Text] [PDF]
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