© 1996 American Heart Association, Inc.
Articles |
Protein Kinase C–Induced Changes in the Stoichiometry of ATP Binding Activate Cardiac ATP-Sensitive K+ Channels
A Possible Mechanistic Link to Ischemic Preconditioning
the Departments of Medical Physiology (P.E.L., A.A.S., R.J.F.) and Medical Biochemistry (B.G.A., M.P.W.), University of Calgary (Canada).
Correspondence to Dr Peter E. Light, Department of Medical Physiology, University of Calgary, Calgary, Alberta, Canada, T2N 4N1. E-mail plight@acs.ucalgary.ca.
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Abstract |
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Activation of both ATP-sensitive K+ (KATP) channels and the enzyme protein kinase C (PKC) has been associated with the cardioprotective response of ischemic preconditioning. We recently showed that at low cytoplasmic ATP (
50 µmol/L), PKC inhibits KATP channel activity. This finding is surprising, as both KATP channels and PKC are activated during preconditioning. However, PKC also altered ATP binding to the channel, changing the Hill coefficient from 
2 to 1. This apparent change in stoichiometry would lead to a PKC-induced activation of KATP channels at more physiological (millimolar) levels of ATP. The aim of the present study was to determine whether PKC activates cardiac KATP channels at millimolar levels of ATP. The effects of PKC on single KATP channels were studied at millimolar internal ATP levels using excised inside-out membrane patches from rabbit ventricular myocytes. Application of purified constitutively active PKC (20 nmol/L) to the intracellular surface of the patches produced an approximately threefold increase in the channel open probability. The specific PKC inhibitor peptide PKC(19-31) prevented this increase. Heat-inactivated PKC had no effect on KATP channel properties. KATP channel activity spontaneously returned to control levels after washout of PKC. This spontaneous reversal did not occur in the presence of 5 nmol/L okadaic acid, suggesting that the reversal of PKC's action is dependent on activity of a membrane-associated type 2A protein phosphatase (PP2A). In the presence of exogenous PP2A (7.5 nmol/L), PKC had no effect. We conclude that the PKC-induced increase in KATP channel activity at millimolar ATP results from a crossing of the ATP concentration-response curves for inhibition of the phosphorylated and nonphosphorylated forms of the channel. This identifies a mechanism by which PKC activates KATP channels at near physiological levels of ATP and thus could link these two components in a signaling pathway that induces ischemic preconditioning.
Key Words: ATP-sensitive K+ channel • protein kinase C • cardiac ventricular myocytes • ischemic preconditioning • patch clamp
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Introduction |
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ATP-sensitive K+ channels are found at high density in the heart.1 2 These channels are thought to play a major role in protecting the heart from ischemia-induced damage. Activation of KATP channels reduces action potential duration, thus decreasing contractility and conserving energy during periods of ischemia.1 2 3 A role has also been suggested for KATP channels in the phenomenon of ischemic preconditioning.4 5 In several species, a short period of ischemic preconditioning protects the heart by reducing the size of infarcts resulting from subsequent prolonged bouts of ischemia.6 Preconditioning may also occur in the human heart.7 The mechanism by which activation of KATP channels could provide the "memory" associated with ischemic preconditioning is still under debate.4 8 One possible basis for the prolonged protection of ischemic preconditioning might be provided by long-term modulation of KATP channel activity by phosphorylation.
Recently, PKC has been implicated in ischemic preconditioning,9 10 11 12 and there is evidence that PKC's action involves activation of KATP channels.12 13 14 15 16 However, there have been no direct observations that PKC can activate single cardiac KATP channels at physiological levels of ATP, nor is there knowledge of a specific mechanism by which this may occur.
We have recently presented evidence that phosphorylation by PKC inhibits ventricular KATP channel activity at low levels of ATP (50 µmol/L) and that PKC alters the stoichiometry of ATP binding to the channel.17 From those results, we predict that at higher (physiological) ATP concentrations, the change in stoichiometry of ATP binding would result in a PKC-mediated activation of KATP channels. In the present study, we tested the effects of PKC on the activity of single KATP channels at millimolar ATP levels. Our present results provide direct evidence that in the presence of physiological levels of ATP, PKC upregulates KATP channel activity and that the reversal of this effect is dependent on the activity of a membrane-associated PP2A. Thus, we have identified a mechanism by which PKC could act as a link in one or more known receptor-mediated pathways to increase KATP channel activity during ischemic preconditioning.
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Materials and Methods |
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ATP (as K2ATP, Sigma Chemical Co) was added as required from a 10 mmol/L stock, which was prepared, immediately before use, in high-K+ bath solution. The PKC inhibitor peptide PKC(19-31)18 was synthesized as described previously.17 It was stored at a concentration of 0.97 mmol/L in 20 mmol/L Tris-HCl (pH 7.5) and used at a final concentration of 2 µmol/L. OA (Calbiochem) was stored at a stock concentration of 100 µmol/L in ethanol at 4°C and used at a final concentration of 5 nmol/L.
Purification and Use of PKC and PP2A
A constitutively active oxidized form of PKC, which does not require phospholipid, diacylglycerol, or calcium for activity, was used during this study. PKC (a mixture of 
, ß, 
, and 
isoenzymes) was purified from rat brain using the techniques described previously.19 The enzyme was rendered constitutively active by air oxidation19 at 4°C and stored at -80°C at a concentration of 2.0 µmol/L in 20 mmol/L Tris-HCl (pH 7.5), 1 mmol/L EGTA, 1 mmol/L EDTA, 10 mmol/L dithiothreitol, 25% (vol/vol) glycerol, and 0.05% (vol/vol) Triton X-100. PKC was used at a final concentration of 20 nmol/L. The PKC concentration of 20 nmol/L (or 1.6 U/mL), which we used in the present study, reflects the level of PKC typically found within cells, which is in the range 0.62 to 8.7 U/mL, assuming the tissue to be 10% (wt/vol) protein.20
Type 2A protein serine/threonine phosphatase was purified from chicken gizzard smooth muscle as previously described21 and stored at -80°C at a concentration of 0.75 µmol/L in 20 mmol/L Tris-HCl (pH 7.5), 1 mmol/L EDTA, 20 mmol/L NaCl, and 1 mmol/L dithiothreitol. The phosphatase was used at a final concentration of 7.5 nmol/L.
In several instances, heat-inactivated PKC was used as a negative control; this was produced by immersing samples of stock enzyme solutions in boiling water for 5 minutes immediately before use.
Cell Isolation
Single rabbit ventricular myocytes were enzymatically dissociated and isolated using the methods described previously.22 Rabbits were anesthetized by injection of pentobarbital (65 mg/mL, 1 mL/kg body wt), heparin (1000 IU/mL), and 2% benzyl alcohol into the marginal ear vein and then killed by cervical dislocation and exsanguination.
Single-Channel Recordings and Data Acquisition
The pipette solution used for all excised inside-out patch recordings contained the following (in mmol/L): NaCl 140, KCl 5, HEPES 10, CaCl2 1, MgCl2 1, and glucose 10 at pH 7.4. The standard bath solution contained (in mmol/L): potassium aspartate 130, KCl 10, HEPES 10, EGTA 1, MgCl2 1.4, and glucose 10. EGTA (1 mmol/L) was included in the bath solution to prevent the Ca2+-induced rundown of KATP channels. The pH of the bath solution was adjusted to 7.4 with KOH.
Standard patch-clamp recording techniques23 were used to record single-channel currents in the inside-out patch configuration. Pipettes were pulled from borosilicate glass (PG52151-4, World Precision Instruments Inc); their shanks near the tip were coated with a silicone resin (Sylgard 184, Corning), and the tips were fire-polished. Typical pipette resistance was 1 to 5 M
. After the establishment of a seal (>10 G), the pipette was rapidly pulled away from the cell, yielding an excised inside-out patch. Patches were then directly exposed to test solutions via a multi-input perfusion pipette with a common outlet at a flow rate of 100 to 150 µL/min. The time taken to change solutions was <2 seconds. All recordings were carried out at room temperature (20°C to 22°C).
Single-channel currents were recorded at a holding potential of 0 mV, amplified (Axopatch 200, Axon Instruments Inc), digitized (Neuro-corder DR-384, Neuro Data Instruments Corp), and then stored on videotape. Data were replayed through a four-pole Bessel filter, low pass–filtered at 100 Hz (LPF-100, Warner Instruments Corp), and sampled at 250 Hz using a computer interface (Axolab 1100, Axon Instruments Inc) connected to an IBM PC-compatible computer (486) for analysis. Data were analyzed using pCLAMP v 5.5 and 6.0 software (Axon Instruments Inc).
Rundown of KATP Channels
The activity of KATP channels in cardiac and other tissues decreases slowly with time after patches are excised into ATP-free solution. This phenomenon is known as "rundown."24 Upon excision, patches were continuously exposed to 1 mmol/L ATP, except for a brief exposure to zero ATP at the beginning and end of experiments to estimate (1) the number of channels in a patch and (2) the degree of rundown. Data from patches exhibiting >25% rundown were discarded.
In experiments designed to test the effects of PKC on KATP channel activity, patches were continuously exposed to 1 mmol/L ATP unless otherwise stated. This concentration of ATP was chosen to represent a near-physiological level of ATP, while still giving a sufficient Po to allow single-channel events to be observed. The concentration of ATP (1 mmol/L) used in the present study is 200-fold greater than the Km (ATP) of rat brain PKC previously reported.25
Data Analysis
In order to obtain an accurate assessment of KATP channel Po, the following equation was used:
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1 minute) at zero ATP, by the mean unitary current amplitude.
In Fig 2B
, and for the data taken at 50 and 100 µmol/L ATP (Figs 3C and 4 and associated text), the KATP channel Po was expressed as NPo. NPo was calculated by dividing the mean patch current (over a 30- to 120-second test period) by the mean unitary current amplitude.
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Statistics
Statistical significance was evaluated by Student's paired t test. Differences at P<.05 were considered to be significant. All values in the text are mean±SEM.
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Results |
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PKC Increases KATP Channel Po at Millimolar ATP Concentrations
In a previous study, we showed that PKC is capable of inhibiting KATP channel activity at low levels of ATP (50 µmol/L) and that the Hill coefficient for ATP binding was reduced from 2.2 in the control condition to 1.2 in the presence of PKC.17 The reduction in the Hill coefficient would reduce the efficacy of ATP inhibition at higher (more physiological) concentrations of ATP so that phosphorylation would actually facilitate KATP channel opening (see Fig 1
) under these conditions. Therefore, we tested the effects of PKC on the activity of single KATP channels using excised inside-out patches in the presence of 1 mmol/L ATP.
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) were fitted to the Hill equation in the following form: normalized Po=Po/Po(max)=1/[1+([ATP]/Ki)n], where Po is the open probability at a given [ATP], Po(max) is the control open probability at zero [ATP], Ki is the inhibition constant for ATP, and n is the Hill coefficient. For the PKC data (
), the value at zero ATP cannot be measured experimentally because the action of PKC requires ATP. Hence, the normalized Po in the presence of PKC was scaled relative to the control value at 50 µmol/L, so that at this [ATP] level, normalized Po,PKC=0.52xnormalized Po,control. The ratio 0.52 is the mean value obtained from numerous single-patch experiments in our previous study (0.52±0.04, n=18).
The mean Po of KATP channels in the presence of 1 mmol/L ATP was 0.0074±0.0023 (n=20). The application of PKC to the internal side of the membrane patch caused a 160% increase in Po of KATP channels to 0.0194±0.0035 (n=20). This value was significantly different from the Po before the addition of PKC (P=.0002). Fig 2
shows a representative single-channel recording of this effect. In the presence of 2 µmol/L of the specific PKC inhibitor peptide PKC(19-31), PKC had no effect (P=.73) on channel Po (Po=0.0089±0.043, n=5; see Fig 3A and 3B). The application of heat-inactivated enzyme also had no effect (Po=0.00725±0.0042, n=5; see Fig 3B) compared with control (P=.69).
In six patches, the effects of PKC were tested on KATP channel Po in the presence of 100 µmol/L ATP. This concentration of ATP was chosen because this concentration is predicted to be close to the isoactive, or crossover, point on the two ATP concentration-response curves, at which PKC is expected to have no effect on KATP channel Po (Fig 1). The addition of PKC produced no significant effect on the time-averaged NPo (the ratio NPo(PKC)/NPo(control)=0.96±0.27) when compared with control (P=.83; see Fig 3C).
PKC-Induced Activation and Inhibition of KATP Channels, in the Same Patch, at Different ATP Concentrations
In general, it is more convenient to study patches containing many KATP channels if using millimolar ATP and to use smaller patches with fewer channels when working at micromolar ATP concentrations, for which Po is much higher. However, in order both to confirm our previous findings17 of PKC-induced KATP channel inhibition at low ATP concentration and to further demonstrate PKC-induced KATP channel activation at millimolar ATP levels (the present study), we investigated the effects of PKC at both 50 µmol/L and 1 mmol/L ATP in the same patch. In four patches, application of PKC in the presence of 1 mmol/L ATP caused a 321±68% increase in KATP channel activity. PKC was then removed, and channel activity returned to control levels. Patches were then exposed to 50 µmol/L ATP, with a resultant increase in Po. At this point, a second application of PKC caused a 44±11% decrease in KATP channel activity (P<.05 compared with control). Again, this effect was reversible upon washout of PKC. A representative single-channel trace showing these effects is shown in Fig 4.
Reversibility of PKC Activation Is Dependent on Membrane-Associated PP2A
We have previously shown that the reversal of PKC inhibition at 50 µmol/L ATP is dependent on the activity of PP2A.17 In the present study, we observed that the reversal of PKC activation of KATP channels at millimolar ATP levels is also dependent on PP2A. OA, a potent inhibitor of type 1 and 2A protein phosphatases, was used at a low concentration (5 nmol/L) to specifically block the activity of PP2A26 27 in excised inside-out patches. In the five patches tested, application of PKC in the presence of 1 mmol/L ATP caused a 317±77% increase in the Po of KATP channels; these data are significantly different from the control data (P<.05). If PKC was then removed and OA applied to the patches, no reversal of KATP channel activation was observed, and channel Po was maintained at 303±72% above control levels (P<.05). Upon removal of OA, KATP channel activity returned essentially to control levels (29±10% above control, in these patches). A representative single-channel trace showing OA's action and pooled data from the five patches are presented in Fig 5A and 5B.
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In three patches, the effect of applying purified PP2A in the presence of PKC was observed. In these patches, PKC caused a 225±77% increase in KATP channel activity. However, application of purified active PP2A (7.5 nmol/L) with PKC present resulted in the reversal of the PKC-mediated KATP channel activation, returning channel activity to near control levels (7±8% above control Po; see Fig 5C).
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Discussion |
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PKC and ATP Sensitivity of KATP Channels
Data from the present study demonstrate that PKC activates single KATP channels at millimolar levels of ATP. We concluded previously,17 on the basis of a reduction of the Hill coefficient from
2 to 1, that phosphorylation by PKC alters the stoichiometry of ATP binding to the channel. Extrapolation of the concentration-response curves, fitted in the range of 0 to 100 µmol/L ATP, suggested that at physiological (millimolar) concentrations of ATP, PKC-mediated phosphorylation of the KATP channel should increase channel activity (see Fig 1). Our present data support this prediction in two ways: (1) PKC increases the Po of KATP channels in the presence of 1 mmol/L ATP, and (2) at 100 µmol/L ATP, close to the predicted crossover point of the ATP-dependence curves for phosphorylated and nonphosphoryated channels (Fig 1), PKC had no effect on channel Po. Overall, it seems that phosphorylation functionally eliminates an ATP binding site on the channel, with a consequent reduction in the apparent ATP binding stoichiometry. In the simplest scenario consistent with our data, two sites must bind ATP to inhibit a nonphosphorylated channel. Phosphorylation appears to lock one site in an inhibitory state, without changing the properties of the other site. Hence, only one ATP molecule is subsequently required to bind to prevent channel activity. Thus, phosphorylation increases the effectiveness of ATP in inhibiting channel activity at low concentrations (<100 µmol/L) and reduces its inhibitory effect at high (millimolar) concentrations (see Figs 1 and 6). This interpretation is supported by experiments in the present study showing that the population of KATP channels in a single patch can be either activated or inhibited by PKC, depending on the concentration of ATP to which they are exposed (see Fig 4).
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Recent studies by Hu and colleagues have demonstrated that PKC is capable of activating KATP channels in the intact cell.15 28 However, these authors reported that the PKC activator phorbol-12, 13-didecanoate did not detectably activate KATP channels with ATP concentration of >1 mmol/L. It is possible that the twofold to fourfold increase over the KATP channel Po expected at millimolar ATP levels may not have been detected in their whole-cell recordings, because the expected change in whole-cell current is similar in magnitude (100 pA) to the SEMs in their collected data (Fig 4C in the study of Hu et al15 ). Thus, we do not consider the data of Hu et al to be in conflict with our own. In another recent study, Liu et al16 demonstrated at the whole-cell level that PKC is capable of activating KATP channels and that this effect is augmented by adenosine. These two studies independently support our findings that PKC is capable of activating KATP channels from ventricular myocytes.
PP2A Reverses the Effects of PKC
The present results demonstrate the following points: (1) OA, at a concentration of 5 nmol/L, prevents the spontaneous reversal of PKC-induced activation of KATP channels (at this concentration, OA specifically inhibits PP2A).26 27 (2) Application of purified PP2A in the presence of PKC reverses the PKC-induced activation of KATP channels. Taken together, these data suggest that an endogenous membrane-associated PP2A is responsible for the reversal of PKC-induced activation of KATP channels (see Fig 5). This is in accordance with our previous findings17 and strongly implies that at physiological levels of ATP, ventricular KATP channels are under the control of both PKC and PP2A. Thus, these processes of phosphorylation and dephosphorylation could dynamically regulate the activity of KATP channels in the myocardium and provide a mechanism by which KATP channel activity and hence cellular excitability can be reversibly controlled.
PKC: Physiological Concentrations and Isoforms
The isoforms present in the brain PKC preparation that we used are , , ß, and .19 In heart, the major PKC isoforms present are , , and 
.29 Although it would be useful to confirm our observations using PKC prepared specifically from rabbit heart, the strong parallels between our own results and studies using dialyzed myocytes and whole-heart preparations make it likely that the mechanism that we have identified has relevance to the intact organism.
Effect of PKC on KATP Channels in Other Tissues
It has recently been reported that PKC can either inhibit or activate KATP channels from insulin-secreting cell lines, depending on the time course of experiments.30 It has also been demonstrated that PKC activates KATP channels from insulin-secreting cell lines via somatostatin receptor stimulation coupled to G proteins.31 In follicle-enclosed oocytes,32 33 smooth muscle,34 35 and kidney,36 activation of PKC, induced by acetylcholine32 33 34 35 or bradykinin,36 leads to an inhibition of KATP channel activity. The results from our present study demonstrate that PKC is capable of activating ventricular KATP channels at near physiological levels of ATP. Thus, it appears that the effects of PKC on KATP channel function are tissue specific and depend on the signaling pathway to which PKC activation is linked.
Physiological Implications
Because of the relatively large conductance of KATP channels (70 to 90 pS) and their high density in the heart, these channels represent a large reserve of available conductance.1 2 At resting levels of ATP, the net K+ conductance through these channels is very low indeed. However, it has been calculated that only a small increase in Po is needed to significantly shorten the cardiac action potential,1 2 37 38 and it has been estimated that a Po of 0.002 can increase the action potential repolarization rate by 50%.2 Measurable action potential shortening will occur if ATP levels fall significantly below resting levels (5 to 10 mmol/L),1 as may be expected to occur during sustained periods of ischemia.39 40 Any factor that affects the ATP sensitivity of these channels, such as the PKC-induced change in the stoichiometry of ATP binding, will change the concentration at which the KATP conductance becomes a dominant influence and thus could have significant physiological repercussions.
PKC, KATP Channels, and Ischemic Preconditioning
Previous studies have associated activation of both KATP channels4 5 and PKC9 10 11 41 with the process of ischemic preconditioning. More specifically, several investigators have suggested recently that the KATP channels may be a link in a signaling pathway by which activation of PKC triggers ischemic preconditioning,12 13 14 even in human heart.12 To date, most studies on this issue have been performed at the whole-heart level. Our results now show that PKC can directly activate single cardiac KATP channels at physiological (millimolar) levels of ATP. Therefore, the present findings are consistent with the hypothesis that PKC-catalyzed phosphorylation of KATP channels, or some associated protein in the membrane patch, leads to preconditioning.
Phosphorylation immediately increases Po for KATP channels at millimolar ATP levels. Because the dose-response curve is relatively flat, channel activity will attenuate contractile work output over a wide range of ATP concentrations and will thus conserve the cell's reserves of metabolic fuel, until the channel is again dephosphorylated. Thus, long-term phosphorylation could provide a measure of cardioprotection even in the face of substantial temporal or spatial fluctuations in ATP concentration. This is consistent with the idea that during sustained ischemia, these channels open more readily in hearts that are preconditioned than in nonpreconditioned hearts.4 8 The opening of KATP channels would reduce the action potential duration and thus reduce the rate of calcium loading into the cell, an important factor in ischemic damage.
The exact receptor-coupled pathways involved in preconditioning remain to be identified. Likely extracellular agonists are those whose circulating levels increase under conditions that activate KATP channels; these conditions include ischemia and ischemic preconditioning. Potential physiological agonists include the following: (1) catecholamines, whose levels are known to rise during periods of ischemia42 (stimulation of 1-adrenoceptors by norepinephrine and 1-agonists mimics ischemic preconditioning,43 perhaps by the sequential activation of phospholipase C [a key intermediate in PKC activation44 45 46 47 48 ] and then PKC41 ); (2) adenosine, which binds to A1 receptors, producing a cardioprotective effect during ischemia and ischemic preconditioning49 50 (the effects of adenosine are likely to be mediated by activation of KATP channels,5 and adenosine seems to mimic ischemic preconditioning via activation of PKC9 10 ; recent evidence also suggests that adenosine and PKC act synergistically in the activation of KATP channels16 ); (3) acetylcholine, whose binding to muscarinic receptors may activate cardiac KATP channels via second-messenger pathways coupled to PKC51 (acetylcholine also appears to mimic ischemic preconditioning through activation of KATP channels52 ); and (4) bradykinin, which is cardioprotective when released locally during ischemia53 (bradykinin, too, has been shown to mimic ischemic preconditioning, perhaps through a PKC-linked mechanism54 ). If all of these pathways should be verified by future studies, this would point to a highly redundant system for activating ischemic preconditioning, suggesting a powerful selective pressure over the course of evolution to incorporate this regulatory machinery into the cardiovascular system. This may imply that the preconditioning pathways are frequently activated and are fundamental to the normal long-term function of the heart.
The relatively rapid appearance and reversal of the PKC-induced upregulation of KATP channels in the present study argue against the idea that this particular reaction determines the time course of preconditioning. We consider it to be more likely that the in situ time course of KATP channel modulation by PKC depends secondarily on the complex factors that determine the level of PKC activity. For example, proteolytic cleavage of PKC forms a constitutively active fragment, PKM, which is released from the membrane.55 Such a mechanism might not only prolong kinase activity for an extended period but could also enable feedback via pathways composed of soluble cytoplasmic elements.
Given our use of a constitutively active preparation of PKC, there is no reason to expect that the time course for KATP channel upregulation in our experiments should match that of preconditioning in the intact heart, even if KATP activation is an essential part of the preconditioning mechanism. If PKC activation is a prerequisite for KATP current upregulation and preconditioning, a complex sequence of events, including PKC translocation from the cytoplasm to the membrane phase, must occur before the onset of preconditioning (for example, see Reference 4). On the other hand, the fast decrease in activity after removal of PKC, or after addition of excess PP2A, clearly argues against the idea that the duration of the protective effect of preconditioning (tens of minutes, or longer4 56 ) might reflect the lifetime of the phosphorylated state of the channel (a few seconds, or less). Rather, the duration of PKC-induced preconditioning may reflect the period over which PKC activity is elevated or a period of inhibition of PP2A, thus favoring the prolonged phosphorylation of KATP channels.
In conclusion, it seems likely that KATP channels can be regulated by several intracellular signaling pathways, which act via PKC to alter the ATP dependence of channel activity. We identify a mechanism by which activation of KATP channels via PKC-dependent phosphorylation may provide a link in one or more of the signaling pathways that trigger ischemic preconditioning. The fast onset and reversal (<1 minute) of the direct effect of PKC suggest that the time course of the relatively long-term phenomenon of ischemic preconditioning is regulated at some point in the signaling pathway other than the phosphorylation reaction per se.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by grants from the Medical Research Council of Canada (Drs French and Walsh). Dr French is a Senior Scholar and Dr Walsh is a Medical Scientist of the Alberta Heritage Foundation for Medical Research (AHFMR). Dr Allen is a Heart and Stroke Foundation of Canada and AHFMR Fellow. The authors are very grateful to Drs W.R. Giles, H. Tanaka, and N. Satoh (Department of Medical Physiology, University of Calgary) for generously providing the isolated rabbit ventricular myocytes and to Dr Larry Haynes for critical comments on a draft of the manuscript. We thank Dr S. Nattel for generously providing a prepublication copy of the study by Hu et al.15
Received October 27, 1995; accepted May 14, 1996.
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