Editorial |
From the Division of Cardiology, University of Utah Health Sciences Center, Salt Lake City, Utah.
Correspondence to William H. Barry, MD, University of Utah Health Sciences Center, Division of Cardiology, 50 North Medical Dr, Salt Lake City, UT 84132. E-mail whbarry{at}med.utah.edu
Key Words: myocardium Na+-Ca2+ exchange sarcoplasmic reticulum
| Introduction |
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10% of relaxation. In rabbits, which have a
lower [Na+]i and SR
Ca2+-ATPase activity, NCX contributes more
significantly to the decline of the Ca2+
transient, especially during the terminal phase of the
transient.6 NCX can also produce Ca2+ influx by operating in the reverse mode. Electrochemical considerations indicate that early after the upstroke of the action potential, before a rise in intracellular [Ca2+]i occurs because of Ca2+-induced Ca2+ release, Ca2+ influx on the exchanger will occur.7 Ca2+ influx can also occur after decline of the [Ca2+]i transient if the duration of the action potential is long. The magnitude of this influx is dependent on the magnitude and rate of rise of the [Ca2+]i transient, the density of NCX in the sarcolemmal membrane, and the [Na+] adjacent to NCX in the subsarcolemmal space, which is influenced by the Na+ pump activity and INa as well as by the bulk cytosolic [Na+].8 The functional importance of reverse-mode NCX (Ca2+ influx) has been debated. This mode of NCX function has been proposed to increase the content of Ca2+ in SR,9 10 11 modulate the effectiveness of the L-type Ca2+ channel current in inducing Ca2+ release,12 13 14 and directly induce Ca2+ release,15 16 17 18 although other experimental work does not support a significant role for NCX-induced Ca2+ release in excitation-contraction (EC) coupling.19 20
Recent work in which NCX activity has been increased or decreased in isolated myocytes has provided conflicting data regarding the physiological importance of Ca2+ influx via NCX. Studies in transgenic murine myocytes that overexpress the exchanger by 2.5-fold have indicated that rather than producing Ca2+ depletion, increased activity of NCX produces an increased diastolic Ca2+ influx and SR Ca2+ loading21 or an increase in Ca2+ influx during EC coupling, which contributes to the Ca2+ transient and can produce a reduced dependence on L-type Ca2+ channel current during EC coupling.14 On the other hand, Satoh et al22 reported that 5 µmol/L KBR-7943, an inhibitor of reverse-mode NCX, had no effect on the magnitude of the Ca2+ transient or contraction in rat myocytes. Yang et al23 have reported that 5 µmol/L KBR-7943 decreases the [Ca2+]i transient in rabbit myocytes. Although KBR effects at concentrations of >1 µmol/L could be attributable to an effect of the drug on L-type Ca2+ channels, Yang et al23 also observed that submicromolar concentrations of KBR inhibited the increase in [Ca2+]i transient induced by endothelin-1 and have suggested that this effect is attributable to inhibition of an endothelin-1induced increase in reverse-mode NCX. Unpublished work from our laboratory has indicated that 5-µmol/L KBR-7943 also produces a small but significant decrease in the magnitude of the Ca2+ transient in mouse ventricular myocytes. Some of these differences in experimental results may relate to species-dependent variations in expression of NCX,24 [Na+]i, and action potential duration, factors that influence reverse-mode NCX. Thus, NCX in cardiac myocytes can function in both forward and reverse modes, although the physiological importance of Ca2+ influx on NCX remains somewhat controversial.
A thorough understanding of the mechanisms and importance of NCX function is important, because the activity of this transporter is altered in heart hypertrophy and failure. Experiments in several laboratories have shown that hypertrophy in animals is associated with a switch to a fetal pattern of gene expression,25 including changes in actin and myosin isoforms, an increase in atrial natriuretic factor, a decrease in SR Ca2+-ATPase, and an increase in NCX expression. The possible functional importance of increased NCX expression and reduced SR Ca2+-ATPase activity has been studied in immature hearts and animal models of hypertrophy and failure. Haddock et al26 and Chin et al27 reported an apparent greater dependence on Ca2+ influx via NCX during an action potential and a reduced dependence on SR function for maintenance of the [Ca2+]i transient in newborn versus adult rabbit myocytes. Litwin and Bridge28 showed that in hypertrophied myocytes isolated from a peri-infarct area in a rabbit heart, NCX expression was increased and L-type Ca2+ current was decreased by 30% to 40%. In voltage-clamp studies, NCX seemed to provide Ca2+ influx to load the SR. The authors proposed that the increased activity of the NCX was maintaining SR Ca2+ loading in spite of some decrease in L-type Ca2+ current. ORourke et al29 found increased NCX and decreased SR Ca2+-ATPase expression in myocytes from a pacing-induced failure canine model and showed that forward function of NCX seemed to compensate partially for reduced SR Ca2+-ATPase function in reducing [Ca2+]i during a transient. Pogwizd et al30 found increased NCX expression in a rabbit model of left ventricular pressure and volume overload, with no change in SR Ca2+-ATPase or Ca2+ current density. Twitch amplitude was decreased by 21% and SR Ca2+ content was not altered, but the rate of decline of a caffeine-induced [Ca2+]i transient was accelerated. They proposed that increased NCX activity was reducing the amplitude of contraction and that increased NCX-dependent currents contributed to arrhythmias in this model.
In this issue of Circulation Research, Ito et al31 report studies of isolated left ventricular myocytes from mice with ascending aortic stenosis (AS) and compensatory hypertrophy of 4 and 7 weeks duration. Although protein levels of NCX were increased at both 4 and 7 weeks, the SR Ca2+-ATPase to phospholamban protein ratio was depressed only in the 7-week AS myocytes. Under resting conditions, the amplitude of shortening and peak systolic [Ca2+]i were not different from controls in myocytes from animals at 7 weeks, although contraction, relaxation, and the decline of the Ca2+ transients were slower in the hypertrophied myocytes. In response to rapid pacing stimulation or exposure to high [Ca2+]o, cell shortening and peak systolic Ca2+ increased in controls, but the responses were depressed in 7-week AS myocytes, and SR Ca2+ content was reduced during rapid pacing in 7-week hypertrophied myocytes. These abnormalities cannot be ascribed to increased expression of NCX, because they were not present in 4-week AS myocytes. These results suggest that during hypertrophy in mice, reduced SR Ca2+-ATPase activity rather than increased NCX is the most important factor producing a functional abnormality during stress.
It is also known that the NCX protein may be increased and SR Ca2+-ATPase may be decreased in myocardium patients with heart failure,32 and this may have functional importance. Houser and colleagues33 34 35 have reported that in failing human ventricular myocytes isolated from explanted hearts, there is a late tonic component of contraction and [Ca2+]i transient. They suggest that this is attributable to influx of Ca2+ on NCX, possibly caused by increased expression of the exchanger and the prolonged action potential duration that is seen in human failing myocardium.36 This late tonic component could be inhibited by exposure to KBR-7943, providing some additional support for this hypothesis.33 This idea is also consistent with the early observations of Gwathmey et al,37 who noted a delayed secondary increase in the aequorin [Ca2+]i transient in failing myocardium. This was insensitive to ryanodine but was eliminated by verapamil, which could have shortened the prolonged action potential. The work of Flesch et al38 also suggests that enhanced expression of the exchanger could support contraction in failing myocytes by providing an additional source of Ca2+ influx to provide activation of the contractile elements and maintain SR Ca2+ loading.
On the other hand, studies by Schillinger et al39 and Hasenfuss et al40 have shown that failing human myocardium with an increased NCX exchanger but normal SR Ca2+-ATPase protein levels develop normal contractile force at rates of 40 to 60 min-1 but show a negative inotropic response to an increased pacing rate. To test the hypothesis that a reduced contractile force at high frequency of pacing is related to increased NCX activity, Schillinger et al41 report in this issue of Circulation Research important studies in which adenoviral transfection of the NCX gene in rabbit ventricular myocytes increased the level of expression of protein by 2- to 3-fold. This resulted in no significant change in fractional shortening during stimulation at 30 to 60 min-1 but caused a reduced positive inotropic response at faster rates of pacing. In support of the hypothesis that this effect was attributable to enhanced extrusion of Ca2+ from the myocyte by NCX, Schillinger et al show that SR Ca2+ content, as estimated from the contractile response to abrupt exposure to caffeine, was reduced in myocytes overexpressing the exchanger. These data support the hypothesis that increased expression of NCX in failing human myocardium promotes enhanced extrusion of Ca2+ from the myocyte, particularly at fast heart rates when action potential durations are relatively short, and suggest that this contributes, along with reduced expression of the SR Ca2+-ATPase, to the reduction in SR Ca2+ content that has been observed in failing myocardium.42 43
Do these findings, that a reduced Treppe response in rabbit myocardium is caused by an increased expression of NCX, mean that NCX activity, although helpful in maintaining diastolic function, is detrimental to systolic function in failing human myocardium? It is not certain that this is always the case. First, as mentioned previously, the [Na+]i and the action potential duration are of critical importance in determining the balance between Ca2+ influx and efflux on the exchanger. In failing human myocardium, the action potential is prolonged,35 especially at slow rates of stimulation,35 36 44 and the [Na+]i in failing human myocardium may be elevated. These factors could increase the importance of Ca2+ entry via reverse-mode NCX in failing human myocardium and produce a situation in which increased expression of NCX would, in fact, be beneficial rather than detrimental with respect to SR Ca2+ loading, especially at slow heart rates. This may explain why systolic function of failing myocardium is relatively normal at slow rates of stimulation39 and account for some of the benefits of ß-blocker therapy, which slows heart rate in patients with heart failure.
In summary, presently data are somewhat conflicting regarding the influence of increased expression of the NCX on myocyte function. The experiments of Schillinger et al41 are important in that they demonstrate for the first time that increased expression of NCX in rabbit myocytes with a relatively low [Na+]i and longer duration action potential can have a negative inotropic effect and produce depletion of SR Ca2+. This effect may be important in impairing contraction of failing human myocardium at rapid rates of contraction, but increased NCX expression may benefit systolic as well as diastolic function at slower rates of contraction, especially in myocardium with reduced activity of the SR Ca2+-ATPase.
| Footnotes |
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