ANNUAL REVIEWS

Further

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PROPERTIES OF TWO INWARD

.1228

MEMBRANE CURRENTS IN THE HEART Harald Reuter Department of Pharmacology, University of Berne,

3010

Berne, Switzerland.

INTRODUCTION During the last 12 years impressive experimental evidence has accumulated that two distinct inward membrane currents are responsible for excitation of the heart. The first inward current

(INJ is abolished by removal of

external Na ions or by tetrodotoxin (1TX) and, at least qualitatively, resem­ bles Na currents in nerve or skeletal muscle fast upstroke velocity

(78). INa is responsible for the

(VmaJ of the cardiac action potential (AP). V

max

is

an important factor in impulse conduction velocity in myocardial tissue (38, 60). The much smaller secondary inward current (lsJ is very sensitive to

variation in the external Ca ion concentration and has many features in

common with Ca currents in other excitable tissues (29,65). lsi is important for the characteristic plateau phase of the cardiac AP (8, 53) and for excitation-contraction coupling (reviewed in

17, 51, 79).

Some physiological and pharmacological properties of these inward cur­ rents are described in this review. Since the length of this article is limited,

I can discuss only a few of the numerous papers that lead to the concept

of two distinct inward membrane currents in cardiac muscle. The literature untii about 1974 has been reviewed in several major articles and books (13,

60, 65, 75). Several articles in the Annual Review series have dealt with

certain aspects of this subject (17, 40, 51, 79, 81). This review emphasizes voltage-clamp results and includes a brief discussion of methodological limitations. 413

0066-4278/79/0301-0413$01.00

414

REUTER

METHODOLOGICAL LIMITATIONS There can be little doubt that multicellular preparations, like strands of

cardiac muscle, are much less suitable for voltage clamping (VC) than the

classical single cell preparation, the squid axon. This view has been empha­

sized forcefully by Johnson & Lieberman (40). Since then several theoretical

and experimental papers have been published dealing with the problems of

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various VC methods for multicellular preparations (reviewed in

2, 5, 18,

38). Resistances in series

(Rs) with the membranes

within a fiber bundle limit

quantitative experimental evaluation of membrane currents

(6, 39, 47, 66). A major fraction of Rs is most likely located in clefts between individual cells or cell strands and hence cannot be compensated (2, 5, 39). The problem of narrow clefts and consequently of radial voltage non-uniformi­ ties (and of ion accumulation and depletion) is probably more severe in

ungulate Purkinje fibers and frog heart than in working myocardial fibers

from larger mammals

(2, 40, 66).

However, in all preparations VC is obvi­

ously impossible when the membrane resistance approaches the value of the

(distributed) Rs, e.g. during the How OflNa

(2, 6, 47).

Though more severe,

the problem of Rs is not confined to multicellular preparations like cardiac

muscle; it also holds true for single cell preparations, particularly if their membranes are folded or have narrow invaginations (neuron somata, skele­

tal muscle fibers).

A search in the literature showed that in most prepara­

tions (including squid axon) the ratio between measured Rs and the nega­ tive slope resistance of the membrane during the flow of inward currents

(Rs/-Rslope) is between 1/2 and 1/15. In mammalian cardiac muscle this lsi is at least 1110 [Figure IB; (54, 66)], which is acceptable; but the ratio becomes larger than 1 during the flow of INa, which means that the membrane potential is no longer under control (6, 47).

ratio for

With sucrose-gap methods one is faced with additional problems due to

(a) shunt current across the gaps,

and

(b) mixing of

sucrose solution with

saline solution (Ringer. Tyrode. etc) 'within the bundle

(2, 56).

The shunt

current depends on the ratio of the internal and external resistances of the

bundle in the sucrose gap (Ril'Ro). Ri can be kept relatively constant for

some time (1-2 hr) if a small concentration (1o-s-1Q4 M) of CaCl2 is added to the sucrose solution

(45, 54, 66),

although this reduces

Ro.

Under fa­

vorable conditions R/Ra is smaller than 0,1 (54, 66). but even then the shunt current is not negligible. Goldman & Morad (24) suggest that a "guard gap" added to the single sucrose-gap arrangement is effective in

trapping a large portion of the shunt current. The problem of interdiffusion of sucrose and saline solutions in the muscle bundle can be reduced

(70) by

using rubber membranes with holes small enough to squeeze the bundle at the solution interface

(6, 24, 54, 56, 66).

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INWARD MEMBRANE CURRENTS IN THE HEART

415

A promising new approach is the application of the modified three­ microelectrode VC technique of Adrian et al (1) to mammalian ventricular preparations (42,66). This method makes use of the voltage drop along the internal resistance during current flow in a cable-like structure. The voltage gradient between two intracellular microelectrodes is proportional to the current flowing across the membrane. Current can be applied either through a third intracellular microelectrode (1, 42) or through a sucrose gap (66). So far this method has been used successfully in cardiac preparations in the evaluation of lsi (42, 66), but it may also be suitable for measurements of INa' Generally one may conclude that VC analysis of cardiac membrane currents, though difficult. can be done with a reasonable degree of reliabil­ ity, provided the necessary experimental precautions are taken and the investigated membrane conductances are small compared to lilts. Our knowledge of the plateau phase of the AP, of pacemaker activity, of "slow responses," of mechanisms of drug actions. and of excitation-contraction coupling would be much less advanced without this technique, despite its problems. Since INa cannot at present be adequately measured in cardiac muscle by VC methods. the upstroke velocity (Vmax> of the membrane AP is often used as a measure of I Na [Vmax = -In/Cm, where 1m is ionic membrane current (lin + lout). and Cm is membrane capacity]. From model computations of the squid axon AP it has recently been argued (12) that Vmax is a non­ linear and highly unreliable measure not only of the limiting N a conduc­ tance, GNa• but also of INa, since Vmax 0 if lout INa' However, in squid axon. total lout increases steeply during depolarization. while this is not true in cardiac muscle where lout falls during depolarization (inward­ going rectification). Vmax is reached around -20 mV (68), and at this poten­ tial the contribution of lout to 1m is only a few percent. Even in the absence of INa, e.g. from a reduced resting potential, the much smaller lsi can still produce APs. Computations of the cardiac AP show an excellent correla­ tion between INa> GNa, and Vmax (32), although this may be a feature of the particular AP model (8) used. As pointed out by Strichartz & Cohen (73a), in squid axon the relation between Vmax and GNa is still nonlinear even in the absence of any outward conductance. Therefore, the exact relation between INa, GNa. and Vmax in cardiac muscle can only be resolved by a complete experimental analysis. =

SODIUM CURRENT

=

(INJ

Several attempts have been made to analyze INa of different cardiac prepara­ tions by VC methods (reviewed in 40, 60, 75, 81). Unfortunately, all studies suffer from the lack of membrane-potential control during the flow of INa

416

REUTER

and from other methodological difficulties. The only conclusions that can be drawn are the following: INa depends on the external Na concentration and is sensitive to TIX, albeit at rather high concentrations; INa is a large and rapid inward current lasting for only a few msec; the current inactivates upon depolarization from -90 to -50 mY; recovery from inactivation may be slower than inactivation. Beyond this nothing can be said about the kinetic properties of this inward current. However, the data are not incon­

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sistent with the view that INa in cardiac muscle is similar to that in nerve and skeletal muscle (60, 78). This assumption was made for modelling

Vmax

in two computer reconstructions of cardiac APs, one for Purkinje

fibers (53) and the other for ventricular myocardial fibers (8).

Vmax of the AP is often used as a measure of INa' Weidmann (80) showed that after an AP during which INa is inactivated,

Vmax recovers within a few

msec at membrane potentials (VuJ between -106 and -80 mV. This finding has been confirmed (20), but it has also been shown that at less-negative Vm the recovery of INa and

Vmax is considerably

prolonged and becomes much

slower than the inactivation rate of INa (20, 28, 83). A similar feature of the

Na system has been reported for other excitable tissues and has been

ex­

plained in terms of coupled activation-inactivation kinetics of Na channels

(23). In the heart the steep potential dependence of the recovery kinetics of Vmax (20) may cause large inhomogeneities in impulse conduction be­

tween normal and slightly depolarized tissue regions, e.g. near infarcted areas. Membrane potential also affects the potency of some drugs acting on the Na system (33). The effects of quinidine and lidocaine (11, 30, 83), two

important antiarrhythmic and local anesthetic drugs, strongly depend on the electrical activity of the cardiac cell membrane. If quinidine is applied

during a long period of rest, Vmax of the first post-rest AP is virtually

unaffected. However, during continuous stimulation there is a very rapid reduction of

Vmax,

which recovers slowly when the rate of stimulation

is reduced (30). Similarly, lidocaine strongly delays the rate of recovery of Vmax after a preceding depolarization (II, 83). Both drugs shift the

Vmax-Vm relationship (inactivation) towards more negative potentials. Since

these drugs interact with receptors linked to the Na channels, the voltage­ dependent states of these channels (resting, open, inactivated), and hence

Vm, may influence the drug-receptor interaction (31, 33). Kinetic analyses of the action of local anesthetic drugs on INa in nerve fibers (31) have indeed shown a strong voltage dependence of the action of these drugs, depolariza­ tion causing a larger receptor occupancy than hyperpolarization. The phe­ nomena observed in heart muscle (11, 30, 33, 83) agree, at least qualitatively, with the more rigorous data available from myelinated nerves

(31).

INWARD MEMBRANE CURRENTS IN THE HEART

417

Surprisingly, in mammalian cardiac muscle the TTX effect on Vmax not only occurs at more than a thousand times higher concentrations than in nerve and skeletal muscle, but it is also strongly voltage-dependent (3, 68). A 18-20 mV depolarization from a resting potential of about -90 mV causes a large shift of the concentration-response curve with a ten-fold increase in the apparent affinity. Moreover, the toxin effect depends on the rate of stimulation, the recovery kinetics of Vmax are greatly prolonged, and the Vmax V m relationship is shifted towards more negative potentials. These and other results led to the suggestion (3, 68) that TTX dissociates much less readily from inactivated than from resting Na channels, a hypothesis simi­ lar to that proposed for the action of local anesthetics (31, 33). Various toxins (batrachotoxin, grayanotoxin, Anemonia sulcata toxin, veratrine, germitrine) increase the Na permeability in cardiac muscle (3436, SO, 63), as in other excitable tissues (57). One of the most interesting aspects of these studies is that an increase in the Na permeability of the membrane is associated with an increase in force of contraction. This is most likely due to the Na-Ca exchange system in the membrane, which promotes Ca influx when the internal Na concentration is raised (16,22).

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-

SLOW INWARD CURRENT (Isu Initial evidence for Ca-dependent lsi came from VC results in Purkinje fibers (64). lsi has since been shown to occur in all cardiac tissues investigated so far (65, 75), although its analysis is sometimes complicated by the overlap of other current components (37, 72). lsi not only determines the plateau phase of cardiac APs [Figure lA; (8, 53)]1 but it is also the primary inward current during spontaneous activity of the sinus node (9,61). When Vm is dep olarized, lsi generates repetitive activity in atrial (10) and ventricular (8, 26, 65) fibers. The evidence that lsi is an inward current distinct from the fast INa has been obtained from kinetic data, from ion substitution, and from pharmacological experiments (7, 20, 41, 54, 64-66, 69, 75). lsi can be described (8, 65) as lsi Gsi ·d(V,t)·f(V,t)·(Vm-Vo). The voltage ranges of steady-state activation (d.., Figure 1C) and inactivation (fex>, Figure IC) ofIsi are different from INa (20,54,65,66,76). lsi can be activated from holding potentials (V� at which INa is completely inactivated (Figure 1 A-C), and it is still recorded after Na removal or in the presence of TTX (7,64,65,69,75). During VC steps lsi reaches a peak in the range -15 to o mV [Figure IB; (54, 65, 66, 75)J. Inactivation is not always complete =

lIn contrast to suggestions by Goldman & Morad (25), "linear" instantaneous current­ voltage relations with little decrease in slope [i.e. very positive "rotation potential" (25)] during the plateau of the AP are quite compatible with the concept (8, 53) of independent ion channels for lsi and lout (G. W. Beeler, unpublished computations).

418

REUTER a

A

b

I =0 -�;;....---r· �.J"""''''' ... P.·]5"A -5 mV

B VR I

"A 4

Annu. Rev. Physiol. 1979.41:413-424. Downloaded from www.annualreviews.org Access provided by Australian National University on 01/29/15. For personal use only.

:=

/

� =�,..v

1=0 -�-··········r·

....

�5

d

·

L mV 60

I

-80

'".v

f

VH I

.......... r

l...-.-...J

300 msec Figure I

(A) Relation between Ioi (upper traces) and APs (lower traces). Resting potential

(v0 -75 mY; 1= 0 corresponds to YR' VC steps (middle traces) from a holding potential (Va> of-45 mY, at which IN. is inactivated, to -5, +5, +15, and +24mV (a.,.d) produce inward currents that partially inactivate during the 500 msec steps; net membrane current is zero at peak of action potential (+15 mY). (B) Current-voltage relations (ordinate /LA; abscissa mY) of peak inward or outward currents 10--20 msec after beginning of VC steps (X) and currents

at the end of the 500 msec VC steps

('e);

I = 0 at VH' (C) Voltage range of steady-state

activation (doo) and inactivation (foo). Experimental results from a cow ventricular trabecula;

c..

=

1.6 /LF; R"

=

360 n. [H. Reuter, unpublished experiment; for method

see

(66)].

during prolonged depolarization (Figure IA). This is partly, but not exclu­ sively

(43),

due to the crossover of do. and foo (Figure IC;

66, 76). While the -20 mV (8),

time constants of activation (Td) reach a maximum around

the time constants of inactivation (Tf) seem to increase continuously in the range

-70

to

+30 mV (8, 54, 66, 76).

It is still unsettled whether the rates

of inactivation and of recovery from inactivation of lsi are different

66, 76).

(20, 54,

Furthermore, since there are considerable differences in AP config­

uration, not only between different species but even between different parts

of the same ventricle, it is not surprising that the absolute kinetic values of

lsi (and of other currents) are somewhat variable.

Systematic ion-substitution experiments indicate that lsi is largely, but

not exclusively, carried by Ca ions. The reversal potential, V0' of lsi is considerably more negative than the Ca equilibrium potential calculated from the Nemst equation

(54, 65, 66, 75). However, Vo could be fitted by (66). The membrane ion channels carrying lsi

the constant field equation

have been estimated as being at least one hundred times more selective for

Ca than for Na or K ions (66), which justifies the term "Ca channels." Since

Na and K ions are much more concentrated than Ca ions in both the

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INWARD MEMBRANE CURRENTS IN THE HEART

419

external medium and in the cytoplasm of the cell, some fraction of lsi is carried by these ions. This explains·(66) why lsi does not decrease propor­ tionally to the reduction in the external Ca concentration, [Calo, and why Na ions are the predominant charge carriers when [Ca]o is low or absent (19, 25). With high [Ca]o, Ca channels seem to saturate (29, 65), indicating deviation from the independence principle (29; 78). Furthermore,the influ­ ence of intracellular electrolyte composition on ion permeabilities and selec­ tivities of Ca channels (48, 49) is unknown in cardiac muscle. Intracellular Ca injection in Purkinje fibers seems to increase lsi in the range -65 to -35 mY (37), an effect opposite to that seen in snail neurons (49). Such an effect could arise from an involvement of the sarcoplasmic reticulum (37), but more likely from a negative shift of do. and foo along the voltage axis, or from changes in the ion permeabilities of the channels. Most significantly,adrenergic and cholinergic transmitters have a strong effect on lsi' tl-Adrenergic drugs increase lsi (64; reviewed in 10, 65, 77), while muscarinic agonists reduce it (21, 74). A recent analysis of the epi­ nephrine effect on lsi (67) indicates that neither the kinetics of lsi nor the selectivity of the corresponding conductance channels are altered by the drug. However, the limiting conductance, Gsi, is greatly increased. This has been interpreted as caused by an increase in the number of functional Ca channels (67). The same conclusion has been reached on the basis of more indirect results (59). Figure 2 shows a hypothetical scheme involving cell metabolism for the regulation of the availability of Ca channels (46, 67, 73). Catecholamines may increase the availability of functional channels by a cAMP-dependent phosphorylation reaction (27,59,67,73,77),while aceB

in Figure 2

?@[ g �' c

Hypothetical scheme for regulation of Ca channels in cardiac muscle. The channel

contains a filter (s) determining its Ca selectivity (78), and two gates (g and g'); g is the voltage-dependent d,f gate [assuming coupled activation - inactivation reactions (23,78)]; g' is a phosphorylation-dependent, voltage-independent gate. Phosphorylation of g' may be due to a cAMP-dependent proteinkinase reaction (27); dephosphorylation may depend on a phospha­ tase. (A) Without phosphorylation g' is closed and hence channels are not available. (B) Channels are available but nonconducting when g' is phosphorylated (P�g') but g is closed. (C) Phosphorylated channels conduct when g opens upon depolarization of the membrane.

REUTER

420

tylcholine could reduce the availability by dephosphorylation of the chan­ nels, possibly either by a decrease in cAMP or by an increase in cGMP (71). This implies that the respective ratios cAMP/cGMP could regulate the number of functional channels and thereby also the contractility of the heart (15) It would be highly desirable to have specific inhibitors for Ca channels, like TIX for Na channels. Although verapamil and its methoxy derivative, D 600, have been proposed as such inhibitors (14), they unfortunately lack the desired specificity. In addition to the reduction of lsi, they alter its kinetics (58) and have considerable depressant effects on INa [Vmax' (4)] and lout (41), although the action of these drugs on lsi> particularly of the (-)isomers (4), is somewhat more potent. Similarly, La, Mn, and related ions must be used with caution as Ca channel blockers, since they also have effects on lout (41). Moreover, Mn ions are themselves quite permeable (62). Both an increase (82) and a reduction (55) of lsi by nontoxic concentra­ tions of cardiac glycosides have been reported. A novel, transient, inward current (TI), partly carried by Na ions, has been described as occurring during toxic concentrations of these drugs (44, 52). TI is responsible for certain digitalis-induced arrhythmias in Purkinje fibers (52). It resembles neither INa nor lsi but may depend on shifts of intracellular Ca. Binding of Ca to the inner surface of the membrane could open rather nonspecific ion channels, thus inducing TI (44). Slow APs can be generated from a depolarized membrane potential (around -50 mY) at which INa is inactivated. They are often called "slow responses" or "Ca action potentials" since they depend on lsi (8, 13, 65). The literature on these APs is vast (13) and cannot be reviewed in this article. However, since slow responses are often used as indicators for lsi, particularly in pharmacological studies, a word of caution may be in order. In most instances it is very difficult to decide without VC analysis, whether external conditions and drugs have altered lSi' or lout> or both. Since lout is not negligible during the flow of lsi> slow responses, their Vmax' and their amplitudes can be altered by changes in either current component.

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.

CONCLUSIONS The existence of two separate inward membrane currents, INa and lsi, in cardiac cell membranes is well established. Although up to now technical limitations of the VC method have not permitted a quantitative evaluation of INa, there are sufficient data to conclude that INa in cardiac muscle is probably similar to that in other excitable cells. While INa is responsible for the rapid rising phase of the AP, lsi is activated by this depolarization and generates the plateau of the AP. Under normal conditions lsi is carried

INWARD MEMBRANE CURRENTS IN THE HEART

421

primarily by Ca ions and can be described by Hodgkin-Huxley kinetics. An intriguing feature of lsi is its modulation by adrenergic and cholinergic transmitters. The number of functional Ca channels may be regulated by cyclic nucleotides in the cell (chemical gating). Embryonic development of cardiac cells, a topic that could not be covered in this review, may provide an unique model for further investigation of channel regulation.

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ACKNOWLEDGMENT Support by the Swiss National Science Foundation is gratefully acknowl­ edged. Literature Cited 1. Adrian, R. H., Chandler, W. K., Hodg­

kin, A. L. 1970. Voltage clamp experi­ ments in striated muscle fibres. J. PhysioL London 208:607-44 2. Attwell, D., Cohen, I. 1977. The voltage clamp of multicellular preparations.

hog. Biophys. Mol Biol 31:201-45 3. Baer, M., Best, P. M., Reuter, H. 1976.

Voltage-dependent action of tet­ rodotoxin m mammalian cardiac mus­ cle. Nature 263:344-45 4. Bayer, R., Kalusche, D., Kaufmann, R., Mannhold, R. 1975. Inotropic and electrophysiological actions of verapa­ mil and D 600 in mammalian myocar­ dium. III. Effects of optical isomers on transmembrane action potentials. Naunyn-Schmiedeberg's macal 290:81-97

Areh.

Phar­

5. Beeler, G. W., McGuigan, J. A. S. 1978. Voltage clamping of multicellular car­ diac preparations; capabilities and limi­ tations of existing methods. Prog. Bio­ phys. MoL Biol In press 6. Beeler, G. W. Jr., Reuter, H. 1970. Voltage clamp experiments on ventricu­ lar myocardium fib res. J. Physiol Lon­ don 207:165-90 7. Beeler, G. W. Jr., Reuter, H.

1970.

Membrane calcium current in ventricu­ lar myocardium fibres. /. PhysioL Lon­ don

207:191-209

8. Beeler, G. W., Reuter, H. 1977. Recon­

struction of the action potential of ven­ tricular myocardial fibres. J. Physiol

London 268:177-210 9. Brown, H. F., Giles, W., Noble,

S. J. 1977. Membrane currents underlying

activity in frog sinus venosus. J. PhysioL

London

271:783-816 10. Brown, H. F., McNaughton, P. A., No­ ble, D., Noble, S. J. f97 5 . Adrenergic control of pacemaker currents. Philos. Trans. R. Soc. Land. Ser. B.

527-37

270:

11. Chen, C.-M., Gettes, L. S., Katzung, B. G. 1975. Effect of lidocaine and quini­

dine on steady-state characteristics and recovery kinetics of (dVIdt).... in guinea pig ventricular myocardium. Cire. Res. 37:20-29 12. Cohen, I. S., Strichartz, G. R. 1977. On the voltage-dependent action of tet­ rodotoxin. Biophys. J. 17:275-79 13. Cranefield, P. F. 1975. The Conduction of the Cardiac Impulse. Mount Kisco, NY: Futura. 404 pp. 14. Fleckenstein, A. 1977. Specific pharma­ cology of calcium in myocardium, car­ diac pacemaker, and vascular smooth muscle. Ann. Rev. Pharmacal Toxicol

17:149-66 15. Flitney, F. W., Lamb, J. F., Singh, J.

1978. Intracellular cyclic nuc1eotides and contractility of the hypodynamic frog ventricle. J. Physiol London

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17.

molecular aspects of Na+ and ea2+ up­ takes by embryonic cardiac cells in cul­ ture. /. BioL Chern. 252:6112-17 Fozzard, H. A. 1977. Heart: excitation­ contraction co upling. Ann. Rev. PhysioL

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21. Giles, W.,Noble, S. J. 1976. Changes in membrane currents in bullfrog atrium produced by acetylcholine. J. PhysioL

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