Tetanic hyperpolarization of single medullated nerve fibers in sodium and lithium.

AMERICAN

JOURNAL

OF

Vol. 231, No. 4, October

PHYSIOLOGY

1976.

Printed

in U.S.A.

Tetanic hyperpolarization of single fibers in sodium and lithium GORDON M. SCHOEPFLE Department of Physiology and Biophysics, Birmingham, Alabama 35294

University

SCHOEPFLE, GORDON M. Tetanic hyperpolarization of single medullated nerve fibers in sodium and lithium. Am. J. Physiol. 231(4): 1033-1038. 1976. -Repetitive stimulation of a single medullated nerve fiber of Xenopus yields a succession of postspike voltage-time curves which are nearly coincident until attainment of a voltage that corresponds to that of the maximum attained by the normal postspike undershoot. Initially the interspike potential returns toward a resting level after this brief phase of hyperpolarization. However, as tetanization proceeds, a pattern of hyperpolarization develops with the result that, in the tetanic steady state, there exists a progressive hyperpolarization throughout each interspike interval. Extent of postspike hyperpolarization in terms of a deviation 8V, from the resting level of membrane potential is approximated by the variation 6V, = 6[M,, + MK]/[GNa + GK] where M,, and M, are current densities associated with active pumping of sodium and potassium ions and GNa and G, are corresponding time-dependent leak conductances. Tetanic hyperpolarization is reversibly abolished by cyanide and by exposure to lithium Ringer. Eventual reappearance of tetanic hyperpolarization in the presence of lithium Ringer suggests lithium pumping. electrogenic sodium pump; active extrusion of lithium; cyanide depression in nerve; postspike change in membrane potential; Xenopus

STUDY IS CONCERNED with the time course of change in membrane potential induced by repetitive stimulation of large single medullated nerve fibers of Xenopus. If the fiber is stimulated with a single suprathreshold short shock, the subsequent voltage-time pattern is often characterized by a transient postspike undershoot which reflects a high potassium conductance. At the minimum of this undershoot, the potential attains its nearest approach to EK, the potassium equilibrium potential. The decay of the undershoot is then associated with a return of potassium conductance G, to a normal resting level. However, when a steady state is attained during prolonged repetitive stimulation, the potential again attains essentially the same value as before at a time corresponding to that of the undershoot minimum, but subsequent depolarization does not occur. Instead, the membrane potential continues to change in the direction of hyperpolarization throughout the remainder of the interspike interval. This pattern of progressive hyperpolarization is, then, repeated throughout successive interspike intervals. THIS

medullated

of Alabama,

Medical

nerve

Center,

Whereas lithium replacement of sodium in the external medium leads to immediate loss of tetanic hyperpolarization, a very prolonged exposure to lithium Ringer may result in eventual reappearance of a tetanic hyperpolarization. Prolonged exposure to cyanide invariably leads to the eventual disappearance of tetanic hyperpolarization. However, complete recovery often occurs on removal of the cyanide. Experimental findings are interpreted in terms of an electrogenic sodium pump. METHODS

Responses of large single medullated nerve fibers from the Xenopus sciatic nerve were recorded by means of the single air-gap technique previously described (33, 34) Continuous fluid exchange was maintained at all times in the fluid pool containing the active nodes. Potentials were recorded by means of a Picometric MA amplifier in conjunction with a Tektronix lA7A amplifier and a Tektronix 549 storage oscilloscope. In obtaining a calibration, the air gap was gradually widened to a width of several millimeters so that a considerable portion of an internode was subjected to drying. The resistance of the external fluid film surrounding the exposed section of the internode is then assumed to be so high that it can be neglected in comparison to that of the internodal axoplasm. This assumption is justified by the finding that the recorded voltage approaches a limiting maximal value as the exposed section of the internode approaches several millimeters in length. The system may then be considered as a simple series circuit of elements consisting of the two nodes adjacent to the air gap and the axoplasmic resistance between them together with the external elements in series which connect the two fluid pools. These external elements in series consist of a high resistance of lo-30 Ma, a very low-resistance polarizing source, and a very lowresistance stimulating source (33, 34). However, in the experiments to be described, the records were taken at a time when the air gap was only a few tenths of a millimeter in width. Although this maneuver resulted in attentuation of recorded potential, it greatly facilitated the stability of the system and minimized deterioration of the fiber. Experiments were confined to those preparations in which an early postspike undershoot was in evidence. In each experiment

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1034

G. M.

shock duration was maintained at a constant value between .Ol and .03 ms. All nodes in the indifferent pool on one side of the air gap were inactivated by procaine. The slightly modified frog Ringer solution contained 110 mM NaCl, 2.5 mM KCl, 2 mM CaC1,=2H,O, 2 mM NaHCO,, and 2 mM Na,HPO, with 10 mM glucose. The pH of this solution is very near 7.45. The lithium Ringer consisted of 110 mM LiCl, 2.5 mM KCI, 2 mM CaC1,*2H,O, and 10 mM Trizma buffer (pH 7 . 5) . RESULTS

Figure 1 shows records of membrane changes induced by repetitive stimulation

potential of a large

4 0F 4 0K

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1111

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,111

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FIG. 1. Oscillographic records of changes in membrane potential induced by repetitive stimulation of a large single medullated nerve fiber ofxenopus. Only postspike events are clearly in evidence. Zero position of each ordinate scale indicates graticule line from which changes are to be measured. Two oscilloscope sweep samples of a tetanic train are superimposed in A and B. Trace that is uppermost throughout most of interspike interval is obtained 1 s after initiation of 20/s-train of responses. Trace lowest throughout most of interspike interval is obtained during steady-state tetanic activity, about 20 s after initiation of repetitive stimulation. Single sweep records in C and D illustrate changes occurring early in tetanic train. Postspike undershoots are prominent near beginning of each interspike interval. Potential at end of interspike interval is observed to increase in direction of hyperpolarization with successive responses.

SCHOEPFLE

single medullated nerve fiber of Xenopus. Superimposed traces in A and B illustrate the finding that after a second or so of tetanic stimulation, successive postspike voltage changes follow a very nearly identical time course until attainment of a potential corresponding to that of the normal postspike undershoot. However, as tetanization proceeds further, a pattern of progressive hyperpolarization develops with the result that in the final steady state, postspike hyperpolarization increases throughout the entire interspike interval. Similar results are illustrated in the control trace sets of Fig. 3A and Fig. 4A. Progressive changes shown in record D of Fig. 1 are consistent with these findings. In this particular instance, the postspike undershoot shows very little change when the tetanic activity has been initiated. However, record C is representative of an often-observed exception that requires several tenths of a second for the postspike undershoot to attain a relatively constant minimum value. Then as tetanic activity proceeds, there emerges a pattern of progressive hyperpolarization throughout successive interspike intervals so that in the final steady state, records assume the form illustrated in Fig. 2, B and C. In this series, Fig. 2, B and C, the voltage-time pattern prior to break of the tetanic stimulus train is essentially that of the lower traces in Fig. 1, A and B. Only the time scales are different. Determination of the extent of hyperpolarization in any event is complicated by uncertainties in base line associated with a progressive nonspecific depolarization induced by successive impulses in a train of responses (36). The depolarization appearing at the end of the earlier interspike intervals in Fig. 1C is eventually masked by the progressively increasing hyperpolarization which is presumably associated with electrogenic pumping of sodium ions. This underlying depolarization can be revealed by means of cyanide poisoning as indicated in Figs. 20 and 5B. On termination of a repetitive train, a subsiding of GNa quite reasonably accounts for the decline in potential during the first few milliseconds after initiation of the last impulse in the train, but thereafter, the very slow return of potential to the resting base level over many seconds appears to represent the decline of a nonspecific depolarization that is not associated with conductance changes (36). In the uppermost record of Fig. 2A, it is evident that a peak of hyperpolarization occurs about 400 ms after termination of the repetitive stimulation. However, a straightforward subtraction of the nonspecific depolarization then yields a component of hyperpolarization which is maximal at time of stimulus break (36). In other words, if curve D were subtracted from A, the resultant voltage-time curve would exhibit a maximum at essentially the time 0 of the posttetanic interval. This is, of course, as it should be if the hyperpolarization is accounted for in terms of electrogenic sodium pumping which should be maximal at termination of tetanic stimulation. Record C of Fig. 2 indicates the effect of sudden reduction of stimulus frequency after a steady state had previously been attained with a rate of 200/s. The


TETANIC

HYPERPOLARIZATION

OF

SINGLE

NERVE

1035

FIBERS

sistent with the idea that the pumping mechanism has now begun to act on lithium ions. Effects of prolonged exposure to 2 mM NaCN for almost 4 h are illustrated in Fig. 4B. At this time there exists no trace of tetanic hyperpolarization. Nor at anytime during continued exposure to cyanide is there any evidence of curves sugges.ting a revival of pumping. However, in many instances complete recovery occurs after removal of the cyanide (36). Records in Fig. 5 encompass both tetanic and posttetanic intervals. A is obtained from a normal fiber and B,

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Posttetanic record in Fig. 5C was obtained under conditions such that, in all probability, electrogenic sodium pumping had not as yet been completely eliminated by exposure to cyanide. Record 50 is representative of effects resulting from very prolonged exposure to lithium Ringer; in this event the pumping mechanism has now presumably taken over the active extrusion of lithium ions. Both C and D, then, describe instances of a type previously reported in which the pumping proc-

4 0K

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80

160

milliseconds 2. Oscillographic records of tetanic and posttetanic changes in membrane potential induced by repetitive stimulation of a large single medullated nerve fiber of Xenopus. Coordinates are those of Fig. 1. In every instance a steady state had been attained after stimulation for some 20 s or more at a rate of 200/s. Record A is representative of those fibers for which there exists a considerable delay in attainment of maximum posttetanic hyperpolarization. Record B is representative of many fibers for which attainment of maximum posttetanic hyperpolarization is almost immediate. Record C illustrates effects of suddenly reducing stimulus frequency after a steady state had been attained with a stimulation rate of 200/ s. Slowly changing base level of potential is unaffected by responses at lower frequencies. Record D illustrates tetanic and posttetanic depolarization obtained after prolonged exposure (225 min) to 2 mM NaCN.

4 E-

FIG.

changing base level of potential is now unaffected by responses at the lower frequency. In Fig. 3, there are shown effects of prolonged exposure to a Ringer solution in which sodium has been replaced by lithium. Traces in Fig. 3B indicate that after 30 min of exposure to sodium-free Ringer there exists no evidence of tetanic hyperpolarization corresponding to the pattern previously described. This is, of course, consistent with the generally accepted view that lithium ions are not pumped out of the fiber (23). However, as exposure to lithium Ringer continues for 95 min, tetanic hyperpolarization reappears, assuming the pattern indicated in Fig. 3C. This finding is, then, con-

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milliseconds FIG. 3. Data illustrating effects of replacing external sodium ions with lithium ions. Coordinates and procedures applicable to control traces in A are identical with those corresponding to Fig. lA . In set B record lowermost throughout each interspike interval is obtained 1s after initiation of repetitive stimulation in a fiber previously exposed to lithium Ringer for 30 min. Other superimposed traces are obtained about 20 s after initiation of tetanic train. Uppermost trace corresponds to final steady-state voltage-time pattern. Traces in C were obtained after 95 min exposure to lithium Ringer. Trace of each pair that exhibits a pronounced postspike undershoot is obtained 1s after initiation of repetitive stimulation. Second trace of each pair showing greater hyperpolarization at end of interspike interval is obtained about 20 s later during steady-state activity.


1036

G. M.

4

SCHOEPFLE

for external fluid and axoplasm, respectively. brane potential V, is then given also as V m = [GN$Na

+ GKEK - (MNa + M K > - CdV Id-t]/ (GNa

0

8 milliseconds

16

FIG. 4. Data illustrating effects of prolonged exposure to 2 mM NaCN. Control records are represented in set A. Uppermost trace for each interspike interval is obtained 1 s after initiation of repetitive stimulus train. Several superimposed traces are shown as lower composite record for each interspike interval. Lowest trace of this superimposed set represents limiting steady-state voltage-time pattern obtained after some 20 s of repetitive stimulation. Records in set B illustrate effects of exposure to 2 mM NaCN for a period of 225 min. Lowest trace shown in first complete interspike interval corresponds to first response of tetanic train. Middle records immediately above base line are obtained 1 s after initiation of repetitive stimulation. Uppermost set of several superimposed traces is obtained after about 20 s of repetitive stimulation. Upper level of this set corresponds to steady-state tetanic activity.

Mem-

J

GK)

(3)

This treatment is basically similar to that developed by Moreton (28), except that it is not derived from constant field theory. For the slow transients under investigation, the contribution of the dVm/& term is very small, even at times other than that of peak activity (36). On analyzing the records of Fig. 1, A and B, and Fig. 3A, and even Fig. it is obvious that for each interspike interval the patterns of the two superimposed records voltage-time are very nearly coincident throughout a time interval that includes the falling phase of the spike and the earlier time course of the postspike undershoot. At times prior to the peak (or absolute minimum) of the normal postspike undershoot, it is presumed that the GNJZNa and GKEK terms of equation 3 would be much greater than (MNa + MK) so that any contribution of the c"Na

+

4

esses are presumably of a magnitude insufficient to completely overshadow the underlying nonspecific depolarization (36). Findings in Fig. 5, C and D, are, then, consistent with the concept that the hyperpolarization of electrogenic origin is superimposed on a nonspecific depolarization (36). DISCUSSION

In relating active transport to membrane potential, ionic concentration gradients, and ionic conductances, one may, for purposes of simplication, provisionally disregard the relatively involved Nernst-Planck type analysis that Frankenhaeuser and Huxley (13) have justified as applicable to the Xenopus node and consider, then, a modified Hodgkin-Huxley (17) type of equation M,,

+ M, + GNa W,

- ENa) + G, W,

- J&J

+ CdV,/dt

= 0

(1)

in which pump active transport terms M,, and M, for sodium and potassium ions are represented in terms of charge per second per square centimeter of membrane. The MNa/MK ratio is assumed to be greater than unity in accordance with a variety of experimental findings (1,2, 6, 7, 12, 15, 21, 23, 26, 38). Sodium and potassium conductances are given by GNa and GK, respectively, whereas ENa and E, define the equilibrium potentials for the sodium and potassium ions in terms of the Nernst equation which for the sodium ion would assume the form E Na = (RWF) Id Here INal, and INal; indicate

(Na),/OWJ sodium ion concentrations

(2)

FIG. 5. Oscillographic records of tetanic and posttetanic changes in membrane potential induced by repetitive stimulation of a large single medullated nerve fiber of Xenopus. Record A is that of a normal control, and B is that obtained after 225 min exposure to 2 mM NaCN. Voltage-time patterns of both A and B included within period of tetanic stimulation are envelopes of a curve whose ordinate indicates potential at end of an interspike interval. Tetanic records of C and D are obscured by artifact. Posttetanic record of C was obtained after 189 min exposure to 2 mM NaCN and thereby for this particular fiber illustrates incomplete depression by cyanide. Posttetanic record in D is that of a fiber subjected to a prolonged exposure of 102 min to lithium Ringer.


TETANIC

HYPERPOLARIZATION

OF

SINGLE

NERVE

FIBERS

A high potassium conductance is presumably the dominant factor in determining membrane potential at peak time (absolute minimum time) of the postspike undershoot. It is at this time, then, that membrane potential attains its nearest approach to E, in the course of response to a single shock. However, from this time onward, the two curves diverge as the potassium conductance declines toward its resting level. In the tetanic steady state, this gradual decline in potassium conductance throughout each interspike interval together with a high sustained level of the (MNa + M,) term of equation 3 would lead to a progressive voltage deflection in the direction of hyperpolarization. To a first approximation the difference between any two curves in Fig. 1, A or B, is given as the variation

wn = [&/a&J 6MN,+ [&/~M,l 6MK = 6[MN, + MK]/[GNa+ GKI (4) where 6(M,, + MK) represents a change from a very small resting value to one that is quite appreciable in the tetanic steady state. Whereas the (GNa + G,) term decreases throughout each interspike interval, the variation 6(M,, + M,) remains essentially constant, thereby accounting for the progressive hyperpolarization. The extent to which V, approaches E, at peak of the postspike undershoot does not bear on the validity of the argument just presented. It is the divergence of the superimposed tracings in Fig. 1, A and B, that is central to the argument for an electrogenic mechanism. The progressive hyperpolarization from peak undershoot time onward also precludes the possibility that a change in the tetanic steady-state level of E, could account for tetanic hyperpolarization. An increase in the magnitude of E, would then lower the potential at the time of the peak undershoot but would not account for the progressive hyperpolarization from this time onward throughout the interspike interval. Changes in voltage-time pattern with successive responsesare also illustrated in Fig. 1D. Here the successive changes in postspike undershoot are small in comparison with progressive variations of potential at the end of successive interspike intervals. Admittedly the comparisons are not so clear in Fig. 1C; however, it may be concluded that in some preparations the time course of conductance changes does vary considerably from response to response until a tetanic steady state is attained. The continuity of events linking tetanic and posttetanic intervals involves the finding that on termination of repetitive stimulation the potential drops toward a level of hyperpolarization below that in evidence at the end of the last interspike interval. Evidence for this fact is provided in records A, B , and C of Fig. 2. A consistent interpretation of this result is afforded by equation 4. In the Xeonpus fiber G, has not as yet returned to normal at the end of a 5-ms interspike interval (27) so that on termination of the last spike in a train the denominator (GNa + GK) n ow f a11s t o a value below that achieved at

1037 any time during stimulation. At this point it is worthy of mention that in a fiber poisoned with 10 mM tetraetheylammonium Cl [TEA] the postspike potentials in the tetanic steady state remain far above the base level of potential. In fact, at the amplification employed here the persistent interspike depolarization is such that all interspike potentials are off the record. However, on termination of the tetanic stimulus train, the potential drops precipitously, with the result that after about 10 ms the voltage-time pattern of posttetanic hyperpolarization is essentially a normal one. This, of course, would be expected in a situation where G, does not change during activity. Additional evidence is thereby provided that is consistent with the idea that GK has little to do with most of the posttetanic voltage-time pattern. Because E,, would be expected to decrease during repetitive stimulation (3) and thereby induce hyperpolarization, it is of interest to analgze possible effects of increased ’ intracellular sodium ion concentration. Because membrane potential returns to its previous resting level after repetitive stimulation in the presence of cyanide, it is concluded that no time-dependent changes in J& or E, can account for the nonspecific tetanic depolarization. This is at once obvious because changes in intracellular concentrations of sodium or potassium would not be offset by subsequent pumping in the poisoned fiber. It follows at once, then, that tetanic hyperpolarization of the normal fiber cannot be attributed to a change in ENa because any change in ENa would be less than that of the poisoned fiber. By the same token, a change in E, can also be eliminated as a factor that might determine tetanic or posttetanic changes in membrane potential of the normal fiber. The conclusions just reviewed in support of an electrogenie mechanism are consistent with the findings of previous investigations relating to posttetanic hyperpolarization in whole-nerve preparations (4-6, 8-11, 14, 15, 19, 20, 25, 26, 31, 32, 38, 39) and in the crayfish stretch receptor (30). Relevant to this discussion are the findings of Hurlbut (21) who observed a posttetanic hyperpolarization in the presence of salicylate which effectively blocks active movements of both sodium and potassium ions. However, these results were obtained from whole desheathed frog nerve after 15 min of repetitive stimulation at a rate of 50/s. Furthermore, the posttetanic hyperpolarization was observed to decline over a period of several hours duration, with the result that one might suppose that it involves a mechanism different from the one proposed here. The eventual reappearance of tetanic and postetanic hyperpolarization after prolonged exposure to sodiumfree lithium Ringer suggests that the pump may actually extrude lithium ions if the intracellular lithium concentration is markedly increased. An alternative possibility might involve some adaptive mechanism with the result that prolonged exposure to lithium would lead to a structural change in the ion extrusion mechanism. Preliminary experiments suggest that even 10 mM lithium in the external fluid may eventually augment


1038

G:

tetanic and posttetanic pus fiber. This

study

was a contribution

hyperpolarization of the Neurosciences

in the XenoProgram.

This investigation Grant NS-08802. Received

for publication

was supported 1 January

by National

M.

SCHOEPFLE

Institutes

of Health

1976.

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20. HURLBUT, W. P. Sodium fluxes in desheathed frog sciated nerve. J. Gen. Physiol. 46: 1191-1222, 1963. 21. HURLBUT, W. P. Salicylate: effects on ion transport and after potentials in frog sciatic nerve. Am. J. PhysioZ. 209: 1295-1303, 1965. 22. KERNAN, R. P. Membrane potential changes during sodium transport in frog sartorius muscle. Nature 193: 986-987, 1962. 23. KEYNES, R. D., AND R. C. SWAN. The permeability of frog muscle fibers to lithium ions. J. PhysioZ., London 147: 626-638, 1959. 24. KOSTYUK, P. G., 0. A. KRISHTAL, AND V. I. PIDOPLICHKO. Potential dependent membrane current during the active transport of ions in snail neurones. J. Physiol., London 226: 373-392, 1972. 25. LANDOWNE, D., AND J. M. RITCHIE. The binding of tritiated ouabain to mammalian non-myelinated nerve fibers. J. PhysioZ., London 207: 259-537, 1970. 26. LANDOWNE, D., AND J. M. RITCHIE. Optical studies on the kinetics of the sodium pump in mammalian non-myelinated nerve fibers. J. Physiol., London 212: 483-502, 1971. 27. MEVES, H. Die Nachpotentiale isolierter markhaltiger Nervenfasern des Froches bei tetanischer Reizung. Pfluegers Arch. 272: 336-359, 1961. 28. MORETON, R. B. An investigation of the electrogenic sodium pump in snail neurons, using the constant-field theory. J. Exptl. BioZ. 51: 181-201, 1969. 29. MULLINS, L. J., AND F. J. BRINLEY. Potassium fluxes in dialyzed squid axons. J. Gen. Physiol. 53: 704-740, 1969. 30. NAKAJIMA, S., AND K. TAKAHASHI. Post-tetanic hyperpolarization and electrogenic sodium pump in stretch receptor neurone of crayfish. J. Physiol., London 187: 105-127, 1966. 31. RANG, H. P., AND J. M. RITCHIE. On the electrogenic sodium pump in mammalian non-myelinated nerve fibers and its activation by various external cations. J. Physiol., London 196: 183221, 1968. 32. RITCHIE, J. M., AND R. W. STRAUB. The hyperpolarization which follows activity in mammalian non-myelinated nerve fibers. J. PhysioZ., London 136: 80-97, 1957. 33. SCHOEPFLE, G. M. Kinetics of change in spike height during anodal polarization of isolated single nerve fibers. Am. J. PhysioZ. 187: 549-557, 1956. 34. SCHOEPFLE, G. M., AND F. E. BLOOM. Effects of cyanide and dinitrophenol on membrane properties of single nerve fibers. Am. J. Physiol. 197: 1131-1135, 1959. 35. SCHOEPFLE, G. M., AND E. A. EIKMAN. Cyanide depression of sodium eMux in desheathed frog sciatic nerve. Am. J. PhysioZ. 212: 1273-1276, 1967. 36. SCHOEPFLE, G. M., AND C. R. KATHOLI. Post-tetanic changes in membrane potential of single medullated nerve fibers. Am. J. PhysioZ. 225: 1501-1507, 1973. 37. STAMPFLI, R., AND B. HILLE. Electrophysiology of frog peripheral myelinated nerve. In: Frog NeurobioZogy: A Handbook, edited by R. Llinas and W. Precht. New York: Springer-Verlag. In press. 38. STRAUB, R. W. On the mechanism of post-tetanic hyperpolarization in myelinated nerve fibers from the frog. J. Physiol., London 159: 19-20, 1961. 39. THOMAS, R. c. Electrogenic sodium pump in nerve and muscle cells. Physiol. Rev. 52: 563-594, 1972. 40. THOMAS, R. C. Membrane current and intracellular sodium changes in a snail neurone during extrusion of injected sodium. J. PhysioZ., London 201: 495-514, 1969.


Optic nerve decompression. Presumed postoperative development of medullated nerve fibers.

Post-tetanic hyperpolarization, sodium-potassium-activated adenosine triphosphatase and high energy phosphate levels in garfish olfactory nerve.

Adaptation, saturation, and physiological masking in single auditory-nerve fibers.

Aspects of rate-related hyperpolarization in feline Purkinje fibers.

Different sensitivities of acetylcholine-induced "after-hyperpolarization" compared to dopamine-induced hyperpolarization, to oubain or to lithium-replacement of sodium, in rabbit sympathetic ganglia.

A prolonged post-tetanic hyperpolarization in rat hippocampal pyramidal cells in vitro.

Grayanotoxin, veratrine, and tetrodotoxin-sensitive sodium pathways in the Schwann cell membrane of squid nerve fibers.

Clinical assessment of the muscular response to tetanic nerve stimulation.

Effect of a single test dose of lithium carbonate on sodium and potassium excretion in man.

Myelinated retinal nerve fibers.

Remyelination of nerve fibers in the transected frog sciatic nerve.

Coding of information in single auditory-nerve fibers of the goldfish.

Depletion and accumulation of potassium in the extracellular clefts of cardiac Purkinje fibers during voltage clamp hyperpolarization and depolarization: experiments in sodium-free bathing media.

Short-term adaptation and incremental responses of single auditory-nerve fibers.

Time-resolved changes in equatorial x-ray diffraction and stiffness during rise of tetanic tension in intact length-clamped single muscle fibers.

Density of sodium channels in mammalian myelinated nerve fibers and nature of the axonal membrane under the myelin sheath.

Electrogenic sodium extrusion in cardiac Purkinje fibers.

Adrenergic nerve fibers in the human fetal sciatic nerve.

Myelinated nerve fibers and severe myopia.

Unilateral Myelinated Retinal Nerve Fibers.

Sodium-lithium countertransport and body fat distribution.

Myelin intrusions in beaded nerve fibers.

Discrete impulses in ephaptically coupled nerve fibers.

Potassium depletion and sodium block of potassium currents under hyperpolarization in frog sartorius muscle.