Connections:
heart
cellular
disease,
aid
electrophysiology,
ion
channels ROBERT
E. TEN EICX” of Pharmacolog
DAVID
%%.
WHAL1ET Umveisit
Northwestern
The Royal North Shore Hospital, St Leonaith,
and
that
at
least
one
intrinsic
conductance
property of the inward rectifier can be altered by ischemia. We speculate that the control of expression, function, and regulation of cardiac ion channels can be affected at the molecular level by heart disease and myocardial ischemia. -Ten Eick, R. E.; Whalley, D. W.; Rasmussen, H. H. Connections: heart disease, cellular electrophysiology, and ion channels. FASEB J. 6: 2568-2580; 1992. Key Words:
sodium channels
c/ziori.dechannels
calcium channels
ATP -sensitive potamwn
.
potassium channels
channels
cvtJid
ische-
mia . myocardial hyperirophy intracellular ion activities ext racellular ion activities lysophosphatidylcholine channel phosphotylation . channel
regulation
WITH DISEASED HEARTS ARE more prone to cardiac rhythm disturbances and sudden death than those with healthy hearts. This has resulted in the hypothesis that disease can alter the electrophysiological character of the heart and its constituent cells (1, 2). The electrophysiological activity of the mammalian heart is largely governed by the activity of sarcolemmal ion channels. These in turn regulate the passive transmembrane ion fluxes underlying the several components of the membrane current (e.g., Na, K, Ca2, and Cl-), which are important for the production of cellular action potentials (3-5). Therefore, it is reasonable to think PEOPLE
that disease alters either the ionic compositions of the interstitial and intracellular milieus, the characters of the ion channels themselves, or both. There is much evidence indicating that the composition of the extracellular milieu is altered during acute and chronic myocardial ischemia and that these changes could play an 2568
K
RASMUSSEN1
Chicago, Illinois 60611, USA, and tDepartment
New South W:,
ABSTRACT Our purpose in this article is to examine the hypothesis that both myocardial disease and ischemia can alter the electrophysiologic function of the ion channels responsible for the cellular electrical activity of the heart. Changes in the intracellular and extracellular milieus occur during ischemia and can alter the dcctrophysiology of several species of ionic channels and the cellular electrophysiologic activity of cardiac myocytes. Included are 1) changes in extracellular [K] and pH and in intracellular [NaJ, [Ca2’], and pH; 2) accumulation of noxious metabolic products such as lysophosphatidyicholine; and 3) depletion of intracellular ATP. Finally, ischemia or disease (e.g., hypertrophy) can alter the dcctrophysiology of at least two types of K channels, the A-like channels underlying the transient outward current and the inward rectifier, by mechanisms that apparently do not involve alteration of either the intra- or extracellutar milieus. Findings suggest that the expression of cardiac A-like channel function can be altered by hypertrophy
AND HELE
of Cardiology
2)65 Australia
important role in the associated disturbances of the heart rhythm (6, 7). There also is information available on the behavior of sarcolemmal ion channels found in normal cardiac cells when exposed to environments thought to mimic the interstitial fluid during acute ischemia (8-10). Despite these data, the hypothesis that heart disease can alter the functional character of any of the several types of ion channels has yet to be rigorously examined, probably because of the dearth of relevant feasible models. The patch clamp technique is beginning to be used to investigate ion channel function in models of diseased or ischemic heart. A variant, the whole-cell-patch clamp technique (11, 12), allows the investigator to manipulate the extracellular effects on
and intracellular channel function
milieus (13) and permits the of disease and/or ischemia-
induced changes in the intracellular milieu to be characterized. For example, the effects of ischemia-induced changes in cellular pH, pCa, or ATP or cAMP contents or increases in cellular metabolic products on any of the constituent components of the membrane current (i.e., the Na, Cap, or K currents) can be addressed using patch clamping. Whether disease and/or ischemia can cause fundamental changes in the intrinsic electrophysiologic properties of cardiac ion channels that would alter channel behavior when exposed to a normal extracellular environment, although not yet clarified, is under investigation (14-21). The models being studied include cells from specimens of diseased and/or ischemic human atrial appendage (22) and ventricular strips (14), from and from
feline normal
hypertrophic right feline ventricular
culture (15-17). Evidence nel properties can change
suggesting in response
cellular environment despite being perimental assessment to a milieu mal” physiological conditions will
THE NORMAL VENTRICULAR ACTION POTENTIAL Resting
(18, 19, 23, 24), maintained in
that fundamental to a chronically
chanaltered
exposed at the time presumed to mimic be presented.
RESTING
of ex“nor-
AND
potential
In the absence tively
ventricle myocytes
stable
of excitation ventricular cells maintain membrane potential of -80 to -95 mV,
a relatermed
‘To whom correspondence should be addressed, at: Department Pharmacology, Northwestern University, 320 East Superior Street, Chicago, IL 60611, USA. 2Abbreviations: AP, action potential; CHF, congestive heart failure; DAD, delayed afterdepolarization; E, equilibrium potential; g, conductance; I,,,, cellular membrane current; I,, component of of
I,,, carried by X; LPC, lysophosphatidylcholine;
pHi, intracellular
pH;
pH0, extracellular PH; RV, right ventricle (or ventricular); Vmax, maximum depolarization rate of AP upstroke; V, resting potential.
0892-6638/92/0006-2568/$01 .50. © FASEB
www.fasebj.org by Univ Louisiana Dupre Library/Serials Dept (130.70.8.131) on January 14, 2019. The FASEB Journal Vol. ${article.issue.getVolume()}, No. ${article.issue.getIssueNumber
the resting potential (V7).2 The ability of cardiac cells to generate and propagate a normal action potential (AP) depends on the level of V7. The resting potential arises as a result of the selective permeability of the cell membrane to K4 and the transmembrane K4 gradient, which in turn is maintained by the Na4, K4 pump. By extruding three intracellular Na4 in exchange for two extracellular K, the pump maintains steep Na4 and K4 concentration gradients, inward for Na4 and outward for K4, and in the process generates an outward current termed the electrogenic Na, K4 pump current (Ipump). Normally V7 is largely determined by the ratio of the extracellular to intracellular K activities (K0/K1) because the membrane permeability to K far exceeds that to Na, Ca24, or C1 in the resting state. V,. usually slightly positive to the equilibrium potential for K4 predicted by the Nernst equation because of a small depolarizing “leak” current carried primarily by Na4. The resting potential may be altered by changes in the intraor extracellular ionic milieu, by neurohumoral influences; and by drugs that affect the relative permeabilities of the cell membrane to K4 and Na4 or inhibit the Na4, K4 pump. Depolarization of Vr from the normal level (approximately -80 to -90 mV) appears to be a prominent feature of several pathological staies associated with cardiac arrhythmias (25).
upstroke. It is followed by a prolonged (up to hundreds of milliseconds) three-phase repolarization that returns membrane voltage to the resting potential and consists of 1) an early phase of rapid repolarization, 2) a secondary depolarization
(usually
The AP
The
transmembrane
action
potential
When an excitatory stimulus depolarizes the membrane beyond the threshold potential (mV), an AP is produced that is manifest as a propagating wave of transient depolarization (see Fig. 1). Inscription of the cardiac AP
?
results
from
a rapid
(
92% vs. 67%). Second, the average I current density was about 65% greater in hypertrophied RV myocytes than in normal RV myocytes. Finally, the steady-state and kinetic parameters of I that characterize the functional behavior of the A channels supporting the current were unchanged from those observed normally (see co-workers
B
Normal
H V Hypertrophy
A.
Fig. +40 mV
C.
50
.4OmVI1_
p4
pAJpF
0
100
ma
Figure 5. Effect of severe right ventricular (RV) hypertrophy (in the absence of uncompensated failure) on the action potential recorded from normal (A) and hypertrophied (B) RV papillary muscles. The changes associated with hypertrophy in the time to achieve 90% of complete repolarization (double-tipped arrows) and in the maximal level of potential achieved during the plateau (arrows) are obvious from the comparison between A and B. Notice the greater extent to which the hypertrophied cell repolarized during phase 1 (to + 4 mV in RV hypertrophy vs. +12 mV in normal). C) Transient outward current (normalized to sarcolemmal surface area) recorded from single isolated feline cells from normal and hypertrophied right ventricles in response to voltage clamp pulses from -40 to + 40 mV for 100 ms (see inset of C). The peak amplitude of I,,, (indicated by arrows) was greater in the RV hypertrophied cell than in the normal cell. However, notice that the time course of I,,, decay did not change. In addition, a greater percentage of the RV cells exhibited I,,, in the hypertrophied case (92%) than in the normal case (67%). Therefore I,,, is augmented and exhibited more frequently by cells from hypertrophied heart. We speculate that the additional current observed in the hypertrophied cells may reflect overexpression of the I channels induced by or in association with RV hypertrophy (see text). Initially it was suggested that the Ca24 current flowing during the plateau inactivated with a slower time course. The implication was that somehow hypertrophy altered the functional properties of sarcolemmal Ca24 channels. This hypothesis has not been borne out by whole-cell-patch voltage clamp studies done by several laboratories employing different animal models (21, 23). Attention then focused on components of the K’ current flowing during the plateau phase of the AP, including the delayed outwardly rectifying K4 current and the inwardly rectifying K4 current. As with the Ca24 current, no striking changes in either the size or kinetic properties of either current were found in cells obtained from hypertrophied hearts of either rats, guinea pigs, or cats (24). Because ‘Ca, ‘K, and ‘K! are regarded as principal contributors to the net membrane current flowing during the AP plateau, the failure to find any striking change in the character of any of them presented a quandary. Therefore, motivated by the increased degree of the repolarization achieved at the finish of the early phase of repolarization (marked by the voltage notch at the onset of the AP plateau) frequently
HEART DISEASEAND ION CHANNEL ELECTROPHYSIOLOGY
in hypertrophied compared
I
5).
The simplest interpretation of these three findings is that the channel density of normal cardiac channels was enhanced (relative to normal) in hypertrophied RV and that this occurs in all myocytes constituting the RV free wall whether they are located in the endo- or epicardial portions. The mechanism for the increase in the channel density could be that the rate of synthesis and sarcolemmal insertion of functional channels is increased over normal during hypertrophy or that the turnover rate (i.e., loss) of functional membrane channels is decreased below normal during hypertrophy, or both. The implication is that hypertrophy may “stimulate” or “inhibit” processes at the molecular level that are involved in regulating or modulating the functional expression of cardiac A-like channels subserving the transient outward current. We speculate, as a working hypothesis, that gene products involved in regulating or modulating cardiac A-like channel function are overexpressed in association with hypertrophy, perhaps in response to a primal stimulus that initiates the events that are ultimately manifest as hypertrophy. Of particular interest is the question of whether the increase in the density of I has any role in the change from normal in the shape of the AP associated with hypertrophy. In other words, could an increase in I cause depression of plateau voltage and prolongation of the AP duration? The finding that inhibition of I by approximately 30% with a low concentration of 3,4-diaminopyridine can cause the plateau voltage to become more positive and the AP duration to shorten (18) suggests that the hypertrophy-induced change in may, in fact, at least partially underlie the changes in the AP that are associated with hypertrophy. The explanation is that a larger I causes the plateau phase to be initiated from a less positive potential. This causes ‘Ca to inactivate less rapidly, and the total and peak ‘Ca is enhanced owing to the resulting greater difference between the membrane potential and Ea. The net result is that increasing I can prolong AP duration and depress plateau voltage.
SUMMARY, CONCLUSIONS, SPECULATIONS
IMPLICATIONS,
It is tempting to speculate that, just as unloading myocytes electrically or mechanically could underlie the loss of I in cells maintained in primary culture and surviving cells in infarcted heart tissue, increasing cellular loading, such as occurs when the heart must pump in the chronically hypertensive patient, could underlie the functional overexpression of channels responsible for Iv,, as well as the gene-regulated events leading to the molecular, cellular, and organ-based changes associated with hypertrophy. However, independent of whether this notion is even partially correct, it is provoca-
2577
www.fasebj.org by Univ Louisiana Dupre Library/Serials Dept (130.70.8.131) on January 14, 2019. The FASEB Journal Vol. ${article.issue.getVolume()}, No. ${article.issue.getIssueNumber
live that two different myocardial loading conditions known to be associated with clinical evidence of heart disease seem to cause change in at least one fundamental aspect of channel function, the channel density. This change would alter cardiac electrical activity independently of and in addition to any other concurrent changes associated with disease and/or ischemia. Evidence has been presented in support of the ideas that 1) the sensitivity of the inwardly rectifying K’ channel to the extracellular K’ concentration is altered in surviving human ventricular cells found in chronically ischemic or infarcted tissue and that 2) the density of the channels responsible for the transient outward current in heart can be altered in response to altering the load borne by the individual cells that make up the heart as an organ. Therefore, the answer to the question posed at the inception of this article-can heart disease or ischemia alter the functional behavior of cardiac sarcolemmal ion channels?-appears to be affirmative. We have presented data and arguments in support of the hypothesis that altered channel function would be expected both because of the well-documented changes in the extra- and intracellular milieus and because of intrinsic changes in at least one parameter defining ion channel function that appear to occur independently of any of the changes in milieus. If this hypothesis is true, many conclusions concerning the cellular mechanisms underlying many cardiac arrhythmias and the mechanisms of action of antiarrhythmic drugs, which have been largely derived from data obtained with preparations of normal heart, will require reevaluation. The challenge of the 1990s will be to address these questions rigorously by employing the power and sophistication of the patch clamp and molecular biological technologies now available to the field. R. E. T was recipient of the Warren McDonald International Fellowship of the National Heart Foundation of Australia when this article was conceived. D. W. W. was a Postgraduate Medical Research Scholar of the National Heart Foundation of Australia when the article was being written. Previously unpublished data reported in this article were obtained during experiments supported by grants HL-27026 and HL-3804l to R. E. T. from the U.S. National Institutes of Health (NHLBI). The extent to which this article may be found understandable by people who are not practicing cellular cardiac electrophysiologists is credited to the editorial help provided by Drs. P. L. Barrington, R. L. Martin, T E. Schackow, J. A. Wasserstrom, and K. Zhang. The authors thank them for their critical comments and suggestions during the development of this article; special thanks to Professor Harry A. Fozzard for taking time to offer critical comments and encouragement.
REFERENCES 1. Hoffman,
B. F.,and Cranefield, P. F. (1964) Physiological basis
of cardiac arrhythmias. Am. j Med. 37, 670-689 2. Bigger, J. T., Jr., Dresdale, R. J., Heissenbuttel, R. H., Weld, F. M., and Wit, A. L. (1977) Ventricular arrhythmias in ischemic heart disease: mechanism, prevalence, significance and management. Pmg. Cardiovasc. Dis. 19, 255-277 3. Noble, D. (1984) The surprising heart: a review of recent progress in cardiac electrophysiology. j Physiol. (Lond.) 353, 1-50 4. Fozzard, H. A., and Arnsdorf, M. F. (1986) Cardiac electrophysiology. In The Heart and Cardiovascular Syst#{128}m (Fozzard, H. A., et al.; eds.) pp. 1-30, Raven Press, New York 5. Wasserstrom, J. A., and Ten Eick, R. E. (1991) The dcctrophysiology of mammalian ventricular musde. In Electrophysiology and Pharmacology of the Heart (Dangman, K. H., and Miura, D. S., eds) pp. 199-233, Marcel Dekker, New York 2578
Vol. 6
May 1992
6. Harris, A. S., Bisteni,A., Russel, R. A., Brigham, J. C., and Firestone, J. E. (1954) Excitatory factors in ventricular tachycardia resulting from myocardial ischemia: potassium as a major excitant. Science 119, 200-203 7. Kleber, A. G. (1987) Extracellular K4 and H4 shifts in early ischemia: mechanisms and relation to changes in impulse propagation. J. Mol. Cell. Cardiol. (Suppl V): 35-44 8. Yatani, A., Brown, A., and Akaike, N. (1984) Effects of extracellular pH on sodium current in isolated, single rat ventricular cells. j Membr. Biol. 68, 163-168 9. Krafte, D. S., and Kass, R. S. (1988) Hydrogen ion modulation of Ca channel current in cardiac ventricular cells.j Gen. Physiol. 91, 641-657 10. Clarkson, C. W., and Ten Eick, R. E. (1983) On the mechanism of lysophosphatidylcholine induced depolarization of cat ventricular myocardium. Circ. Res. 52, 543-556 11. Hamill, 0. P., Marty, A., Neher, E., Sakmann, B., and Sig-
worth, F. J. (1981) Improved resolution current recording Pjluegers
Arch.
Eur.
J.
PhysioL
patch clamp technique for highfrom cells and cell-free patches. 391, 85-100
12. Ten Eick, R. E. (1990) Biophysical techniques for the study of cardiac tissue. In Cardiac Electrophysiology: A Textbook (Rosen, M., Janse, M., and Wit, A., eds) pp 3-27 Futura, Mount Kisco, NY 13. Mogul, D. J., Singer, D. H., and Ten Eick, R. E. (1989) Ionic diffusion in voltage-clamped isolatedcardiac myocytes: implications for Na,K-pump studies. Biophys. J. 56, 565-577 14. McCullough, J., Chua, W., Rasmussen, H., Ten Eick, R. E., and Singer, D. (1990) Effects of potassium on the diastolic
potential of partially depolarized cells in human ventricular myocardium. Circ. Res. 66, 191-201 15. Schackow, T. E., Barrington, P. B., Cook, M., Simpson, D., Decker, R. S., and Ten Eick, R. E. (1989) Sodium current can be affected by introduction of isolated cat ventricular myocytes into a primary culture environment. Biophys. j 55, 295 (abstr.) 16. Schackow, T. E., Cook, M. G., Behnke, M. M., Decker, M. L., Decker, R. S., and Ten Eick, R. E. (1990) Culture alters morphology, biochemistry and electrophysiology of adult cat cardiocytes. Biophys. j 57, 140 (abstr.) 17. Schackow, T. E., La Pres, J. J., Decker, R. S., and Ten Eick, R. E. (1991) Alterations in sodium currents in cultured cat cardiocytes are unrelated to changes in cell morphology. Biophys. j 59, 97 (abstr.) 18. Zhang, K., Harvey, R. D., Barrington, P. L., Schackow, T E., Bassett, A. L., and Ten Eick, R. E. (1991) Transient outward current (Ito) in normal and hypertrophied cat right ventricular
myocytes. Biophys. j 59, 588 (abstr.) 19. Zhang, K., Harvey, R. D., Martin, R. L., Bassett, A. L., and Ten Eick, R. E. (1991) Inward rectifying K current in normal and hypertrophied cat right ventricular myocytes. Biophys. j 59, 279 (abstr.) 20. Ten Eick, R. E., Bassett, A. L., and Robertson, L. L. (1983) Possible electrophysiological basis for decreased contractility associated with myocardial hypertrophy: a voltage clamp approach. Perspect. Cardiovasc. Res. 7, 245-259 21. Ten Eick, R. E., Houser, J. R., and Bassett, A. L. (1989) Cardiac hypertrophy and altered cellular electrical activity of the myocardium. In Physiology and Pathophysiology of the Heart, (2nd ed. (Sperelakis, N., ed) pp. 573-594 Martinus Nijhoff, Boston 22. Ten Eick, R. E., and Singer, D. H. (1979) Electrophysiological properties of diseased human atrium (I): low resting potential and altered sensitivity to potassium. Circ. Res. 44, 545-557
23. Kleinman, R. L., and Houser, S. R. (1988) Calcium currents in normal and hypertrophied isolated feline ventricular myocytes. Am. j Physiol. 255, Hl434-H1442 24. Kleinman, R. L., and Houser, S. R. (1989) Outward currents in normal and hypertrophied isolated feline ventricular myocytes. Am. J. PhysioL 256, H1450-H1459 25. Ten Eick, R. E., Baumgarten, C. M., and Singer, D. H. (1981) Ventricular dysrhythmia: Membrane basis, or, Of currents, channels, gates and cables. Prog. Cardiovasc. Dis. 24, 157-188 26. Coraboeuf, E. (1978) Ionic basis of electrical activity in cardiac tissues.Am. j Physiol. 234, H101-H116 27. DiFrancesco, D., and Noble, D. (1985) A model of cardiac dcc-
The FASEB Journal
TEN EICK ET AL.
www.fasebj.org by Univ Louisiana Dupre Library/Serials Dept (130.70.8.131) on January 14, 2019. The FASEB Journal Vol. ${article.issue.getVolume()}, No. ${article.issue.getIssueNumber
trical activity incorporating ionic pumps and concentration changes. Philos. Trans. R. Soc. London B (BioL Sci.) 307, 353-398
50. Kurachi,
28. Giles, W. R., and van Ginneken, A. C. (1985) A transient Outward current in isolated cells from the crista terminalis of rabbit heart. j Physiol. (London) 368, 243-264 29. Hiraoka, M., and Kawano, 5. (1989) Calcium-sensitive and insensitive transient outward current in rabbit ventricular myocytes. J. Physiol. (London) 410, 187-212 30. Tseng, G. N., and Hoffman, B. F. (1989) Two components of transient outward current in canine ventricular myocytes. Circ. Res. 64, 633-647 31. Zygmunt, A. C., and Gibbons, W. R. (1991) Calcium-activated chloride current in rabbit ventricular myocytes. Circ. Res. 68, 424-437 32. Harvey, R. D., and Hume, J. R. (1989) Autonomic regulation of a chloride current in heart. Science 244, 983-985 33. Zhang, K., Barrington, P. L., and Ten Eick, R. E. (1991) Cardiac chloride current activated by cs-adrenergic agonists. j MoL CelL Cardiol. 23 (III), S-102 (abstr.) 34. Yue, D. T., and Marban, E. (1988) A novel cardiac potassium channel that is active and conductive at depolarized potentials. Pfluegers Arch. Eur. J. Physiol. 413, 127-133
35. Rasmussen, H. H., Singer, D. H., and Ten Eick, R. E. (1986) Characterization of an electrogenic Na pump induced hyperpolarization in human atrial myocardium. Am. j Physiol. 251, H331-H339 36. Braasch, W., Gudbjarnason, S.,Pun, P. S.,Ravens, K. G., and Bing, R. J. (1978) Early changes in energy metabolism in the myocardium following acute coronary artery occlusion in anesthetized dogs. Circ. Res. 23, 429-438 37. Garlick, P. B., Radda, G. K., and Seely, P. J. (1979) Studies of
acidosis in the ischemic heart by phosphorus nuclear magnetic resonance. Bioche,n. j 184, 547-554 38. Ugurbil, K. (1985) Magnetization transfer measurements of creatine kinase and ATPase rates in intacthearts. Circulation 72 (Suppl IV): 94-96 39. Jennings, R. B., Reimer, K. A., Hill, M. L., and Mayer, S. E. (1981) Total ischemia in dog hearts in vitro. I. Comparison of
high energy phosphate production, utilization and depletion, and of adenine nucleotide catabolism in total ischemia in vitro vs. severe ischemia in vivo. Circ. Res. 49, 892-900 40. Podzuweit, T., Dalby, A. J., Cherry, G. W., and Opie, L. H. (1978) Cyclic AMP levels in ischemic and non-ischemic myocardium following coronary artery ligation: relation to ventricular fibrillation. J. MoL CelL C’ardiol. 10, 81-94 41. Steenbergen, C., Hill, M. L., and Jennings, R. B. (1985) Volume regulation and plasma membrane injury in aerobic, anaerobic and ischemic myocardium in vitro. Circ. Res. 57, 864-875
42. Tani, M., and Neely, J. R. (1989) Role of intracellular Na4 and Ca2 overload and depressed recovery of ventricular function of reperfused ischemic rat hearts. Circ. Res. 65, 1045-1056 43. Ferrier, G. R. (1977) Digitalis arrhythmias, role of oscillatory afterpotentials. Prog. Cardiovasc. Dis. 19, 459-474 44. Sobel, B. E., Corr, P. B., Robinson, A. K., Goldstein, R. A., Witkowski, F Y., and Klein, M. S. (1978) Accumulation of lysophosphoglycerides 45.
46.
47.
48.
49.
with
arrhythmogenic
properties
in
ischemic myocardium. j Clin. Invest. 62, 546-553 Corr, P. B., Synder, D. W., Cain, M. B., Crafford, W. A., Gross, R. W., and Sobel, B. E. (1981) Electrophysiological effects of amphiphiles on canine Purkinje fibres. Implications for dysrhythmia secondary to ischemia. Circ. Res. 49, 354-363 Maisel, A. S., Motulsky, H. J., and Insel, P. A. (1985) Externalization of beta-adrenergic receptors promoted by myocardial ischemia. Science 230, 183-186 Orchard, C. H., and Kentish, J. C. (1990) Effects of changes in pH on the contractile function of cardiac muscle. Am. j PhysioL 258, C967-C981 Irisawa, H., and Sato, R. (1986) Intra and extracellular actions of protons on the calcium current of isolated guinea pig ventricular cells. Circ. Res. 59, 348-355 Kaibara, M., and Kameyama, M. (1988) Inhibition of the calcium channel by intracellular protons in single ventricular myocytes of the guinea pig. j PhysioL (London) 403, 621-640
HEART DISEASE AND ION CHANNEL
ELECTROPHYSIOLOGY
Y. (1982)
The
effects
of intracellular
electrical activity of single ventricular PhysioL 394, 264-270
protons
on the
cells. PftuegersArch. Eur. j
51. Sato, R., Noma, A., Kurachi, Y., and Irisawa, H. (1985) Effects of intracellular acidification on membrane currents in ventricular cells of the guinea-pig. Circ. Res. 57, 553-561 52. Hagiwara, S., Miyazaki, S., Moody, W., and Patlak, J. (1978) Blocking effects of barium and hydrogen ions on the potassium
current
during
anomalous
rectification
in the starfish egg. j
Physiol. (Lond.) 279, 167-185 53. Harvey, R. D., and Ten Eick, R. E. (1989) On the role of sodium ions in the regulation of the inward rectifying potassium conductance in cat ventricular myocytes. J. Gen. PhysioL 94, 329-348 54. Fry, C. H., and Poole-Wilson, P. A. (1981) Effects of acid-base changes on excitation-contraction coupling in guinea-pig and rabbit cardiac ventricular muscle. J. PhysioL (Lond.) 313, 141-160 55. Hisatome, I., Sato, R., and Singer, D. H. (1989) Direct proton block of sodium current in guinea pig ventricular myocytes. Biophys. j 55, 288 (abstr.) 56. Moorman, J. R., Yee, R., Bjornsson, T., Starmer, C. F., Grant, A. 0., and Strauss, H. C. (1986) PKa does not predict potentia-
tion of sodium channel blockade by lidocaine and W6211 in guinea pig ventricular myocardium. J. Pharmacol. Exp. Ther. 238, 159-165 57. Yeh, J. Z., and Tanguy, J. (1991) Internal and external protons modulate voltage dependence of recovery from use-dependent block of lidocaine. Biophys. j 59, 26 (abstr.) 58. Kameyama, M., Kakei, M., Sato, R., Shibasaki, T., Matsuda, M., and Irisawa, H. (1984) Intracellular Na activates a K channel in mammalian cardiac cells. Nature (London) 309, 354-356
59. Harvey, R. D., Jurevicius, J. A., and Hume, J. R. (1991) Intracellular Na modulates the cAMP-dependent regulation of ion channels in the heart. Proc. NatL Acad. Sci. USA 88, 6946-6950 60. Hume, J. (1989) Properties of myocardial K channels and their pharmacological modulation. In Molecular and Cellular Mechanisms of Antiarrhythmic Agents (Hondeghem, L., ed.) pp. 113-131 Futura,
Mount
Kisco,
NY
61. Tohse, N. (1990) Calcium-sensitive current in guinea pig ventricular
delayed rectifier potassium cells. Am. j Physiol. 258,
Hl200-H1207 62. January, C. T, and Fozzard, H. A. (1988) Delayed afterdepolarizations in heart muscle: mechanisms and relevance. PharinacoL
Rev. 40, 219-227 J. R., Kirsch, G. E., Lacerda, A. E., and Brown, A. M. (1989) Angiotensin II modulates cardiac Na channels in neonatal rat. Circ. Res. 65, 1804-1809 64. Toro, L., Amador, M., and Stefani, E. (1990) Angiotensin II inhibits calcium-activated potassium channels from coronary smooth muscle in lipid bilayers. Am. j PhysioL 258, H912-H9l5 65. Lindpaintner, K., Markus, M. J., Suzuki, F., Linz, W., Schoelkens, B. A., and Ganten, D. (1988) Intracardiac generation of angiotensin and its physiologic role. Circ. Suppl. 77, 63. Moorman,
118-123 66. The CONSENSUS trial group mortality in severe congestive
cooperative north Scandinavian EngL j Med. 316, 1429-1435
(1987) heart
Effects failure:
enalapril
of enalapnil results of
survival
on the study. N
67. Hartzell, H. C. (1988) Regulation of cardiac ion channels by catecholamines, acetylcholine and second messenger systems. Frog. Biophys. MoL BioL 52, 165-247 68. Bean, B. P., Nowycky, M. C., and Tsien, R. W. (1984) Beta adrenergic modulation of calcium channels in frog ventricular cells. Nature (London) 307, 371-375 69. Nakayama, T., and Fozzard, H. A. (1988) Adrenergic modulation of the transient outward current in isolated canine purkinje cells. Circ. Res. 62, 162-172 70. Walsh, K. B., Begenisich, T. B., and Kass, R. S. (1988) Beta adrenergic modulation in the heart. Independent regulation of K and Ca channels. Fftuegers Arch. Eur. j Physiol. 411, 232-234
71. Schubert, B., VanDongen, A. M. J., Kirsch, G. E., and Brown, A. M. (1988) Adrenergic inhibition of cardiac sodium channels
2579
www.fasebj.org by Univ Louisiana Dupre Library/Serials Dept (130.70.8.131) on January 14, 2019. The FASEB Journal Vol. ${article.issue.getVolume()}, No. ${article.issue.getIssueNumber
72.
73.
74.
75.
76.
77.
2580
by dual G-protein pathways. Proc. Nati. Acad. Sci. USA 85, 8360-8364 Arnsdorf, M. F, and Sawicki, G. J. (1981) The effects of lysophosphatidylcholine, a toxic metabolite of ischemia, on the components of cardiac excitability in sheep Purkinje fibres. Circ. Res. 49, 16-30 Sakata, K., Hayashi, H., Kobayashi, A., and Yamazaki, N. (1989) Mechanism of arrhythmias induced by palmitylcarnitine in guinea pig papillary muscle. Cardiovasc. Res. 23, 505-511 Katz, A. M., and Messineo, F C. (1981) Lipid membrane interactions and the pathogenesis of ischemic damage in the myocardium. Circ. Res. 48, 1-16 Noma, A., and Shibasaki, T. (1985) Membrane current through adenosine-triphosphate-regulated potassium channels in guinea pig ventricular cells. j Physiol. (Lond.) 363, 463-480 Nichols, C. G., Ripoli, C., and Lederer, W. J. (1991) ATPsensitive potassium channel modulation of the guinea pig ventricular action potential and contraction. Circ. Res. 68, 280-287 Kirsch, G. E., Codina, L., Birnbaumer, L., and Brown, A. M. (1990) Coupling of ATP-sensitive channels to A1 receptors by G proteins in rat ventricular myocytes. Am. j PhysioL 259,
Vol. 6
May 1992
H820-H826 78. Schackow, stimulated
(III),
T.
E.,
and
Ten
by /3-receptor
Eick,
R.
stimulation.
‘K,ATP can be MoL Cell. Cardiol. 23
E. (1991)
J.
S-97
79. Cameron,J. S., Kimura, S.,Jackson-Burns, D. A., Smith, D. B., and Bassett, A. L. (1988) ATP-sensitive K channels are altered in hypertrophied ventricular myocytes. Am. j Physiol. 255,
Hl254-H1258 80. Nichols,
C. G.,
and
Lederer,
W.
J.
(1990)
The
regulation
of
ATP-sensitive K4 channel activity in intact and permeabilized rat ventricular myocytes. J. Physiol. (Lond.) 423, 91-110 81. Catteral, W. A. (1988) Structure and function of voltagesensitive ion channels. Science 242, 50-61 82. Stuhmer, W., Conti, F, Suzuki, H., Wang, X., Noda, M., Yahangi, N., Kubo, H., and Numa, 5. (1989) Structural parts involved with activation and inactivation of the sodium channel. Nature (London) 339, 597-603
83. Leu, W. M., and Boyden, P. A. (1989) The transient outward current is markedly decreased in canine myocytes from the epicardial border zone of the infarcted heart. Circulation 80, II-500 (abstr. 1989)
The FASEBJournal
TEN EICK EF AL.
www.fasebj.org by Univ Louisiana Dupre Library/Serials Dept (130.70.8.131) on January 14, 2019. The FASEB Journal Vol. ${article.issue.getVolume()}, No. ${article.issue.getIssueNumber
heart
cellular
disease,
aid
electrophysiology,
ion
channels ROBERT
E. TEN EICX” of Pharmacolog
DAVID
%%.
WHAL1ET Umveisit
Northwestern
The Royal North Shore Hospital, St Leonaith,
and
that
at
least
one
intrinsic
conductance
property of the inward rectifier can be altered by ischemia. We speculate that the control of expression, function, and regulation of cardiac ion channels can be affected at the molecular level by heart disease and myocardial ischemia. -Ten Eick, R. E.; Whalley, D. W.; Rasmussen, H. H. Connections: heart disease, cellular electrophysiology, and ion channels. FASEB J. 6: 2568-2580; 1992. Key Words:
sodium channels
c/ziori.dechannels
calcium channels
ATP -sensitive potamwn
.
potassium channels
channels
cvtJid
ische-
mia . myocardial hyperirophy intracellular ion activities ext racellular ion activities lysophosphatidylcholine channel phosphotylation . channel
regulation
WITH DISEASED HEARTS ARE more prone to cardiac rhythm disturbances and sudden death than those with healthy hearts. This has resulted in the hypothesis that disease can alter the electrophysiological character of the heart and its constituent cells (1, 2). The electrophysiological activity of the mammalian heart is largely governed by the activity of sarcolemmal ion channels. These in turn regulate the passive transmembrane ion fluxes underlying the several components of the membrane current (e.g., Na, K, Ca2, and Cl-), which are important for the production of cellular action potentials (3-5). Therefore, it is reasonable to think PEOPLE
that disease alters either the ionic compositions of the interstitial and intracellular milieus, the characters of the ion channels themselves, or both. There is much evidence indicating that the composition of the extracellular milieu is altered during acute and chronic myocardial ischemia and that these changes could play an 2568
K
RASMUSSEN1
Chicago, Illinois 60611, USA, and tDepartment
New South W:,
ABSTRACT Our purpose in this article is to examine the hypothesis that both myocardial disease and ischemia can alter the electrophysiologic function of the ion channels responsible for the cellular electrical activity of the heart. Changes in the intracellular and extracellular milieus occur during ischemia and can alter the dcctrophysiology of several species of ionic channels and the cellular electrophysiologic activity of cardiac myocytes. Included are 1) changes in extracellular [K] and pH and in intracellular [NaJ, [Ca2’], and pH; 2) accumulation of noxious metabolic products such as lysophosphatidyicholine; and 3) depletion of intracellular ATP. Finally, ischemia or disease (e.g., hypertrophy) can alter the dcctrophysiology of at least two types of K channels, the A-like channels underlying the transient outward current and the inward rectifier, by mechanisms that apparently do not involve alteration of either the intra- or extracellutar milieus. Findings suggest that the expression of cardiac A-like channel function can be altered by hypertrophy
AND HELE
of Cardiology
2)65 Australia
important role in the associated disturbances of the heart rhythm (6, 7). There also is information available on the behavior of sarcolemmal ion channels found in normal cardiac cells when exposed to environments thought to mimic the interstitial fluid during acute ischemia (8-10). Despite these data, the hypothesis that heart disease can alter the functional character of any of the several types of ion channels has yet to be rigorously examined, probably because of the dearth of relevant feasible models. The patch clamp technique is beginning to be used to investigate ion channel function in models of diseased or ischemic heart. A variant, the whole-cell-patch clamp technique (11, 12), allows the investigator to manipulate the extracellular effects on
and intracellular channel function
milieus (13) and permits the of disease and/or ischemia-
induced changes in the intracellular milieu to be characterized. For example, the effects of ischemia-induced changes in cellular pH, pCa, or ATP or cAMP contents or increases in cellular metabolic products on any of the constituent components of the membrane current (i.e., the Na, Cap, or K currents) can be addressed using patch clamping. Whether disease and/or ischemia can cause fundamental changes in the intrinsic electrophysiologic properties of cardiac ion channels that would alter channel behavior when exposed to a normal extracellular environment, although not yet clarified, is under investigation (14-21). The models being studied include cells from specimens of diseased and/or ischemic human atrial appendage (22) and ventricular strips (14), from and from
feline normal
hypertrophic right feline ventricular
culture (15-17). Evidence nel properties can change
suggesting in response
cellular environment despite being perimental assessment to a milieu mal” physiological conditions will
THE NORMAL VENTRICULAR ACTION POTENTIAL Resting
(18, 19, 23, 24), maintained in
that fundamental to a chronically
chanaltered
exposed at the time presumed to mimic be presented.
RESTING
of ex“nor-
AND
potential
In the absence tively
ventricle myocytes
stable
of excitation ventricular cells maintain membrane potential of -80 to -95 mV,
a relatermed
‘To whom correspondence should be addressed, at: Department Pharmacology, Northwestern University, 320 East Superior Street, Chicago, IL 60611, USA. 2Abbreviations: AP, action potential; CHF, congestive heart failure; DAD, delayed afterdepolarization; E, equilibrium potential; g, conductance; I,,,, cellular membrane current; I,, component of of
I,,, carried by X; LPC, lysophosphatidylcholine;
pHi, intracellular
pH;
pH0, extracellular PH; RV, right ventricle (or ventricular); Vmax, maximum depolarization rate of AP upstroke; V, resting potential.
0892-6638/92/0006-2568/$01 .50. © FASEB
www.fasebj.org by Univ Louisiana Dupre Library/Serials Dept (130.70.8.131) on January 14, 2019. The FASEB Journal Vol. ${article.issue.getVolume()}, No. ${article.issue.getIssueNumber
the resting potential (V7).2 The ability of cardiac cells to generate and propagate a normal action potential (AP) depends on the level of V7. The resting potential arises as a result of the selective permeability of the cell membrane to K4 and the transmembrane K4 gradient, which in turn is maintained by the Na4, K4 pump. By extruding three intracellular Na4 in exchange for two extracellular K, the pump maintains steep Na4 and K4 concentration gradients, inward for Na4 and outward for K4, and in the process generates an outward current termed the electrogenic Na, K4 pump current (Ipump). Normally V7 is largely determined by the ratio of the extracellular to intracellular K activities (K0/K1) because the membrane permeability to K far exceeds that to Na, Ca24, or C1 in the resting state. V,. usually slightly positive to the equilibrium potential for K4 predicted by the Nernst equation because of a small depolarizing “leak” current carried primarily by Na4. The resting potential may be altered by changes in the intraor extracellular ionic milieu, by neurohumoral influences; and by drugs that affect the relative permeabilities of the cell membrane to K4 and Na4 or inhibit the Na4, K4 pump. Depolarization of Vr from the normal level (approximately -80 to -90 mV) appears to be a prominent feature of several pathological staies associated with cardiac arrhythmias (25).
upstroke. It is followed by a prolonged (up to hundreds of milliseconds) three-phase repolarization that returns membrane voltage to the resting potential and consists of 1) an early phase of rapid repolarization, 2) a secondary depolarization
(usually
The AP
The
transmembrane
action
potential
When an excitatory stimulus depolarizes the membrane beyond the threshold potential (mV), an AP is produced that is manifest as a propagating wave of transient depolarization (see Fig. 1). Inscription of the cardiac AP
?
results
from
a rapid
(
92% vs. 67%). Second, the average I current density was about 65% greater in hypertrophied RV myocytes than in normal RV myocytes. Finally, the steady-state and kinetic parameters of I that characterize the functional behavior of the A channels supporting the current were unchanged from those observed normally (see co-workers
B
Normal
H V Hypertrophy
A.
Fig. +40 mV
C.
50
.4OmVI1_
p4
pAJpF
0
100
ma
Figure 5. Effect of severe right ventricular (RV) hypertrophy (in the absence of uncompensated failure) on the action potential recorded from normal (A) and hypertrophied (B) RV papillary muscles. The changes associated with hypertrophy in the time to achieve 90% of complete repolarization (double-tipped arrows) and in the maximal level of potential achieved during the plateau (arrows) are obvious from the comparison between A and B. Notice the greater extent to which the hypertrophied cell repolarized during phase 1 (to + 4 mV in RV hypertrophy vs. +12 mV in normal). C) Transient outward current (normalized to sarcolemmal surface area) recorded from single isolated feline cells from normal and hypertrophied right ventricles in response to voltage clamp pulses from -40 to + 40 mV for 100 ms (see inset of C). The peak amplitude of I,,, (indicated by arrows) was greater in the RV hypertrophied cell than in the normal cell. However, notice that the time course of I,,, decay did not change. In addition, a greater percentage of the RV cells exhibited I,,, in the hypertrophied case (92%) than in the normal case (67%). Therefore I,,, is augmented and exhibited more frequently by cells from hypertrophied heart. We speculate that the additional current observed in the hypertrophied cells may reflect overexpression of the I channels induced by or in association with RV hypertrophy (see text). Initially it was suggested that the Ca24 current flowing during the plateau inactivated with a slower time course. The implication was that somehow hypertrophy altered the functional properties of sarcolemmal Ca24 channels. This hypothesis has not been borne out by whole-cell-patch voltage clamp studies done by several laboratories employing different animal models (21, 23). Attention then focused on components of the K’ current flowing during the plateau phase of the AP, including the delayed outwardly rectifying K4 current and the inwardly rectifying K4 current. As with the Ca24 current, no striking changes in either the size or kinetic properties of either current were found in cells obtained from hypertrophied hearts of either rats, guinea pigs, or cats (24). Because ‘Ca, ‘K, and ‘K! are regarded as principal contributors to the net membrane current flowing during the AP plateau, the failure to find any striking change in the character of any of them presented a quandary. Therefore, motivated by the increased degree of the repolarization achieved at the finish of the early phase of repolarization (marked by the voltage notch at the onset of the AP plateau) frequently
HEART DISEASEAND ION CHANNEL ELECTROPHYSIOLOGY
in hypertrophied compared
I
5).
The simplest interpretation of these three findings is that the channel density of normal cardiac channels was enhanced (relative to normal) in hypertrophied RV and that this occurs in all myocytes constituting the RV free wall whether they are located in the endo- or epicardial portions. The mechanism for the increase in the channel density could be that the rate of synthesis and sarcolemmal insertion of functional channels is increased over normal during hypertrophy or that the turnover rate (i.e., loss) of functional membrane channels is decreased below normal during hypertrophy, or both. The implication is that hypertrophy may “stimulate” or “inhibit” processes at the molecular level that are involved in regulating or modulating the functional expression of cardiac A-like channels subserving the transient outward current. We speculate, as a working hypothesis, that gene products involved in regulating or modulating cardiac A-like channel function are overexpressed in association with hypertrophy, perhaps in response to a primal stimulus that initiates the events that are ultimately manifest as hypertrophy. Of particular interest is the question of whether the increase in the density of I has any role in the change from normal in the shape of the AP associated with hypertrophy. In other words, could an increase in I cause depression of plateau voltage and prolongation of the AP duration? The finding that inhibition of I by approximately 30% with a low concentration of 3,4-diaminopyridine can cause the plateau voltage to become more positive and the AP duration to shorten (18) suggests that the hypertrophy-induced change in may, in fact, at least partially underlie the changes in the AP that are associated with hypertrophy. The explanation is that a larger I causes the plateau phase to be initiated from a less positive potential. This causes ‘Ca to inactivate less rapidly, and the total and peak ‘Ca is enhanced owing to the resulting greater difference between the membrane potential and Ea. The net result is that increasing I can prolong AP duration and depress plateau voltage.
SUMMARY, CONCLUSIONS, SPECULATIONS
IMPLICATIONS,
It is tempting to speculate that, just as unloading myocytes electrically or mechanically could underlie the loss of I in cells maintained in primary culture and surviving cells in infarcted heart tissue, increasing cellular loading, such as occurs when the heart must pump in the chronically hypertensive patient, could underlie the functional overexpression of channels responsible for Iv,, as well as the gene-regulated events leading to the molecular, cellular, and organ-based changes associated with hypertrophy. However, independent of whether this notion is even partially correct, it is provoca-
2577
www.fasebj.org by Univ Louisiana Dupre Library/Serials Dept (130.70.8.131) on January 14, 2019. The FASEB Journal Vol. ${article.issue.getVolume()}, No. ${article.issue.getIssueNumber
live that two different myocardial loading conditions known to be associated with clinical evidence of heart disease seem to cause change in at least one fundamental aspect of channel function, the channel density. This change would alter cardiac electrical activity independently of and in addition to any other concurrent changes associated with disease and/or ischemia. Evidence has been presented in support of the ideas that 1) the sensitivity of the inwardly rectifying K’ channel to the extracellular K’ concentration is altered in surviving human ventricular cells found in chronically ischemic or infarcted tissue and that 2) the density of the channels responsible for the transient outward current in heart can be altered in response to altering the load borne by the individual cells that make up the heart as an organ. Therefore, the answer to the question posed at the inception of this article-can heart disease or ischemia alter the functional behavior of cardiac sarcolemmal ion channels?-appears to be affirmative. We have presented data and arguments in support of the hypothesis that altered channel function would be expected both because of the well-documented changes in the extra- and intracellular milieus and because of intrinsic changes in at least one parameter defining ion channel function that appear to occur independently of any of the changes in milieus. If this hypothesis is true, many conclusions concerning the cellular mechanisms underlying many cardiac arrhythmias and the mechanisms of action of antiarrhythmic drugs, which have been largely derived from data obtained with preparations of normal heart, will require reevaluation. The challenge of the 1990s will be to address these questions rigorously by employing the power and sophistication of the patch clamp and molecular biological technologies now available to the field. R. E. T was recipient of the Warren McDonald International Fellowship of the National Heart Foundation of Australia when this article was conceived. D. W. W. was a Postgraduate Medical Research Scholar of the National Heart Foundation of Australia when the article was being written. Previously unpublished data reported in this article were obtained during experiments supported by grants HL-27026 and HL-3804l to R. E. T. from the U.S. National Institutes of Health (NHLBI). The extent to which this article may be found understandable by people who are not practicing cellular cardiac electrophysiologists is credited to the editorial help provided by Drs. P. L. Barrington, R. L. Martin, T E. Schackow, J. A. Wasserstrom, and K. Zhang. The authors thank them for their critical comments and suggestions during the development of this article; special thanks to Professor Harry A. Fozzard for taking time to offer critical comments and encouragement.
REFERENCES 1. Hoffman,
B. F.,and Cranefield, P. F. (1964) Physiological basis
of cardiac arrhythmias. Am. j Med. 37, 670-689 2. Bigger, J. T., Jr., Dresdale, R. J., Heissenbuttel, R. H., Weld, F. M., and Wit, A. L. (1977) Ventricular arrhythmias in ischemic heart disease: mechanism, prevalence, significance and management. Pmg. Cardiovasc. Dis. 19, 255-277 3. Noble, D. (1984) The surprising heart: a review of recent progress in cardiac electrophysiology. j Physiol. (Lond.) 353, 1-50 4. Fozzard, H. A., and Arnsdorf, M. F. (1986) Cardiac electrophysiology. In The Heart and Cardiovascular Syst#{128}m (Fozzard, H. A., et al.; eds.) pp. 1-30, Raven Press, New York 5. Wasserstrom, J. A., and Ten Eick, R. E. (1991) The dcctrophysiology of mammalian ventricular musde. In Electrophysiology and Pharmacology of the Heart (Dangman, K. H., and Miura, D. S., eds) pp. 199-233, Marcel Dekker, New York 2578
Vol. 6
May 1992
6. Harris, A. S., Bisteni,A., Russel, R. A., Brigham, J. C., and Firestone, J. E. (1954) Excitatory factors in ventricular tachycardia resulting from myocardial ischemia: potassium as a major excitant. Science 119, 200-203 7. Kleber, A. G. (1987) Extracellular K4 and H4 shifts in early ischemia: mechanisms and relation to changes in impulse propagation. J. Mol. Cell. Cardiol. (Suppl V): 35-44 8. Yatani, A., Brown, A., and Akaike, N. (1984) Effects of extracellular pH on sodium current in isolated, single rat ventricular cells. j Membr. Biol. 68, 163-168 9. Krafte, D. S., and Kass, R. S. (1988) Hydrogen ion modulation of Ca channel current in cardiac ventricular cells.j Gen. Physiol. 91, 641-657 10. Clarkson, C. W., and Ten Eick, R. E. (1983) On the mechanism of lysophosphatidylcholine induced depolarization of cat ventricular myocardium. Circ. Res. 52, 543-556 11. Hamill, 0. P., Marty, A., Neher, E., Sakmann, B., and Sig-
worth, F. J. (1981) Improved resolution current recording Pjluegers
Arch.
Eur.
J.
PhysioL
patch clamp technique for highfrom cells and cell-free patches. 391, 85-100
12. Ten Eick, R. E. (1990) Biophysical techniques for the study of cardiac tissue. In Cardiac Electrophysiology: A Textbook (Rosen, M., Janse, M., and Wit, A., eds) pp 3-27 Futura, Mount Kisco, NY 13. Mogul, D. J., Singer, D. H., and Ten Eick, R. E. (1989) Ionic diffusion in voltage-clamped isolatedcardiac myocytes: implications for Na,K-pump studies. Biophys. J. 56, 565-577 14. McCullough, J., Chua, W., Rasmussen, H., Ten Eick, R. E., and Singer, D. (1990) Effects of potassium on the diastolic
potential of partially depolarized cells in human ventricular myocardium. Circ. Res. 66, 191-201 15. Schackow, T. E., Barrington, P. B., Cook, M., Simpson, D., Decker, R. S., and Ten Eick, R. E. (1989) Sodium current can be affected by introduction of isolated cat ventricular myocytes into a primary culture environment. Biophys. j 55, 295 (abstr.) 16. Schackow, T. E., Cook, M. G., Behnke, M. M., Decker, M. L., Decker, R. S., and Ten Eick, R. E. (1990) Culture alters morphology, biochemistry and electrophysiology of adult cat cardiocytes. Biophys. j 57, 140 (abstr.) 17. Schackow, T. E., La Pres, J. J., Decker, R. S., and Ten Eick, R. E. (1991) Alterations in sodium currents in cultured cat cardiocytes are unrelated to changes in cell morphology. Biophys. j 59, 97 (abstr.) 18. Zhang, K., Harvey, R. D., Barrington, P. L., Schackow, T E., Bassett, A. L., and Ten Eick, R. E. (1991) Transient outward current (Ito) in normal and hypertrophied cat right ventricular
myocytes. Biophys. j 59, 588 (abstr.) 19. Zhang, K., Harvey, R. D., Martin, R. L., Bassett, A. L., and Ten Eick, R. E. (1991) Inward rectifying K current in normal and hypertrophied cat right ventricular myocytes. Biophys. j 59, 279 (abstr.) 20. Ten Eick, R. E., Bassett, A. L., and Robertson, L. L. (1983) Possible electrophysiological basis for decreased contractility associated with myocardial hypertrophy: a voltage clamp approach. Perspect. Cardiovasc. Res. 7, 245-259 21. Ten Eick, R. E., Houser, J. R., and Bassett, A. L. (1989) Cardiac hypertrophy and altered cellular electrical activity of the myocardium. In Physiology and Pathophysiology of the Heart, (2nd ed. (Sperelakis, N., ed) pp. 573-594 Martinus Nijhoff, Boston 22. Ten Eick, R. E., and Singer, D. H. (1979) Electrophysiological properties of diseased human atrium (I): low resting potential and altered sensitivity to potassium. Circ. Res. 44, 545-557
23. Kleinman, R. L., and Houser, S. R. (1988) Calcium currents in normal and hypertrophied isolated feline ventricular myocytes. Am. j Physiol. 255, Hl434-H1442 24. Kleinman, R. L., and Houser, S. R. (1989) Outward currents in normal and hypertrophied isolated feline ventricular myocytes. Am. J. PhysioL 256, H1450-H1459 25. Ten Eick, R. E., Baumgarten, C. M., and Singer, D. H. (1981) Ventricular dysrhythmia: Membrane basis, or, Of currents, channels, gates and cables. Prog. Cardiovasc. Dis. 24, 157-188 26. Coraboeuf, E. (1978) Ionic basis of electrical activity in cardiac tissues.Am. j Physiol. 234, H101-H116 27. DiFrancesco, D., and Noble, D. (1985) A model of cardiac dcc-
The FASEB Journal
TEN EICK ET AL.
www.fasebj.org by Univ Louisiana Dupre Library/Serials Dept (130.70.8.131) on January 14, 2019. The FASEB Journal Vol. ${article.issue.getVolume()}, No. ${article.issue.getIssueNumber
trical activity incorporating ionic pumps and concentration changes. Philos. Trans. R. Soc. London B (BioL Sci.) 307, 353-398
50. Kurachi,
28. Giles, W. R., and van Ginneken, A. C. (1985) A transient Outward current in isolated cells from the crista terminalis of rabbit heart. j Physiol. (London) 368, 243-264 29. Hiraoka, M., and Kawano, 5. (1989) Calcium-sensitive and insensitive transient outward current in rabbit ventricular myocytes. J. Physiol. (London) 410, 187-212 30. Tseng, G. N., and Hoffman, B. F. (1989) Two components of transient outward current in canine ventricular myocytes. Circ. Res. 64, 633-647 31. Zygmunt, A. C., and Gibbons, W. R. (1991) Calcium-activated chloride current in rabbit ventricular myocytes. Circ. Res. 68, 424-437 32. Harvey, R. D., and Hume, J. R. (1989) Autonomic regulation of a chloride current in heart. Science 244, 983-985 33. Zhang, K., Barrington, P. L., and Ten Eick, R. E. (1991) Cardiac chloride current activated by cs-adrenergic agonists. j MoL CelL Cardiol. 23 (III), S-102 (abstr.) 34. Yue, D. T., and Marban, E. (1988) A novel cardiac potassium channel that is active and conductive at depolarized potentials. Pfluegers Arch. Eur. J. Physiol. 413, 127-133
35. Rasmussen, H. H., Singer, D. H., and Ten Eick, R. E. (1986) Characterization of an electrogenic Na pump induced hyperpolarization in human atrial myocardium. Am. j Physiol. 251, H331-H339 36. Braasch, W., Gudbjarnason, S.,Pun, P. S.,Ravens, K. G., and Bing, R. J. (1978) Early changes in energy metabolism in the myocardium following acute coronary artery occlusion in anesthetized dogs. Circ. Res. 23, 429-438 37. Garlick, P. B., Radda, G. K., and Seely, P. J. (1979) Studies of
acidosis in the ischemic heart by phosphorus nuclear magnetic resonance. Bioche,n. j 184, 547-554 38. Ugurbil, K. (1985) Magnetization transfer measurements of creatine kinase and ATPase rates in intacthearts. Circulation 72 (Suppl IV): 94-96 39. Jennings, R. B., Reimer, K. A., Hill, M. L., and Mayer, S. E. (1981) Total ischemia in dog hearts in vitro. I. Comparison of
high energy phosphate production, utilization and depletion, and of adenine nucleotide catabolism in total ischemia in vitro vs. severe ischemia in vivo. Circ. Res. 49, 892-900 40. Podzuweit, T., Dalby, A. J., Cherry, G. W., and Opie, L. H. (1978) Cyclic AMP levels in ischemic and non-ischemic myocardium following coronary artery ligation: relation to ventricular fibrillation. J. MoL CelL C’ardiol. 10, 81-94 41. Steenbergen, C., Hill, M. L., and Jennings, R. B. (1985) Volume regulation and plasma membrane injury in aerobic, anaerobic and ischemic myocardium in vitro. Circ. Res. 57, 864-875
42. Tani, M., and Neely, J. R. (1989) Role of intracellular Na4 and Ca2 overload and depressed recovery of ventricular function of reperfused ischemic rat hearts. Circ. Res. 65, 1045-1056 43. Ferrier, G. R. (1977) Digitalis arrhythmias, role of oscillatory afterpotentials. Prog. Cardiovasc. Dis. 19, 459-474 44. Sobel, B. E., Corr, P. B., Robinson, A. K., Goldstein, R. A., Witkowski, F Y., and Klein, M. S. (1978) Accumulation of lysophosphoglycerides 45.
46.
47.
48.
49.
with
arrhythmogenic
properties
in
ischemic myocardium. j Clin. Invest. 62, 546-553 Corr, P. B., Synder, D. W., Cain, M. B., Crafford, W. A., Gross, R. W., and Sobel, B. E. (1981) Electrophysiological effects of amphiphiles on canine Purkinje fibres. Implications for dysrhythmia secondary to ischemia. Circ. Res. 49, 354-363 Maisel, A. S., Motulsky, H. J., and Insel, P. A. (1985) Externalization of beta-adrenergic receptors promoted by myocardial ischemia. Science 230, 183-186 Orchard, C. H., and Kentish, J. C. (1990) Effects of changes in pH on the contractile function of cardiac muscle. Am. j PhysioL 258, C967-C981 Irisawa, H., and Sato, R. (1986) Intra and extracellular actions of protons on the calcium current of isolated guinea pig ventricular cells. Circ. Res. 59, 348-355 Kaibara, M., and Kameyama, M. (1988) Inhibition of the calcium channel by intracellular protons in single ventricular myocytes of the guinea pig. j PhysioL (London) 403, 621-640
HEART DISEASE AND ION CHANNEL
ELECTROPHYSIOLOGY
Y. (1982)
The
effects
of intracellular
electrical activity of single ventricular PhysioL 394, 264-270
protons
on the
cells. PftuegersArch. Eur. j
51. Sato, R., Noma, A., Kurachi, Y., and Irisawa, H. (1985) Effects of intracellular acidification on membrane currents in ventricular cells of the guinea-pig. Circ. Res. 57, 553-561 52. Hagiwara, S., Miyazaki, S., Moody, W., and Patlak, J. (1978) Blocking effects of barium and hydrogen ions on the potassium
current
during
anomalous
rectification
in the starfish egg. j
Physiol. (Lond.) 279, 167-185 53. Harvey, R. D., and Ten Eick, R. E. (1989) On the role of sodium ions in the regulation of the inward rectifying potassium conductance in cat ventricular myocytes. J. Gen. PhysioL 94, 329-348 54. Fry, C. H., and Poole-Wilson, P. A. (1981) Effects of acid-base changes on excitation-contraction coupling in guinea-pig and rabbit cardiac ventricular muscle. J. PhysioL (Lond.) 313, 141-160 55. Hisatome, I., Sato, R., and Singer, D. H. (1989) Direct proton block of sodium current in guinea pig ventricular myocytes. Biophys. j 55, 288 (abstr.) 56. Moorman, J. R., Yee, R., Bjornsson, T., Starmer, C. F., Grant, A. 0., and Strauss, H. C. (1986) PKa does not predict potentia-
tion of sodium channel blockade by lidocaine and W6211 in guinea pig ventricular myocardium. J. Pharmacol. Exp. Ther. 238, 159-165 57. Yeh, J. Z., and Tanguy, J. (1991) Internal and external protons modulate voltage dependence of recovery from use-dependent block of lidocaine. Biophys. j 59, 26 (abstr.) 58. Kameyama, M., Kakei, M., Sato, R., Shibasaki, T., Matsuda, M., and Irisawa, H. (1984) Intracellular Na activates a K channel in mammalian cardiac cells. Nature (London) 309, 354-356
59. Harvey, R. D., Jurevicius, J. A., and Hume, J. R. (1991) Intracellular Na modulates the cAMP-dependent regulation of ion channels in the heart. Proc. NatL Acad. Sci. USA 88, 6946-6950 60. Hume, J. (1989) Properties of myocardial K channels and their pharmacological modulation. In Molecular and Cellular Mechanisms of Antiarrhythmic Agents (Hondeghem, L., ed.) pp. 113-131 Futura,
Mount
Kisco,
NY
61. Tohse, N. (1990) Calcium-sensitive current in guinea pig ventricular
delayed rectifier potassium cells. Am. j Physiol. 258,
Hl200-H1207 62. January, C. T, and Fozzard, H. A. (1988) Delayed afterdepolarizations in heart muscle: mechanisms and relevance. PharinacoL
Rev. 40, 219-227 J. R., Kirsch, G. E., Lacerda, A. E., and Brown, A. M. (1989) Angiotensin II modulates cardiac Na channels in neonatal rat. Circ. Res. 65, 1804-1809 64. Toro, L., Amador, M., and Stefani, E. (1990) Angiotensin II inhibits calcium-activated potassium channels from coronary smooth muscle in lipid bilayers. Am. j PhysioL 258, H912-H9l5 65. Lindpaintner, K., Markus, M. J., Suzuki, F., Linz, W., Schoelkens, B. A., and Ganten, D. (1988) Intracardiac generation of angiotensin and its physiologic role. Circ. Suppl. 77, 63. Moorman,
118-123 66. The CONSENSUS trial group mortality in severe congestive
cooperative north Scandinavian EngL j Med. 316, 1429-1435
(1987) heart
Effects failure:
enalapril
of enalapnil results of
survival
on the study. N
67. Hartzell, H. C. (1988) Regulation of cardiac ion channels by catecholamines, acetylcholine and second messenger systems. Frog. Biophys. MoL BioL 52, 165-247 68. Bean, B. P., Nowycky, M. C., and Tsien, R. W. (1984) Beta adrenergic modulation of calcium channels in frog ventricular cells. Nature (London) 307, 371-375 69. Nakayama, T., and Fozzard, H. A. (1988) Adrenergic modulation of the transient outward current in isolated canine purkinje cells. Circ. Res. 62, 162-172 70. Walsh, K. B., Begenisich, T. B., and Kass, R. S. (1988) Beta adrenergic modulation in the heart. Independent regulation of K and Ca channels. Fftuegers Arch. Eur. j Physiol. 411, 232-234
71. Schubert, B., VanDongen, A. M. J., Kirsch, G. E., and Brown, A. M. (1988) Adrenergic inhibition of cardiac sodium channels
2579
www.fasebj.org by Univ Louisiana Dupre Library/Serials Dept (130.70.8.131) on January 14, 2019. The FASEB Journal Vol. ${article.issue.getVolume()}, No. ${article.issue.getIssueNumber
72.
73.
74.
75.
76.
77.
2580
by dual G-protein pathways. Proc. Nati. Acad. Sci. USA 85, 8360-8364 Arnsdorf, M. F, and Sawicki, G. J. (1981) The effects of lysophosphatidylcholine, a toxic metabolite of ischemia, on the components of cardiac excitability in sheep Purkinje fibres. Circ. Res. 49, 16-30 Sakata, K., Hayashi, H., Kobayashi, A., and Yamazaki, N. (1989) Mechanism of arrhythmias induced by palmitylcarnitine in guinea pig papillary muscle. Cardiovasc. Res. 23, 505-511 Katz, A. M., and Messineo, F C. (1981) Lipid membrane interactions and the pathogenesis of ischemic damage in the myocardium. Circ. Res. 48, 1-16 Noma, A., and Shibasaki, T. (1985) Membrane current through adenosine-triphosphate-regulated potassium channels in guinea pig ventricular cells. j Physiol. (Lond.) 363, 463-480 Nichols, C. G., Ripoli, C., and Lederer, W. J. (1991) ATPsensitive potassium channel modulation of the guinea pig ventricular action potential and contraction. Circ. Res. 68, 280-287 Kirsch, G. E., Codina, L., Birnbaumer, L., and Brown, A. M. (1990) Coupling of ATP-sensitive channels to A1 receptors by G proteins in rat ventricular myocytes. Am. j PhysioL 259,
Vol. 6
May 1992
H820-H826 78. Schackow, stimulated
(III),
T.
E.,
and
Ten
by /3-receptor
Eick,
R.
stimulation.
‘K,ATP can be MoL Cell. Cardiol. 23
E. (1991)
J.
S-97
79. Cameron,J. S., Kimura, S.,Jackson-Burns, D. A., Smith, D. B., and Bassett, A. L. (1988) ATP-sensitive K channels are altered in hypertrophied ventricular myocytes. Am. j Physiol. 255,
Hl254-H1258 80. Nichols,
C. G.,
and
Lederer,
W.
J.
(1990)
The
regulation
of
ATP-sensitive K4 channel activity in intact and permeabilized rat ventricular myocytes. J. Physiol. (Lond.) 423, 91-110 81. Catteral, W. A. (1988) Structure and function of voltagesensitive ion channels. Science 242, 50-61 82. Stuhmer, W., Conti, F, Suzuki, H., Wang, X., Noda, M., Yahangi, N., Kubo, H., and Numa, 5. (1989) Structural parts involved with activation and inactivation of the sodium channel. Nature (London) 339, 597-603
83. Leu, W. M., and Boyden, P. A. (1989) The transient outward current is markedly decreased in canine myocytes from the epicardial border zone of the infarcted heart. Circulation 80, II-500 (abstr. 1989)
The FASEBJournal
TEN EICK EF AL.
www.fasebj.org by Univ Louisiana Dupre Library/Serials Dept (130.70.8.131) on January 14, 2019. The FASEB Journal Vol. ${article.issue.getVolume()}, No. ${article.issue.getIssueNumber
