Calcium responses (“calcium spikes”)

Calcium responses (“calcium spikes”)

EDITORIALS Calcium Responses (“Calcium Spikes”) BORYS SURAWICZ, MD, FACC Lexington. Kentucky In 1961 Fleckenstein and his co-workers’ in Freibur...

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Calcium Responses (“Calcium Spikes”) BORYS




Lexington. Kentucky

In 1961 Fleckenstein and his co-workers’ in Freiburg, Germany, reported that adrenaline (5 pg/ml) restores contractility and excitability in amphibian and mammalian myocardium depolarized by potassium (12 to 23 millimoles/liter). These investigators showed that this restitution occurs without change in the resting membrane potential, which ranged from about -30 to -40 mv. The upstroke velocity of action potentials generated by adrenaline in such depolarized tissue was decreased, and the rate of impulse propagation was very slow. However, the overshoot of these action potentials was either normal, or even greater than normal. These unusual findings of Fleckenstein et al. could not be explained by the Hodgkin-Huxley ionic theory governing excitation in the giant squid axon2 and in cardiac Purkinje fibers.3 In the late 1960’s cardiac electrophysiologists made three discoveries that contributed to our understanding of the mechanism of action potentials originating in depolarized myocardium: (1) identification of the inward calcium current, (2) separation of the depolarizing currents into two channels, “rapid” and “slow,” and (3) demonstration that the permeability of the calcium current carrying slow channel, is enhanced by adrenaline. The principal credit for the identification and characterization of the slow inward calcium current in mammalian Purkinje and ventricular myocardial fibers belongs to Reuter. 4-7 He and his co-worker Beeler5p6 described the kinetics of the current and showed that in a sodium-free solution this current was activated at a threshold potential of about -30 to -40 mv. Reuter also demonstrated that adrenaline causes an increase in calcium influx through the depolarized myocardium.4 Role of Calcium in Adrenaline-Induced

Depolarization During the past decade several prominent cardiac electrophysiologists (cited in Ref 8) postulated that the upstroke of the cardiac action potential may be composed of two independent components, a rapid spike and a slower depolarization wave. Strong support of this idea has been provided by the recent voltage-clamp experiments in frog atria1 trabeculae.g These experiments of Rougier et a1.g have shown conFrom the Division of Cardiology, Department of Medicine, University of Kentucky School of Medicine, Lexington, Ky. Address for reprints: Borys Surawicz, MD, Department of Medicine, Division of Cardiology, University of Kentucky Medical Center, Lexington, Ky. 40506.

elusively that the inward depolarizing membrane current flows through two separate “channels”: a rapid, pure sodium channel and a slow “mixed” sodium-calcium channel. The rapid channel can be selectively blocked by tetrodotoxin, and the slow channel by manganese and lanthanides.7,g Vassort et a1.l’ have shown that adrenaline activates the slow channel. In 1969 Carmeliet and Vereeckell repeated and extended the original experiments of the Freiburg group using bovine Purkinje fibers. In their experiments, adrenaline induced propagated action potentials with a slow upstroke in sodium-free solutions and also when the rapid inward sodium current was inactivated by increased extracellular potassium concentration or tetrodotoxin. Such responses did not occur in calcium-free solutions unless calcium was substituted by another divalent ion such as strontium. These experiments confirmed the action of adrenaline on the slow channel and suggested that calcium current was responsible for the slow depolarization. In 1970 Pappano12 demonstrated a strict mathematical correlation between the amplitude of spikes induced by depolarization and the external calcium concentration, and thereby established the predominant, if not the exclusive role of calcium in the production of adrenaline-dependent depolarizations. These studies justify the term “calcium spikes” for action potentials generated in tissue in which the rapid inward sodium current is inactivated. The effect of catecholamine on the “calcium spikes” is due to beta adrenergic action. Depolarized myocardium is more sensitive to isoproterenol than to adrenaline or noradrenaline, and the response is blocked by propranolol. l2 Caffeine and 3’5’ cyclic adenosine monophosphate (AMP) are also capable of inducing similar responses, but their action is weaker than that of catecholamines. l&l4

Slow Calcium Responses and Cardiac Arrhythmias The system of calcium-dependent depolarization appears to be ubiquitous in cardiac muscle since it has been demonstrated in many different types of cardiac fibers in different animal species, including a 9 to 13 day old chick embryo.14 The unique features of the impulse propagation induced by this type of depolarization have been extensively investigated by Cranefield, Hoffman and Wit.l”-lg These investigators have shown that in canine Purkinje fibers depolarized by potassium, and treated with adrenaline, May 1974

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the conduction velocity may be as low as 1 percent of normal,lg and that such slow conduction may be associated with one-way or two-way block, summation, inhibition, reentry and circus movement.‘7J8 Cranefield and his colleaguesi described in detail the differences between the characteristics of the fast and the slow responses and proved conclusively that the pathway for reentry and circus movement of the slow responses may be shorter than 1 cm. Theylg also suggested that acute myocardial ischemia could precipitate such reentrant arrhythmias because in this condition the localized depolarization and local release of catecholamines would create conditions particularly favorable to the appearance of slow responses. Some of the reentrant arrhythmias produced in dogs with acute &hernia show evidence of very slow conduction.20l21 This suggests that the depolarizations induced by calcium may, indeed, play an important role in the critical slowing of conduction in the ischemic or otherwise damaged myocardium.

gation of action potentials without the assistance of impulses generated by pacemaker activity in other parts of the heart. Cranefield et al.lg have pointed out that in most experiments the slow response has been stimulus-dependent. However, spontaneous activity in a depolarized myocardium has been observed. Imanishi22 showed a rapid succession of calcium-dependent depolarizations in cardiac Purkinje fibers after depolarizations induced by square cathodal current pulses. In our laboratory23 we have shown that spontaneous depolarizations occurred after the release of voltage-clamp in short canine Purkinje fibers, and that the amplitude of these depolarizations correlated with the strength of the inward current flowing at the time of clamp release. These observations suggest that when the circumstances are appropriate, either single or repetitive depolarizations could arise spontaneously in the depolarized myocardium due to local action of calcium, catecholamines or other depolarizing stimuli. Future studies will undoubtedly focus on this and other aspects of calcium spikes. The new knowledge of these phenomena may bring us significantly closer toward understanding the mechanism of cardiac arrhythmias in patients with acute myocardial infarction and sudden cardiac death.

Slow Calcium Response and Spontaneous Myocardial Depolarization Another interesting problem emerging from the studies of calcium spikes concerns the possibility that slow depolarizations can induce spontaneous propa-

References 1 Engstfeld G, Antoni H, Fleckenstein A: Die Restitution der Erregungsfortleitung und Kontraktionskraft des K+-gelahmten Frosch- und Saugetiermyokards durch Adrenalin. Pfluegers Arch 273:145-163, 1961 2. Hodgkin AL, Huxley AF: Currents carried by sodium and potassium ions through the membrane of the giant axon of Loligo. J Physiol (Lond) 116:449-472, 1952 3. Weklmann S: Elektrophysiologie der Herzmuskelfaser. Bern and Stuttgart, Verlag Hans Huber, 1956 4. Reefer H: Strom-Spannungsberziehungen von Purkinje-Fasern bei verschiinen extracellularen Calcium-Konzentrationen und unter Adrenalinwirking. Pfluegers Arch 287:357-367, 1966 5. Reeler H: The dependence of slow inward current in Purkinje fibers on the extracellular calcium-concentration. J Physiol (Lond) 192:479-492. 1967 6. Beefar GW Jr, Reuter H: Membrane calcium current in ventricular myocardil fibers. J Physiol (Lond) 207:191-209, 1970 7. Reuter H: Divalent cations as charge carriers in excitable membranes. In, Progress in Biophysics and Molecular Biology, Vol 28 (Butler JAV. Noble D, ed). Oxford and New York, Pergamon Press. 1973 a. Paes de Carvalho A, Hoffman BF, Carvalho D: Two components of the cardiac action potential. I. Voltage-time course and the effect of acetylcholine on atrial and nodal cells of the rabbit heart. J Gen Physiol54:607-635, 1969 9. Rougler 0, Vaasorl 0, Garnler D, et al: Existence and role of a slow inward current during the frog atrial action potential. Pfluegers Arch 308:91-110, 1969 10. Vaaaerf 0, Rougler 0, Garnler D, et al: Effects of adrenaline on membrane inward currents during the cardiac action potential. Pfluegers Arch 308:70-81, 1969 11. Carmellet E, Veraecke J: Adrenaline and the plateau phase of the cardiac action potential. Pfluegers Arch 313:300-3 15, 1969 12. Pappano A& Calcium dependent action potentials produced by


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catecholamines in guinea pig atrial muscle fibers depolarized by potassium. Circ Res 27:379-390, 1970 Verdonck F, Bus&en P, Carmellet E: Ca-action potentials and contractions of heart muscle in Na-free solutions. Influence of caffeine. Arch Int Physiol Biochim 80:167-169. 1972 Shlgenobu K, Sperelakis N: Calcium current channels induced by catecholamines in chick embryonic hearts whose fast sodium channels are blocked by tetradotoxin or elevated potassium. Circ Res 31:932-952. 1972 Craneflekf PF, Klein HO, Hoffman BF: Conduction of the cardiac impulse. I. Delay, block and one-way block in depressed Purkinje fibers. Circ Res 28:199-219, 1971 Craneileld PF, Hoffman BF: Conduction of the cardiac impulse. II. Summation and inhibition. Circ Res 28:220-233, 1971 Wi AL, Hoffman BF, Cranefield PF: Slow conduction and reentry in the ventricular conducting system. I. Return extrasystole in canine Purkinje fibers. Circ Res 30:1-10, 1972 WH AL, Cranefleld PF, Hoffman BF: Slow conduction and reentry in the ventricular conducting system. II. Single and sustained circus movement in networks of canine and bovine Purkinje fibers. Circ Res 30:1 l-22, 1972 Cranefleld PF, Wit AL, Hoffman BF: Conduction of the cardiac impulse. Ill. Characteristics of very slow conduction. J Gen Physiol 59:227-246, 1972 Baschierl L, Palegl L, Pulettl M: Experimental study of the pathogenesis of ventricular extrasystoles. Cardiologia 50:366374, 1967 Han J: Mechanisms of ventricular arrhythmias associated with myocardial infarction. Am J Cardiol 24:800-813, 1969 lmanlshl S: Calcium-sensitive discharges in canine Purkinje fibers. Jap J Physiol21:443-463, 1971 Arlta M, Surawlcr B: Depolarization and action potential duration in cardiac Purkinje fibers. Circ Res 33:39-47. 1973