Membrane calcium current in ventricular myocardial fibres
TL;DR: A slow inward current in ventricular preparations of the dog heart can be measured by the voltage clamp method without interference from the initial rapid sodium current if the sodium system is inactivated by conditioning depolarization.
Abstract: 1. A slow inward current in ventricular preparations of the dog heart can be measured by the voltage clamp method without interference from the initial rapid sodium current if the sodium system is inactivated by conditioning depolarization.2. The slow inward current is very sensitive to variation in [Ca](o). It occurs above the equilibrium potential of I(Na) immediately after changing the bathing fluid to a sodium-free solution and persists under this condition for a long time without much alteration, while I(Na) is rapidly abolished. Tetrodotoxin and [Mg](o) have no effect on this current component. These results strongly support the view that the slow inward current in cardiac tissue is carried by calcium ions.3. The threshold for initiation of the calcium current is around -35 mV in Tyrode solution and is shifted to more negative potentials by either increasing [Ca](o) or reducing [Na](o).4. Calcium sensitive inward current tails associated with repolarization are assumed to represent a proportional measure of calcium conductance activated during the preceding depolarization. Calcium conductance declines rapidly with time in the inside negative potential range and slowly at positive potentials. The time constants for this ;inactivation' process vary between 40 and 700 msec in the potential range -35 to +50 mV.5. By using instantaneous current-voltage relations the reversal potential of calcium current was estimated to be about +60 mV in normal Tyrode solution. As shown in the Appendix, however, the calcium equilibrium potential cannot be considered to be constant.6. The importance of the calcium current for the plateau of the cardiac action potential is discussed.
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TL;DR: In a wide variety of excitable cells the transmembrane exchange of the monovalent marine cations Na and K can be considered the substantial basis of bioelectric membrane activity, whereas Ca ions are required as mediators when, by this superfi cial process, intracellular reactions such as muscular contraction, glandular secre tion, or liberation of transmitter substances are initiated.
Abstract: The essential connection of the basic physiological processes of excitation and contraction with transmembrane movements of Na, K, and Ca ions probably origi nates from an early stage of cellular evolution. Despite innumerable modifications the fundamental processes that developed in the ocean have not undergone major changes during the course of development of higher forms of animal life. Thus in a wide variety of excitable cells the transmembrane exchange of the monovalent marine cations Na and K can be considered the substantial basis of bioelectric membrane activity, whereas Ca ions are required as mediators when, by this superfi cial process, intracellular reactions such as muscular contraction, glandular secre tion, or liberation of transmitter substances are initiated ( 1, 2). Ca ions can exert this messenger function either in a primitive way, by penetrating into the intracellu lar space across the depolarized cell membrane or, at a more advanced stage of evolution, by being released from intracellulariy located endoplasmic stores. As to contractile tissues, the development of large endoplasmic Ca pools is most obvious in skeletal muscle, whereas myocardial fibers and, particularly, smooth muscle cells are less specialized in this respect. The natural consequences are as follows:
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TL;DR: A mathematical model of membrane action potentials of mammalian ventricular myocardial fibres is described, based as closely as possible on ionic currents which have been measured by the voltage‐clamp method.
Abstract: 1. A mathematical model of membrane action potentials of mammalian ventricular myocardial fibres is described. The reconstruction model is based as closely as possible on ionic currents which have been measured by the voltage-clamp method.2. Four individual components of ionic current were formulated mathematically in terms of Hodgkin-Huxley type equations. The model incorporates two voltage- and time-dependent inward currents, the excitatory inward sodium current, i(Na), and a secondary or slow inward current, i(s), primarily carried by calcium ions. A time-independent outward potassium current, i(K1), exhibiting inward-going rectification, and a voltage- and time-dependent outward current, i(x1), primarily carried by potassium ions, are further elements of the model.3. The i(Na) is primarily responsible for the rapid upstroke of the action potential, while the other current components determine the configuration of the plateau of the action potential and the re-polarization phase. The relative importance of inactivation of i(s) and of activation of i(x1) for termination of the plateau is evaluated by the model.4. Experimental phenomena like slow recovery of the sodium system from inactivation, frequency dependence of the action potential duration, all-or-nothing re-polarization, membrane oscillations are adequately described by the model.5. Possible inadequacies and shortcomings of the model are discussed.
1,414 citations
TL;DR: The model takes account of extensive developments in experimental work since the formulation of the M.N. Noble equations, and successfully account for all the properties formerly attributed to i $\_{K2}$ , as well as giving more complete descriptions of i $\_K$ and i $\-K$ .
Abstract: Equations have been developed to describe cardiac action potentials and pacemaker activity. The model takes account of extensive developments in experimental work since the formulation of the M.N.T. (R. E. McAllister, D. Noble and R. W. Tsien, J. Physiol., Lond. 251, 1-59 (1975)) and B.R. (G. W. Beeler and H. Reuter, J. Physiol., Lond. 268, 177-210 (1977)) equations. The current mechanism i $\_{K2}$ has been replaced by the hyperpolarizing-activated current, i $\_f$ . Depletion and accumulation of potassium ions in the extracellular space are represented either by partial differential equations for diffusion in cylindrical or spherical preparations or, when such accuracy is not essential, by a three-compartment model in which the extracellular concentration in the intercellular space is uniform. The description of the delayed K current, i $\_K$ , remains based on the work of D. Noble and R. W. Tsien (J. Physiol., Lond. 200, 205-231 (1969a)). The instantaneous inward-rectifier, i $\_{K1}$ , is based on S. Hagiwara and K. Takahashi's equation (J. Membrane Biol. 18, 61-80 (1974)) and on the patch clamp studies of B. Sakmann and G. Trube (J. Physiol., Lond. 347, 641-658 (1984)) and of Y. Momose, G. Szabo and W. R. Giles (Biophys. J. 41, 311a (1983)). The equations successfully account for all the properties formerly attributed to i $\_{K2}$ , as well as giving more complete descriptions of i $\_{K1}$ and i $\_K$ . The sodium current equations are based on experimental data of T. J. Colatsky (J. Physiol., Lond. 305, 215-234 (1980)) and A. M. Brown, K. S. Lee and T. Powell (J. Physiol., Lond. 318, 479-500 (1981)). The equations correctly reproduce the range and magnitude of the sodium \`window' current. The second inward current is based in part on the data of H. Reuter and H. Scholz (J. Physiol., Lond. 264, 17-47 (1977)) and K. S. Lee and R. W. Tsien (Nature, Lond. 297, 498-501 (1982)) so far as the ion selectivity is concerned. However, the activation and inactivation gating kinetics have been greatly speeded up to reproduce the very much faster currents recorded in recent work. A major consequence of this change is that Ca current inactivation mostly occurs very early in the action potential plateau. The sodium-potassium exchange pump equations are based on data reported by D. C. Gadsby (Proc. natn. Acad. Sci. U.S.A. 77, 4035-4039 (1980)) and by D. A. Eisner and W. J. Lederer (J. Physiol., Lond. 303, 441-474 (1980)). The sodium-calcium exchange current is based on L. J. Mullins' equations (J. gen. Physiol. 70, 681-695 (1977)). Intracellular calcium sequestration is represented by simple equations for uptake into a reticulum store which then reprimes a release store. The repriming equations use the data of W. R. Gibbons & H. A. Fozzard (J. gen. Physiol. 65, 367-384 (1975b)). Following Fabiato & Fabiato's work (J. Physiol., Lond. 249, 469-495 (1975)), Ca release is assumed to be triggered by intracellular free calcium. The equations reproduce the essential features of intracellular free calcium transients as measured with aequorin. The explanatory range of the model entirely includes and greatly extends that of the M.N.T. equations. Despite the major changes made, the overall time-course of the conductance changes to potassium ions strongly resembles that of the M.N.T. model. There are however important differences in the time courses of Na and Ca conductance changes. The Na conductance now includes a component due to the hyperpolarizing-activated current, i $\_f$ , which slowly increases during the pacemaker depolarization. The Ca conductance changes are very much faster than in the M.N.T. model so that in action potentials longer than about 50 ms the primary contribution of the fast gated calcium channel to the plateau is due to a steady-state \`window' current or non-inactivated component. Slower calcium or Ca-activated currents, such as the Na-Ca exchange current, or Ca-gated currents, or a much slower Ca channel must then play the dynamic role previously attributed to the kinetics of a single type of calcium channel. This feature of the model in turn means that the repolarization process should be related to the inotropic state, as indicated by experimental work. The model successfully reproduces intracellular sodium concentration changes produced by variations in [Na] $\_o$ , or Na-K pump block. The sodium dependence of the overshoot potential is well reproduced despite the fact that steady state intracellular Na is proportional to extracellular Na, as in the experimental results of D. Ellis J. Physiol., Lond. 274, 211-240 (1977)). The model reproduces the responses to current pulses applied during the plateau and pacemaker phases. In particular, a substantial net decrease in conductance is predicted during the pacemaker depolarization despite the fact that the controlling process is an increase in conductance for the hyperpolarizing-activated current. The immediate effects of changing extracellular [K] are reproduced, including: (i) the shortening of action potential duration and suppression of pacemaker activity at high [K]; (ii) the increased automaticity at moderately low [K]; and (iii) the depolarization to the plateau range with premature depolarizations and low voltage oscillations at very low [K]. The ionic currents attributed to changes in Na-K pump activity are well reproduced. It is shown that the apparent K $\_m$ for K activation of the pump depends strongly on the size of the restricted extracellular space. With a 30% space (as in canine Purkinje fibres) the apparent K $\_m$ is close to the assumed real value of 1 mM. When the extracellular space is reduced to below 5%, the apparent K $\_m$ increases by up to an order of magnitude. A substantial part of the pump is then not available for inhibition by low [K] $\_b$ . These results can explain the apparent discrepancies in the literature concerning the K $\_m$ for pump activation.
821 citations
TL;DR: Verapamil and D 600 differ in this respect from common local anesthetic compounds such as xylocaine (lidocaine) or procaine which interfere much more with the transmembrane Na conductivity than with the Ca conductivity.
Abstract: According to earlier studies on mammalian papillary muscles, verapamil and compound D 600 (a methoxy-derivative of verapamil) can abolish the Ca dependent contractile responses completely whilst the Na dependent action potentials persist. In an attempt to clarify the mechanism of action separate measurements of the transmembrane Na and Ca currents have been performed on ventricular trabeculae of cats using a special voltage clamp technique. The following results were obtained:
As a functional significance of this dual membrane transport system it is possible to change the contractile force by inotropic substances which act on the Ca conductivity without a corresponding influence on excitation.
547 citations
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TL;DR: This article concludes a series of papers concerned with the flow of electric current through the surface membrane of a giant nerve fibre by putting them into mathematical form and showing that they will account for conduction and excitation in quantitative terms.
Abstract: This article concludes a series of papers concerned with the flow of electric current through the surface membrane of a giant nerve fibre (Hodgkinet al, 1952,J Physiol116, 424–448; Hodgkin and Huxley, 1952,J Physiol116, 449–566) Its general object is to discuss the results of the preceding papers (Section 1), to put them into mathematical form (Section 2) and to show that they will account for conduction and excitation in quantitative terms (Sections 3–6)
19,800 citations
TL;DR: The identity of the ions which carry the various phases of the membrane current is chiefly concerned with sodium ions, since there is much evidence that the rising phase of the action potential is caused by the entry of these ions.
Abstract: In the preceding paper (Hodgkin, Huxley & Katz, 1952) we gave a general description of the time course of the current which flows through the membrane of the squid giant axon when the potential difference across the membrane is suddenly changed from its resting value, and held at the new level by a feed-back circuit ('voltage clamp' procedure). This article is chiefly concerned with the identity of the ions which carry the various phases of the membrane current. One of the most striking features of the records of membrane current obtained under these conditions was that when the membrane potential was lowered from its resting value by an amount between about 10 and 100 mV. the initial current (after completion of the quick pulse through the membrane capacity) was in the inward direction, that is to say, the reverse ofthe direction of the current which the same voltage change would have caused to flow in an ohmic resistance. The inward current was of the right order of magnitude, and occurred over the right range of membrane potentials, to be the current responsible for charging the membrane capacity during the rising phase of an action potential. This suggested that the phase of inward current in the voltage clamp records might be carried by sodium ions, since there is much evidence (reviewed by Hodgkin, 1951) that the rising phase of the action potential is caused by the entry of these ions, moving under the influence of concentration and potential differences. To investigate this possibility, we carried out voltage clamp runs with the axon surrounded by solutions with reduced sodium concentration. Choline was used as an inert cation since replacement of sodium with this ion makes the squid axon completely inexcitable, but does not reduce the resting potential (Hodgkin & Katz, 1949; Hodgkin, Huxley & Katz, 1949).
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TL;DR: This paper contains a further account of the electrical properties of the giant axon of Loligo and deals with the 'inactivation' process which gradually reduces sodium permeability after it has undergone the initial rise associated with depolarization.
Abstract: This paper contains a further account of the electrical properties of the giant axon of Loligo. It deals with the 'inactivation' process which gradually reduces sodium permeability after it has undergone the initial rise associated with depolarization. Experiments described previously (Hodgkin & Huxley, 1952a, b) show that the sodium conductance always declines from its initial maximum, but they leave a number of important points unresolved. Thus they give no information about the rate at which repolarization restores the ability of the membrane to respond with its characteristic increase of sodium conductance. Nor do they provide much quantitative evidence about the influence of membrane potential on the process responsible for inactivation. These are the main problems with which this paper is concerned. The experimental method needs no special description, since it was essentially the same as that used previously (Hodgkin, Huiley & Katz, 1952; Hodgkin & Huxley, 1952b).
1,547 citations
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