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:

Specific Pharmacology of Calcium in Myocardium, Cardiac Pacemakers, and Vascular Smooth Muscle

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.

Reconstruction of the action potential of ventricular myocardial fibres

Calcium antagonists (slow channel blocking agents) are a very heterogeneous group of agents with dissimilar structural, electrophysiologic and pharmacologic properties. Nifedipine is a potent, long-acting vasodilator that has proved highly efficacious in relieving anginal symptoms caused by coronary vasospasm. In vivo, it exerts no myocardial depressant effects and has no antiarrhythmic properties. Treatment with nifedipine can safely be combined with administration of a beta receptor blocking agent. VErapamil prolongs atrioventricular (A-V) conduction (A-H interval) in a dose-dependent manner. It is the drug of choice for the treatment of reentrant supraventricular arrhythmias, irrespective of whether reentry occurs within the A-V node or through an accessory pathway (the Wolff-Parkinson-White syndrome). Verapamil is only moderately effective as an antianginal agent. Diltiazem is efficacious for the treatment of angiospastic angina, but its value as an antiarrhythmic agent remains to be delineated.

Comparative pharmacology of calcium antagonists: Nifedipine, verapamil and diltiazem

Organic inhibitors of calcium influx prevent outward as well as inward current through cardiac calcium channels but do not slow current activation. Although block is antagonized by raising external calcium or barium concentrations, the competitive effect of permeant cations does not occur at the same cation binding site at which inorganic blockers act. Organic drugs show varying degrees of use-dependent block, due in part to blockade of open channels. Nitrendipine blockade of calcium currents requires doses >100-fold higher than expected from radioligand binding to isolated membranes.

Mechanism of calcium channel blockade by verapamil, D600, diltiazem and nitrendipine in single dialysed heart cells

https://www.cell.com/biophysj/pdf/S0006-3495(92)81615-6.pdf

Theory of excitation-contraction coupling in cardiac muscle

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.

Differentiation of the transmembrane Na and Ca channels in mammalian cardiac fibres by the use of specific inhibitors

According to earlier studies on mammalian papillary muscles, Ni and Co ions reduce the Ca dependent mechanical response whilst the action potential persists. In order to clarify the mode of action of these cations together with those of Mn their effects on the transmembrane fast Na and of the slow Ca currents were studied in voltage clamp experiments using the double sucrose gap technique. By a conditioning clamping procedure the Ca current was separated from the Na current. The following results were obtained:

1.

Ni ions (2 mM) and Co ions (2 mM) strongly depress the Ca conductivity of the membrane. The same blockade was observed under the influence of Mn ions (2 mM). Even in the continued presence of Ni, Co or Mn the transmembrane Ca conductivity can be restored to a varying degree by increasing the extracellular Ca concentration.




2.

In contrast to this strong inhibitory effect on the transmembrane Ca inward movements the fast transient Na current is only slightly affected if at all.




3.

Apart from their selective inhibitory action on the transmembrane Ca current, Co ions show some additional features a) enhancement of its inhibitory action by repeated membrane depolarizations. b) Co-induced replacement of the slow Ca inward current by a transitory fast inward current component, c) synergetic effects of Co with Ca in restricting the fast Na current.




4.

The selective inhibition of the transmembrane Ca conductivity clearly demonstrates the existence of a separate channel for Ca which is independent from the fast Na channel of the membrane.

Selective inhibition of the transmembrane Ca conductivity of mammalian myocardial fibres by Ni, Co and Mn ions.

Measurements of transmembrane potentials were performed under different contractile conditions on isolated cat papillary muscles. It was found that the duration of the action potential (within limits of about 20%) depends on the mode of contraction. Isotonic shortening tends to prolong, isometric tension development tends to shorten the duration of the action potential. As a result of the action potential alterations negative or positive inotropic mechanical transients are observed during 5–10 subsequent beats. The decrease in action potential duration is roughly proportional to the force development, and the increase of action potential duration is related to the shortening velocity. By applying a controlled stretch the shortening velocity of the contractile element (V

 CE
 ) was reduced below its value during purely isometric conditions. A further decrease of the action potential duration was observed. IncreasingV

 CE
 by release experiments increased the action potential duration beyond that observed under lightly loaded isotonic contractions. A quick release taking place after repolarization is complete produces a new distinct wave of depolarization (10–15 mV) which can sometimes initiate a new action potential. The quick release experiments fascilitated the estimation of the time delay of the feedback interaction which is less than 10 msecs. The possibility that passive geometrical changes of the plasma membrane is a causitive factor of the described phenomenon was experimentally excluded. Alternative explanations are discussed. It seems likely that a controlling parameter of this excitation contraction feedback system is contained in the force velocity relation of the contractile element influencing the internal Ca++-transients by its mode of contraction.

Feedback interaction of mechanical and electrical events in the isolated mammalian ventricular myocardium (cat papillary muscle)

Calcium-movement controlling cardiac contractility. II. Analog computation of cardiac excitation-contraction coupling on the basis of calcium kinetics in a multi-compartment model ☆ ☆☆

In order to study the kinetics of inactivation and recovery of the slow inward current in the mammalian ventricular myocardium voltage clamp experiments using the double sucrose gap technique were performed on isolated trabeculae and papillary muscles of cats. The separation of the slow inward current from the fast Na current was achieved by use of the conditioning clamp procedure. 1. The decay of the Ca current reflects the inactivation which develops due to depolarization. The rate of inactivation depends upon the membrane potential. Excess Ca (8.8 mM) accelerates the inactivation speed indicating that Ca ions not only act as charge carrier of the slow inward current but might influence in addition the kinetics of the slow membrane channel. In the presence of a lowered temperature a deceleration of inactivation (Q10 2.3) occurs. 2 If the membrane is repolarized a recovery process takes place restoring the availability of the slow membrane channel. As the inactivation the recovery rate depends upon the membrane potential. Excess Ca causes an acceleration whereas a decrease in temperature diminishes the recovery speed (Q10 2.3). Consequently, the Ca supply to the myocardial cell can be modified not only by changes of the transmembrane Ca concentration gradient or by an alteration of the Ca conductance of the slow channel but also by changes in the degree of recovery after a preceding Ca current. 3. Compared with the inactivation the recovery proceeds very slowly. Assuming that this slow recovery represents an inherent kinetic feature of the slow channel the kinetics of inactivation and removal of inactivation are not describable by a single inactivation variable (called as f by Reuter, 1973) which is of the Hodgkin-Huxley type. If a second inactivation variable (called as l) would be introduced additionally a formulation of the inactivation-recovery process of the slow membrane channel on the basis of the Hodgkin-Huxley model becomes feasible.

H. Krause

Papers

Differentiation of the transmembrane Na and Ca channels in mammalian cardiac fibres by the use of specific inhibitors

Selective inhibition of the transmembrane Ca conductivity of mammalian myocardial fibres by Ni, Co and Mn ions.

Feedback interaction of mechanical and electrical events in the isolated mammalian ventricular myocardium (cat papillary muscle)

Calcium-movement controlling cardiac contractility. II. Analog computation of cardiac excitation-contraction coupling on the basis of calcium kinetics in a multi-compartment model ☆ ☆☆

Kinetics of inactivation and recovery of the slow inward current in the mammalian ventricular myocardium.