Pavel Bravený

Electromechanical correlations in the mammalian heart muscle

SummaryThe relationship between contractility and the duration of the action potential (AP) was examined on sheep trabeculae, employing the sucrose gap technique in order to control the duration of AP, and on guinea pig papillary muscles under conditions which alter both the AP configuration and the contractile response. Three significant types of electromechanical correlation were proved:A.The time to peak tension—or more generally the time to the onset of terminal relaxation—closely follows the duration of AP. The level of the membrane potential, at which contraction turns into relaxation is variable, very likely depending on the intracellular concentration of Ca.B.A linear relation was ascertained between the duration of a single prolonged AP or the sum of duration of APs in an interpolated volley of extrasystoles, and total extra tension developed in all augmented contractions. This relation probably reflects loading of the coupling mechanism by activator Ca.C.A steady relation was found between the positive inotropic effect of increased frequency or concentration of Ca in the medium, of decreased temperature and of a prolonged AP on the one hand, and a concurrent increase of the rate of repolarization on the other. It is assumed that this relation represents a parallel effect of Ca on the contractile machine and on movements of other ions across the membrane (probably increased K efflux). It is suggested that this characteristics may play the role of a negative feed back mechanism. The described correlations are constantly reproducible and statistically significant.ZusammenfassungDie Beziehung zwischen Kontraktilität und Aktionspotentialdauer wurde mit zwei verschiedenen experimentellen Ansätzen verfolgt: einmal mit Trabekeln vom Schaf, bei denen durch die „sucrose gap”-Methode die Dauer des AP kontrolliert werden konnte, einmal an Papillarmuskeln von Meerschweinchen, unter solchen Versuchsbedingungen, bei denen sich die Konfiguration des AP und die mechanische Antwort ändern. Es wurden drei bedeutende Korrelationstypen festgestellt:A.Die Gipfelzeit, oder allgemeiner, die Zeit bis zu dem Anfang der terminalen Erschlaffung ist eng mit der Dauer des AP korreliert. Die Höhe des Potentials, bei dem die Kontraktionsphase in die Relaxationsphase übergeht, ist veränderlich. Allen Anzeichen nach hängt sie von der intracellulären Ca-Konzentration ab.B.Es fand sich eine lineare Korrelation zwischen der Dauer eines einzelnen verlängerten AP bzw. der Dauer sämtlicher Aktionspotentiale in einer interpolierten Salve von Extrasystolen und dem Gesamtzuwachs der mechanischen Spannung. Diese Beziehung spiegelt wahrscheinlich die Beladung des Koppelungssystemes mit Kontraktions-wirksamen Ca++ wider.C.Weiterhin wurde eine konstante Beziehung gefunden zwischen der treppenförmigen Kontraktionszunahme nach einem Frequenzanstieg, nach Erhöhung der Ca-Konzentration im Medium, nach Abkühlung oder nach der Verlängerung des AP auf der einen Seite und der parallelen schrittweisen Verkürzung der Repolarisation auf der anderen Seite. Es wird vermutet, daß dieser Beziehung der gleichzeitige Einfluß der Ca-Ionen auf den contractilen Apparat und auf die transmembranären Ionenbewegungen (möglicherweise die Erhöhung des K+-Effluxes) zugrunde liegt. Diese charakteristischen Beziehungen könnten die Grundlage für eine negative Rückkoppelung sein. (Die beschriebenen Korrelationen sind konstant reproduzierbar und statistisch bedeutungsvoll.)

Activity-dependent changes of slow inward current in ventricular heart muscle

Abstract1.The relationships between membrane voltage, contractile force and slow inward current were studied in cat and dog papillary muscles or trabeculae employing the double sucrose gap voltage clamp technique. The experiments were performed at 30°C and the preparations were stimulated at a frequency of 0.5 Hz.2.The known relationships between steady state contractile force, slow inward current and membrane voltage were confirmed.3.Under non-steady state conditions the slow inward current decreases during ascending and increases during descending contraction staircases when the clamp steps of the test train exceed about 60 mV from resting level. Depolarization clamp steps below 60 mV produce parallel changes of the slow inward current and contractile force. Those clamp conditions which increase the contractile force shift the threshold of Isi and of contraction towards more negative values.4.During ascending staircases an increasing background outward current was regularly observed together with diminshing slow inward current.5.The reported current transients agree with the changes of action potential configuration during mechanical transients: the prolongation of plateau during descending staircases corresponds to an increase, and the shortening of action potential during late repolarization corresponds to a decrease of slow inward current in the respective voltage ranges.6.The slow inward current was tentatively separated into two components. The main component is inversely proportional to contractile force and it exhibits the well known current-voltage relationship for this current. The other one is directly proportional to contractile force and may be related to a regenerative response of reticular membranes.

Effect of epinephrine on the duration of action potential of papillary muscles

Im Gegensatz zur Kontrollbedingung (Tyrodelösung 1.8 mM Ca, 31°C, Reizfrequenz 30/min) ruft Adrenalin 6×10−6 M im Ca-freien Milieu eine significante Verlängerung der Aktionspotenziale hervor. Die Zugabe von Ca2+ kehrt die Aktionspotenzialdauer mit voller Entwicklung der positiv inotropen Wirkung zu Ausgangswerten zurück.

A contraction-related component of slow inward current in dog ventricular muscle and its relation to Na(+)-Ca2+ exchange.

1. The slow inward current component related to contraction (Isic) was studied in voltage clamp experiments on canine ventricular trabeculae at 30 degrees C with the aims of (a) estimating its relation to electrogenic Na(+)‐Ca2+ exchange and (b) comparing it with similar currents as reported in cardiac myocytes. 2. Isic may be recorded under conditions of augmented contractility in response to depolarizing pulses below the threshold of the classic slow inward current (presumably mediated by L‐type Ca2+ channels). In responses to identical depolarizing clamp pulses the peak value of Isic is directly related to the amplitude of contraction (Fmax). Isic peaks about 60 ms after the onset of depolarization and declines with a half‐time of about 110 ms. 3. The voltage threshold of Isic activation is the same as the threshold of contraction. The positive inotropic clamp preconditions shift both thresholds to more negative values of membrane voltage, i.e. below the threshold of the classic slow inward current. 4. Isic may also be recorded as a slowly decaying inwardly directed current ‘tail’ after depolarizing pulses. In this representation the peak value of Isic changes with duration of the depolarizing pulses, again in parallel with Fmax. In response to pulses shorter than 100 ms both variables increase with depolarization time. If initial conditions remain constant, further prolongation of the pulse does not significantly influence either one (tail currents follow a common envelope). 5. Isic differs from classic slow inward current by: (a) its direct relation to contraction, (b) the slower decay of the current tail on repolarization, (c) slower restitution corresponding to the mechanical restitution, (d) its relative insensitivity to Ca(2+)‐blocking agents (the decrease of Isic is secondary to the negative inotropic of Ca(2+)‐blocking agents (the decrease of Isic is secondary to the negative inotropic effect) and (e) its disappearance after Sr2+ substitution for Ca2+. 6. The manifestations of Isic in multicellular preparations do not differ significantly from those reported in isolated myocytes (in contrast to calcium current). 7. The analysis of the correlation between Isic and Fmax transients during trains of identical test depolarizing pulses at variable extra‐ and intracellular ionic concentrations (changes of [Ca2+]o, 50% Li+ substitution for Na+, strophanthidin) indicate that the observed effects conform to the predictions based on a quantitative model of Na(+)‐Ca2+ exchange. 8. It is concluded that Isic is activated by a transient increase of [Ca2+]i, in consequence of the release from the reticular stores.(ABSTRACT TRUNCATED AT 400 WORDS)

Voltage dependence of force- and slow inward current restitution in ventricular muscle

SummaryThis study was aimed to assess the relationship among the voltage-dependent processes underlying the excitation-contraction coupling, viz. force restitution (FR), transmembrane Ca fluxes and Ca release. The experiments (n=22) were performed on voltage-clamped dog trabeculae in which force and slow inward current were measured. Standard steady-state was achieved by clamp driving at 0.5 Hz, 300 ms, 70 mV depolarizing pulses from holding=resting potential at 30°C. Voltage and duration of single pulses and intervals in between were varied according to five protocols.The voltage dependence of Ca release was tested by varying single pulses at equal steady-state, i.e., at equal Ca availability. Contractions could be elicited in absence of ICa (20–30 mV step) and in the presence of disproportionately small ICa (above 80 mV).The voltage dependence of Ca availability for the release was tested by constant test pulses following either a variable conditioning clamp pulse or a period of rest at a variable voltage. After a low voltage pulse and, hence, depressed or absent ICa, the test contraction is diminished in presence of normal or even augmented Isi at any test interval (i.e., FR is depressed). Diminished Ca influx thus reduces the Ca availability of the subsequent beat. During prolonged depolarization (by 60 mV and more) a tonic response appears, but a phasic response cannot be elicited (FR is inhibited). Upon subsequent repolarization FR starts from zero and is significantly enhanced.It is concluded that, during depolarization, Ca release channels are in an open state, thus allowing free recirculation of Ca, but no build-up of a sufficient Ca gradient at the release site.

Control of cardiac performance by Ca-turnover

A quantitative model of Ca-turnover in cardiac cells that incorporates negative feedback modulation of sarcolemmal calcium transport (via Ca channels and Na/Ca exchange) has been designed. The Na/Ca exchange current was expressed as INaCa = INaCar + ΔNaca. The component INaCar reflects slow changes of Ca2+ and Na+ concentrations and depends on the Na/K pump. ΔINaCa is the fast component related to the Ca2+ transient. The single input to the model is an arbitrary sequence of intervals between excitations; outputs are sequences of calcium amounts transferred among the compartments during individual intervals. The model operates with a combination of discrete variables (amounts of Ca transferred during contraction, relaxation and rest) and continuous variables — slow changes in ionic concentrations. Since the model is not formalistic but respects the nature of the underlying elements of the system, it enables us to simulate the known effects of cardiotropic drugs or to predict their unknown mechanisms by visualizing the changes in individual Ca compartments. By altering the parameters, the model also simulates the known species and tissue differences in rate-dependent phenomena.