R. Kaufmann

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

SummaryMeasurements 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 (VCE) was reduced below its value during purely isometric conditions. A further decrease of the action potential duration was observed. IncreasingVCE 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.ZusammenfassungAn isolierten Katzenpapillarmuskeln wurden intracelluläre Potentialmessungen bei verschiedenen Kontraktions-Bedingungen durchgeführt.Es wurde gefunden, daß die Aktionspotentialdauer (in Grenzen von etwa 20%) von der Kontraktionsform abhängig ist. Während isotonischer Verkürzung wird das Aktionspotential verlängert, bei isometrischer Spannungsentwicklung abgekürzt.Als Folge dieser Aktionspotential-Veränderungen entwickeln sich treppenartige Zu-oder Abnahmen der mechanischen Aktivität während der folgenden 5–10 Kontraktionen.Durch Anwendung einer kontrollierten Dehnung konnte die Verkürzungsgeschwindigkeit des contractilen Elements (VCE) kleiner als bei isometrischen Bedingungen gemacht werden. Dabei wurde eine weitere Aktionspotentialverkürzung beobachtet. WurdeVCE dagegen durch Entlastungsexperimente (quick release) über die bei leicht belasteten isotonischen Kontraktionen entwickelte Verkürzungsgeschwindigkeit hinaus erhöht, so ergab sich eine weitere Zunahme der Aktionspotentialdauer.Release-Experimente, die nach der vollständigen Repolarisation durchgeführt wurden, führten zur Auslösung einer neuen Repolarisationswelle von 10–15 mV Amplitude. Zuweilen wurde hierdurch ein neues Aktionspotential ausgelöst.Die Entlastungsexperimente ermöglichten die Abschätzung der “mechanoelektrischen Latenzzeit” des beschriebenen Rückkoppelungssystems. Diese betrug weniger als 10 msec.Die beschriebenen Phänomene lassen sich vermutlich nicht auf Änderungen der membranären Oberflächengeometrie zurückführen.Andere Erklärungsmöglichkeiten werden als Arbeitshypothesen diskutiert. Es erscheint zumindest sicher, daß der Control-Parameter des beschriebenen Rückkoppelungssystems in der Kraft-Geschwindigkeits-Relation des contractilen Elementes selbst zu suchen ist. Möglicherweise bestimmt dessen Kontraktionsform die Dynamik der kontraktionswirksamen Calciumbewegungen.

Disorder in Excitation-Contraction Coupling of Cardiac Muscle from Cats with Experimentally Produced Right Ventricular Hypertrophy

The contractile and electrical activity of papillary muscles from hypertrophied right ventricles of cats with artificial stenosis of the pulmonary artery was investigated. Contractility was considerably decreased along the entire force-velocity relationship, whereas no measurable alterations could be detected in the electrical activities as recorded by intracellular microelectrodes. By supramaximal Ca2+ activation, the contractility of both the hypertrophied and the normal control preparations was increased to about the same final value. These findings are consistent with the concept that a disorder in the mechanism of excitation-contraction coupling underlies the depressed contractile state of hypertrophied cardiac muscle. In addition, it could be shown that the increase in volume of each cellular unit is clearly related to the decrease in contractility. This can tentatively be explained by the following assumptions. If the amount of Ca2+ entering the cell per unit area is not changed in hypertrophy, then in a cell of increased diameter, the amount of Ca2+ distributed per unit cell volume will be diminished. Since the excitation-contraction coupling of the heart is very sensitive to Ca2+, this Ca2+ deficit should be reflected in a depression of contractility.

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

Abstract A computer model for excitation-contraction coupling in mammalian cardiac cells was designed based on calcium movements in a multicompartment system. The model includes an extracellular space of constant calcium concentration from which calcium crosses the membrane and reaches the myoplasma by a voltage and time dependent process. The free myoplasmic calcium content is considered to reflect the intensity of the active state. Calcium can be taken up either by a carrier-sustained two step reaction into a compartment representing some parts of the longitudinal system or into another pool representing mitochondria. Calcium can leave the cell or can be released again into the myoplasma by a second order reaction. The behaviour of the model is compared to that of living cardiac ventricular muscle. The model correctly predicts the following groups of inotropic phenomena. Steady state and dynamic force-frequency relationships, positive and negative staircases after both changes of frequency and AP-duration, mechanical transients after a period of rest and aftercontractions.

Right ventricular hypertrophy in the cat--an electrophysiological and anatomical study.

Abstract In right ventricular hypertrophy induced by pulmonary artery coarctation the transmembrane electrical activity of papillary muscles and trabeculae has been studied and correlated to anatomic and electrocardiographic findings. The results of an experimental group with mild hypertrophy (group B, 25 days of exposure, 10% increase of free wall/body weight ratio) and severe hypertrophy (group C, 35 days of exposure, 23% increase) were compared with those of the control group. The average cell volume increased significantly and width/length ratio was augmented by an expansion of cell diameter. There was no obvious dilatation of the right ventricle and no increase in sarcomere length. Connective tissue increased in the subendocardial muscle layers of the right ventricle. The resting potential was augmented in both groups of hypertrophy; the overshoot of the action potential was unchanged in group B and increased in C. The rate of rise of the action potential was progressively reduced with increasing degree of hypertrophy. This reduction was more marked if action potentials with identical resting potentials were compared in normal and in hypertrophied fibres. The conduction velocity of excitation decreased in group B probably as a result of the reduced rate of rise. Surprisingly, the conduction velocity was again at or above control level in group C despite the further depressed rate of rise. This is probably due to the outstanding increase in cell diameter in group C. The QRS duration of the heart in situ was also prolonged in B and normal or below normal in C. The action potential duration was augmented in both groups of hypertrophy, this was not reflected as a QT prolongation in situ.

Autoregulation of contractility in the myocardial cell

SummaryAn investigation was carried out on isolated cats papillary muscle in order to study displacement effects upon the intensity and the time course of the contractile activity. Displacements occurring before or very early during a contractile cycle produce effects which can be entirely explained on the basis of the cardiac active length-tension relation. Displacements occurring later exhibit additional effects in so far as either stretches or releases induce a drop of contractile activation such that the course of the subsequent tension development is markedly below that of the same displacement applied earlier. In order to separate these effects from those based on the active length-tension correlation experiments were performed in which very short release-stretch or stretch-release operations were applied so that the muscle length was virtually the same at the beginning and at the end of the operation. The results obtained under these conditions can be summarized as follows.The extend to which contractile tension drops after a stretch-release or a release-stretch cycle has been applied depends upon (1) the stimulus intervention interval (2) the length change performed (3) the velocity of displacement during the intervention. It is not dependent on the initial muscle length. Increasing the extracellular Ca-concentration considerably reduces the displacement effects. The results are tentatively explained by assuming an internal feedback loop between a variable of the contractile machinary and the preceding mechanism of activation.

Ca-movement controlling myocardial contractility I

Summary1.Tension development and membrane currents have been measured in cat ventricular fibres applying a double sucrose-gap voltage clamp technique.2.A well defined mechanical threshold was found at which a considerable all-or-non response occurred. This threshold obviously coincided with the threshold potential of the fast inward current (INa). Changes in [Cae] (0.8–7.5 mM) did not separate the two thresholds. Ramp clamps of decreasing steepness shifted the threshold of bothINa and that of tension development towards less negative potentials. Ramp clamps ineffective in elicitingINa did not produce phasic tension development. This suggests that a fast inward current normally triggers the internal Ca release.3.In rhythmically activated preparations the steady state voltage-tension relationship rose roughly in parallel toICa in a S-shaped manner up to about zero potential. With further depolarizations the steady-state tension development tended to decline again. It was concluded that this voltage dependent gain of contractile activation reflects the time integral of transmembrane Ca supply provided from the extracellular space.4.Under steady state conditions peak tension produced by square clamps of a given suprathreshold voltage rose with prolongation of the clamp duration up to a maximum at 500–700 msec. This maximum in turn depended on the clamp potential applied. From the results obtained, a tension-time-voltage relationship has been drawn. Even under very long lasting depolarizations (up to 10 sec) usually no tonic responses occurred.5.A muscle once activated by a suprathreshold square clamp did not respond to a second depolarization unless the membrane had been repolarized to a given level and for a given duration. The amplitude of contractile response to second clamp steps depended in a characteristic manner on both the voltage and the duration of the recovery period.6.Mechanical transients typically observed when either the voltage or the duration of clamp steps had been changed were analyzed in order to obtain information about the kinetics of intracellular Ca movements assumed to take place in a multicompartment model derived from structural and functional observations.

The dependence of cardiac membrane excitation and contractile ability on active muscle shortening (Cat papillary muscle)

Abstract1.A quick release of an isometrically contracting cat papillary muscle results in a depression of the ability to redevelop tension (deactivation) and an increase in the duration of the accompanying action potential (prolonged depolarization). The nature of the mechanical perturbation influencing both phenomena was investigated.2.The prolongation of the action potential depends on the amplitude of the release and the time it is applied and, provided quick release-quick restretch cycles of less than 50 ms are used, on the duration of the cycle.3.No change in action potential duration is observed, if initial muscle length, or the velocity of shortening is altered, or if the muscle is stretched at any time during contraction.4.Although stretches and releases both have a “deactivating” effect on the muscle the effect is more pronounced with releases. This difference in “deactivation” is related to the prolongation of the action potential in so far as it is also controlled by the time and extent of release and release-restretch cycle duration, and is independent of shortening velocity.5.Caffeine (8 mmol/l) in the bathing solution prolongs isometric tension development whilst the duration of the action potential is relatively unchanged. Under these conditions release-restretch cycles applied at times when the membrane has apparently repolarized, produce a deactivation and an after depolarization which can reach threshold to elicite an action potential.6.If the membrane is partially depolarized by increasing extracellular potassium to 20 mmol/l, release-restretch cycles still induce deactivation but no change in the action potential.7.The results are in keeping with the hypothesis that shortening during contraction partly contributes to the deactivating effect by reducing the concentration of internal free ionic calcium. This change in [Ca]i decreases the outward potassium current to produce a prolongation of depolarization which can take the form of an increase in action potential duration or an afterdepolarization wave.

Nachweis einer elektromechanischen Koppelungs-Insuffizienz als Ursache der gestorten Kontraktilitat des hypertrophierten Myokards *)

Untersuchungen zum funktionellen Status des chronisch hypertrophierten Herzmuskels sind bisher nahezu ausschlieBlich am Ganzherzen in situ durchgefuhrt worden. Die dabei erfasbaren Parameter der mechanischen Herzaktion betreffen—wie wir heute morgen gehort haben—fast immer die Gesamtleistung des Herzens als Pumpe, lassen jedoch im allgemeinen keine Ruckschlusse auf den kontraktilen Status der einzelnen Herzmuskelzelle zu. Erst 1967 haben Spann, Buccino, Sonnenblick und Braunwald Papillarmuskeln aus hypertrophierten Rechtsherzen der Katze einer genaueren muskelmechanischen Analyse unterzogen. Sie konnten erstmals klar zeigen, das im chronisch hypertrophierten Myokardgewebe die Kontraktilitat der einzelnen Zelle ganz erheblich vermindert ist, liesen die entscheidende Frage aber ungeklart, welche gestorte Elementarfunktion in der Herzmuskelfaser fur die Leistungsminderung verantwortlich sein konnte.