Force-frequency relations in hypertrophic heart muscle: a mathematical model for excitation-contraction coupling.

Static and dynamic chrono-inotropic responses were recorded from both normal and hypertrophic rat auricular myocardium. The slope of the static force-frequency relation for hypertrophic hearts was steeper than that for control hearts. Computer experiments were designed to study the cellular mechanisms underlying the changes in the force-frequency response associated with heart hypertrophy, with the aid of a mathematical model for excitation-contraction coupling in rat heart. A set of equations was derived which permitted to study the effects on the chronoinotropic relations of both the geometrical dimensions of cardiomyocytes and the sarcoplasmic reticulum, and of the variation in activity of mechanisms for Ca movements through the sarcolemma and the sarcoreticular membrane. A comparison of data obtained from simulated and real experiments suggested that the features characteristic of force-frequency relations for hypertrophic heart are a result of an enhanced volume of intracellular Ca-stores rather than of the total volume of the cardiomyocyte.

[The dependence of rhythmic myocardial inotropism on the degree of stretching]. / Zavisimost' ritmoinotropii miokarda ot stepeni rastiazheniia.

The length-dependence of force-frequency relations in rat heart was studied in isometrically contracting papillary muscles. Negative force-frequency relations were observed for all lengths; the slope of the optimal length curve (Lopt) corresponding to peak contractile force during rhythmic pacing at 0.5 Hz, was greater than that for both 0.7 Lopt and 1.20 Lopt. The slope of static force-frequency curve was estimated at various muscle lengths in the range between 70 and 120% of Lopt. It was concluded that: 1) the heart muscle length corresponding to the maximal peak contractile force depends on stimulation frequency; 2) the slope of the force-frequency curve is maximal at the muscle length of 90 to 95% optimal length determined at basis stimulation frequency (0.5 Hz). The operating point for heart muscle in vivo is believed to be biased from the maximum of length-tension curve to its ascending part.

[Chronoinotropic reaction of the hypertrophied myocardium using an electromechanical coupling mathematical model]. / Issledovanie khornoinotropnoi reaktsii gipertrofirovannogo miokarda s pomoshch'iu matematicheskoi modeli élektromekhanicheskogo sopriazheniia.

Static and dynamic chrono-inotropic responses were recorded from both normal and hypertrophic rat auricular myocardium. The slope of the static force-frequency relation from hypertrophied heart was steeper than in the control hearts. The cellular mechanisms underlying changes in the force frequency response associated with hypertrophy of the heart were studied by means of a mathematical model of excitation-contraction coupling. The characteristic features of hypertrophied heart force-frequency relations are shown to be due to the enhanced volume of the intracellular Ca-stores in contrast to the total volume of the cardiomyocyte.

[Evaluation of the effect of cardiotropic agents using a mathematical model of electromechanical coupling]. / Otsenka deistviia kardiotropnykh veshchestv s pomoshch'iu matematicheskoi modeli élektromekhanicheskogo sopriazheniia.

An assessment of the ionic action mechanism of cardiotropic substances with the aid of a mathematical model for excitation-contraction coupling in myocardium is proved to be possible. The technique developed consists in the model parameter identification from the experimental data on electrical and mechanical activity of myocardial strip. The validity of the technique is tested using the known mechanism drugs. An example is given of analysis by the technique suggested of the action mechanism of diltiazem on the rat papillary muscle.

[Action of papaverine on electromechanical coupling in the rat myocardium]. / Issledovanie deistviia papaverina na élektromekhanicheskoe sopriazhenie v miokarde krysy.

It was demonstrated in experiments on the rat heart papillary muscle that papaverine (10(-5)-8 X 10(-5) g/ml) suppressed the contractile activity. The drug exerted the cardiac stimulating effect on the atrial auricular. In both cases papaverine smoothed the rhythm-inotropic activity.

The possible role of intracellular Ca2+-stores in the rhythm-inotropic relationship of frog heart muscle (a simulation study).

The hypothesis that intracellular calcium stores play an essential role in determining force-frequency relationships of frog myocardium was tested quantitatively. A simplified mathematical model of excitation-contraction coupling in frog heart muscle was developed and its behaviour under various patterns of stimulation was analysed by means of computer simulation. The model represents a system of ordinary differential equations for individual fluxes within the cell Ca2+-recirculation system and includes a one-compartmental intracellular pool as opposed to the two-compartmental structure of the mammalian sarcoplasmic reticulum (Kaufmann et al. 1974). The behaviour of the model is consistent with available experimental data concerning the basic rhythm-inotropic characteristics of amphibian myocardium and offers some evidence in favour of the basic concept. Within the framework of the proposed model the staircase phenomena in amphibia were accounted for and the impact of different intracellular Ca-movements on the resulting contractile response and rhythm-inotropic phenomena was elucidated.

[Effect of prodigiozan and pyrogenal on the neural regulation of the frog heart]. / Vliianie prodigiozana i pirogenala na nervnuiu reguliatsii serdtsa liagushki.

The action of bacterial lipopolysaccharides (pyrogenal and prodigiosan) on nervous regulation of the frog heart was studied. Both the substances provoked a considerable increase in the arrest of spontaneous contractility of the atria during stimulation of the extracardial nerves. This effect did not occur after atropine administration, but became manifest during the benzohexonium-induced blockade of conduction in the intracardiac ganglia. The bacterial lipopolysaccharides did not alter acetylcholinesterase activity or myocardial sensitivity to acetylcholine. It is assumed that variation of the nervous regulation of the heart under the effect of prodigiosan and pyrogenal is determined by the effect of these substances on the transmitter release from the presynaptic endings of the extracardial ganglia.

[Mathematical model of electromechanical coupling in the rat myocardium]. / Matematicheskaia model' élektromekhanicheskogo sopriazheniia v miokarde krysy.

A mathematical modelling approach was used to study the negative staircase in the rat papillary muscle. This phenomenon was found to be associated with an excess of the steady-state Ca++-influx in the myocardium cells. The model with a single chamber intracellular Ca-pool simulates satisfactory the experimental data obtained with a standard set of parameter values. It is concluded that the rat myocardium sarcoplasmic reticulum is loaded by Ca++-ions which enter the cell as a potential-independent Ca-influx presumably.

[Role of intracellular calcium stores in the generation of phasic component of K-contraction of the frog myocardium]. / Issledovanie roli vnutrikletochnykh Ca-depo v geneze fazicheskoi komponenty kalievoi kontraktury miokarda liagushki.

Treatment of the frog heart ventricle strip with 24 mM caffeine under condition of repetitive stimulation increases the amplitude of and decelerates relaxation of the phasic component of potassium contraction (100 mM KCl), as well as prevents the phasic component suppression due to 15-min application of Ca-channels blocking agent D-600 (4 X 10(-5) g/ml) or to a long-lasting (15-20 min) inactivity of the preparation. Adrenaline inhibits the phasic component and accelerates its relaxation. Ca++ ions which trigger the phasic component of the K-contraction seems to enter the myoplasm at the onset of membrane depolarization not from the sarcoplasmic reticulum but from some other pools, probably from the hypothetic voltage-dependent caffeine-insensitive submembrane Ca-stores.

[Nature of the phasic component of potassium contracture in the frog myocardium]. / Issledovanie prirody fazicheskoi komponenty kalievoi kontraktury v miokarde liagushki.

High concentrations (4 X 10(-6) g/ml) of D-600 or BAY-1040 applied for 15 min to rhythmically stimulated strip of frog ventricular myocardium inhibited both the twitches and the K-contracture phasic component induced by 200 mM K+ (in the presence of 110 mM Na+). The phasic component, however, also disappeared after a 15-20-min resting in the Ringer solution before substitution of the latter with high K solution. Such a suppression of the phasic component due to myocardiac inactivity was prevented by an increase in Ca ion concentration up to 10 mM or by addition of ouabain (5 X 10(-6) M) to the Ringer solution during the resting period. The increase in [Ca++]0 was effective even after a 15-min preliminary resting in the Ringer solution. In these conditions the amplitude of the phasic component increased as the time of myocardium exposure to high Ca Ringer solution was prolonged from 5 to 15 min. Loading of some intracellular Ca stores seems to be a prerequisite for the phasic K-contractures generation.

[Nature of the dual caffeine-sodium benzoate effect on the tonic component of the potassium contracture of the myocardium in the frog]. / Priroda dvoistvennogo éffekta kofeina-benzoata natriia na tonicheskuiu komponentu kalievoi kontraktury miokarda liagushki.

Application of 12-24 mM caffeine-sodium bensoate (CFB) to the strip of frog ventricular or atrium myocardium in the tonic phase of K-contracture (200 mM KCl) produced a biphasic change of its isometric tension (P): first the rise and then the gradual decay to the "zero" level of P in the control Ringer's solution. A comparison of CFB effect with those of caffeine-base (CF) and sodium bensoate suggests that the first phase of CFB action (increase of P) results from the effect of CF, while the second one (fall of P) is due to the relaxing action of bensoate. Addition of 2 mM tetracaine to the K-rich solution in the tonic phase of K-contracture increases P and totally abolishes the first phase of the CFB effect, whereas the second one remains unchanged. Na-bensoate (12-24 mM) applied during the action of tetracaine induces relaxation of the strip to zero level of P. Blockade of Ca channels by 2.10(-6)-4.10(-5) g/ml D-600 or Bay-1040 does not affect the biphasic action of CFB. The dual CFB effect on the depolarized frog myocardium seems to be due to Ca ions release from the intracellular stores (action of CF) and to an inhibition of the voltage-dependent Ca influx via Na-Ca exchange mechanism (action of bensoate).

[Phase action of ouabain on the electrical and contractile activity of the frog myocardium]. / Fazovoe deistvie ouabaina na élektricheskuiu i sokratitel'nuiu aktivnost' miokarda liagushki.

Ouabain effects (5 X 10(-8)-5 X 10(-5) M) on the isometric contraction and intracellular action potentials were studied on frog atrial and ventricular muscles. It was found that ouabain produced a three-phase action on the electrical and contractile activity of the myocardium under different patterns of stimulation both in normal Ringer and D-600-containing solutions. The data suggest that the three-phase ouabain action is a consequence of its influence on at least two component processes of the excitation-contraction coupling in the frog heart muscle: the slow Na-Ca channels of the sarcolemma and Na+-K+ pump. The contribution of each mechanism depends on the glycoside concentration and the duration of exposure to ouabain.

[Ionic mechanism of the Woodwors staircase]. / Ionnyi mekhanizm lestnitsy Vudvorsa.

Analysis of single-chamber model of electromechanical coupling in the myocardial cell has shown that Woodwors staircase can be imitated in two cases: 1) stationary input current Ca2+ strongly exceeds the potential-dependent uptake of Ca2+ into the cell through the sarcolemma; 2) the action potential (AP) is shortened abruptly with an increase of the myocardium stimulation frequency. The experiments performed on a fragment of the frog heart ventricle supported the conclusions of the model. Blocking of Ca-channels with nifedipine (10(-6) g/mol) at the background of isotonic substitution of 70% of NaCl resulted in the development of "negative staircase" with an increase of stimulation rhythm. An abrupt shortening of AP after rest at joint action of adrenaline (10(-6) g/ml) and blocker of Ca-channels D-600 (10(-6) g/ml) was accompanied by Woodwors staircase.

[Maintenance of myocardial contractivity in dogs following cardioplegia using blood]. / Sokhranenie sokratitel'noi sposobnosti miokarda sobaki posle krovianoi kardioplegii.

Dog hearts were perfused with a cardioplegic solution based on the blood (hemodilution, 20-25%, heparin, 60 mg/l, K, 20 + 25 mEq/l, pH 7.7, temperature 15 degrees C). The hearts were stored for 2 hours at 15 degrees C. Short-term cardioplegic perfusions were made every 20 minutes. It has been shown that the fragments of the left atrial auricle preserve high contractility which is close to the initial level after 1 and 2 hours of storage.

[Role of intracellular Ca-depots in the mechanism of action of caffeine on excitation-contraction coupling in the frog myocardium]. / Rol' vnutrikletochnykh Ca-depo v mekhanizme deistviia kofeina na sopriazhenie vozbuzhdeniia i sokrashcheniia v miokarde liagushki.

Caffeine inotropic effects on frog atrial and ventricular muscle were studied under different patterns of stimulation. It was found that in the course of repetitive stimulation (0.5/s) caffeine produced transient potentiation and following inhibition of contractions which were accompanied by an increase in the rate of tension development, a decrease of the time to peak tension, an increase in relaxation duration and a decrease in the relaxation rate. Caffeine reduced the increment of contraction amplitude in Bowdich staircase under stimulation of the heart muscle with a series of impulses. It was concluded that caffeine caused the depletion of calcium in the intracellular stores. On the basis of literature and our data a scheme was proposed to account for two-phase caffeine action on the frog myocardium. According to this scheme caffeine acts simultaneously on both stages of excitation-contraction coupling: it alters calcium current and prevents Ca accumulation in the intracellular stores.