C. Poggesi

The dual effect of thyroid hormones on contractile properties of rat myocardium

This study was designed to investigate the changes in cardiac contractile properties induced by triiodothyronine (T3) administration in adult rats. Myofibrils and myosin were isolated from ventricular muscles from euthyroid and hyperthyroid animals and enzymatically and electrophoretically characterized. The time course of the isometric response, the force velocity curve, the force interval relation were studied in papillary muscles isolated from the right ventricles of euthyroid and hyperthyroid rats. T3 administration induced significant increases in Mg2+ activated myofibrillar ATPase activity (+11.4%) and in Ca2+ activated myosin ATPase activity (+20.1%). Significant increases in shortening velocity at low and zero loads (+20.4%) were found in papillary muscles from treated animals when compared with the control muscles. These variations in enzymatic activity and shortening velocity could be related to the increase in the amount of the fast isomyosin V1, as shown by pyrophosphate gel electrophoresis. The negative force-frequency relation at steady state, typical of rat cardiac preparations, was observed in treated and control animals; its slope was, however, halved in hyperthyroid papillary muscles when compared with control ones. In accordance with this finding, the potentiating effect of a prolonged diastolic interval was significantly reduced in hyperthyroid papillary muscles. In the frame of an interpretation of the force interval relation on the basis of the excitation contraction coupling processes, these latter observations might indicate an enhanced activity of the sarcoplasmic reticulum. We conclude that thyroid hormone administration has a dual effect on cardiac contractility, on one hand regulating the synthesis of the different isomyosin and, on the other hand, stimulating the activity of the sarcoplasmic reticulum.

Influence of thyroid state on mechanical restitution of rat myocardium.

The purpose of this study was to determine whether thyroid state affects the beat-to-beat regulation of contractile strength in cardiac muscle. Transmembrane action potential and isometric force were simultaneously recorded in right ventricular papillary muscles from euthyroid, hypothyroid, and hyperthyroid rats. Large thyroid state-dependent alterations in the contractile response of the muscles were not accompanied by any significant difference in the action potential. During steady-state stimulation, single test stimuli were interpolated at varying intervals. Action potential duration and peak force of the test responses were plotted against the test stimulus interval to produce electrical and mechanical restitution curves. In all muscles studied, electrical and mechanical restitution followed different time courses; over a wide range of test intervals, action potential duration and peak force of the test responses changed in opposite directions. Thyroid state profoundly affected the recovery of contractile strength, while only minor differences were found among the electrical restitution curves of the three groups of preparations. Mechanical recovery was much faster in hyperthyroid and slower in hypothyroid than in euthyroid muscles. We conclude that electrical and mechanical restitutions occur through separate processes and that the thyroid state affects only the mechanisms responsible for the contractile recovery of rat myocardium. The modifications induced by thyroid dysfunction on contractile recovery might be accounted for by an effect of thyroid state on a time-dependent recycling of calcium by the sarcoplasmic reticulum.

Study and parameters identification of a rheological model for excised quiescent cardiac muscle.

Abstract A non-linear rheological model has been used to represent mathematically the behaviour of isolated quiescent preparations of rat myocardium. The parameters have been identified by means of numerical methods and the experimental responses of the specimens to several stress or strain histories have been predicted by the model. Results obtained show that the model has a good predictive ability and can discriminate among the responses of specimens with different mechanical behaviour (papillary muscles of young and aged rats and papillary muscles contractured in hypertonic solutions).

A four-state cross bridge model for muscle contraction. Mathematical study and validation

A mathematical model of contracting skeletal muscle is studied. The model is composed by an elastic element (SE) in series with a contractile element (CE) that describes the cross bridge kinetics with a formulation derived by that proposed by Eisenberg and Hill (1978).An analytical study of the system of nonlinear partial differential equations of the model allows the existence and the uniqueness of the solution to be proved.A suitable approach to the numerical solution is defined and a series of numerical tests are performed. These tests lead to select an appropriate set of parameters and allow to compare model predictions and experimental observations on frog skeletal muscle.

Age-dependent changes of relaxation and its load sensitivity in rat cardiac muscle.

SummaryThe relaxation phase and its load dependence were studied in papillary muscles isolated from the left ventricle of rats of the following ages: 20 days, 2, 8, 18, and 24 months. The myofibrillar ATPase activity and the force-velocity relation were determined in each age group in order to characterize the kinetic properties of the contractile material. Both shortening velocity and myofibrillar ATPase activity showed a progressive reduction with maturation and aging. This observation suggested an age-dependent decrease in cross bridge formation rate. The relaxation phase was characterized by its duration and the maximum rate of tension decline in isometric conditions, and by the speed of relenthenning in isotonic conditions. Relaxation became faster and of shorter duration with maturation from 20 days to 2 months and then became slower and of longer duration with further maturation and aging. The sensitivity of relaxation to changes in length or load was evaluted by measuring how much earlier tension declined in the presence of a given length change. An increase in load sensitivity of relaxation was observed during maturation from 20 days to 8 months. This increase was followed by a reduction during aging from 8 to 24 months. Such a biphasic trend of the age-related changes in load sensitivity of relaxation could result from the interplay between the progressive decrease in cross bridge formation rate and a reduction in activation decay rate. The latter was suggested by the prolongation of the relaxation phase and by the maintenance of developed tension during aging.

Postextrasystolic potentiation in isolated rat myocardium: dependence on resting muscle length

The degree and decay of postextrasystolic potentiation were studied in isolated rat papillary muscle atLmax, the length at which developed force was maximum, and at shorter lengths.Potentiation curves were constructed relating the degree of potentiation with the time interval between any given extrasystole and the last steady-state beat. At all stimulation rates tested (ranging from 3 to 60/min), potentiation curves were found to be dependent on muscle length: at any interval the degree of potentiation increased progressively with decreasing initial muscle length.At all lengths and stimulation frequencies tested, the decay of potentiation was a function of the number of beats following the extrasystole. This relationship could be fitted by a single exponential equation. The exponential constant of the decay was significantly smaller atLmax than at shorter lengths.These results suggest that muscle length affects more than one step of the E-C coupling processes.

Relaxation in atrial and ventricular myocardium: activation decay and different load sensitivity

SummaryIsolated atrial and ventricular preparations from rat heart have been compared. In atrial specimens relaxation is faster than in papillary muscles both in isometric and isotonic conditions. In papillary muscles the tension decay occurs earlier in isotonic than isometric contractions and a stretch applied at or after the peak of isometric twitches promotes a faster relaxation: this load dependence of relaxation is less pronounced in atrial specimens. The decay of activation, evaluated from the decline of the muscle shortening ability, is faster in atrium than in ventricle. These findings suggest that the sensitivity of relaxation to the loading conditions might be determined by both the activation decay rate and the cross bridge kinetics.ZusammenfassungIn der vorliegenden Arbeit wird die Mechanik isolierter Muskelpräparate vom Vorhof und Ventrikel des Rattenherzens verglichen. Bei Vorhofpräparaten beginnt der Erschlaffungsprozeß unter isometrischen und isotonischen Bedingungen früher als beim Papillarmuskel. Bei Papillarmuskeln tritt der Abfall der Spannung unter isotonischen Bedingungen früher in Erscheinung als bei isometrischen Kontraktionen; eine Streckung zum Zeitpunkt der isometrischen Gipfelzeit oder danach verursacht schnellere Erschlaffung. Diese Abhängigkeit der Erschlaffung von der Last ist bei Vorhofpräparaten weniger ausgeprägt. Der Rückgang der Aktivierung, bewertet aufgrund der abnehmenden Verkürzungsfähigkeit des Muskels, erfolgt beim Vorhof schneller als beim Ventrikel. Die Ergebnisse lassen vermuten, daß die Abhängigkeit der Erschlaffung von den Belastungsbedingungen sowohl durch die Geschwindigkeit des Aktivierungsrückgangs als auch durch die Querbrückenkinetik bestimmt wird.

Factors modulating the sensitivity of the relaxation to the loading conditions in rat cardiac muscle.

The load sensitivity of the relaxation phase was studied in rat papillary muscle, with isotonic afterloaded contractions and stretches applied after the peak of isometric twitches.The tension decay occurred earlier in isotonic than in isometric contractions. When a central region of the preparation was marked with small stainless steel pins, a lengthening of this region could be shown during relaxation of isometric (fixed end) contractions. This lengthening was earlier and faster in isotonic afterloaded contractions. Therefore the sensitivity of relaxation to load or length changes could be described in the context of the general mechanism of relaxation which takes into account the non uniform behaviour of the muscle and the internal movement during contractions.Interventions which decelerate the activation decay rate had different effects on the load dependence of relaxation. Caffeine addition and substitution of strontium for calcium abolished the load sensitivity while a temperature reduction had no influence on it.

Isometric relaxation in rat myocardium: load dependence and influence of caffeine.

When caffeine plus calcium is added to the perfusing medium, isometric relaxation of rat myocardium is no longer affected by length changes occurring during the twitch. The dependence of isometric relaxation on the initial muscle length is still present and more pronounced after caffeine addition.

Tritiated water (HTO) and inulin spaces in isolated skeletal and cardiac muscles: influence of contractile activity

In isolated cardiac and skeletal muscle inulin space increased significantly after isometric contractions: no significant change (in myocardium) or a less pronounced increase (in skeletal preparations) was found following isotonic responses. The HTO space was uninfluenced by the contractile activity.