Effects of halothane on contractile properties of skinned fibers from cardiomyopathic animals

doi:10.1016/0022-2828(89)90675-5

Journal of Molecular and Cellular Cardiology

Volume 21, Issue 12, December 1989, Pages 1293-1304

https://doi.org/10.1016/0022-2828(89)90675-5 Get rights and content

Abstract

The effects of clinical concentrations of halothane (1 and 2% v/v) on detergent treated cardiac fibers were studied in two different models of cardiomyopathic animals, the Syrian hamster UM-X7.1, and the streptozotocin-induced diabetic rat. The changes of contractile properties in cardiac muscle observed on cardiomyopathic animals, although of moderate importance, were different in these two models. The cardiomyopathic hamsters exhibited macroscopic structural changes in cardiac muscle responsible for a significant decrease in maximal activated tension, but myocardial calcium sensitivity was unchanged. On the other hand, in diabetic rats, maximal activated tension was unchanged, while a slight but significant increase in myocardial calcium sensitivity was observed. Addition of halothane produced a similar dose-dependent decrease in myocardial calcium sensitivity, in both the controls and the two groups of cardiomyopathic animals. Halothane exposure was also associated with a dose-dependent decrease in maximal calcium activated tension in all groups, an effect that was more pronounced in cardiomyopathic hamsters than in their control at the lowest anesthetic concentration. These results indicate that the negative inotropic effects of halothane are additive to the myocardial depression observed in these cardiomyopathies.

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Time course of the surface electrical activity was studied in left ventricular trabeculae of Wistar rats made diabetic using streptozotocin. The action potentials were recorded in Tyrode's solution at 32°C, their duration considerably increased in diabetes. By the 8th week, the prolongation was 64% at 25% of repolarization; 112% at 50% and 118% at 75%. Insulin treatment reduced the prolongation of the action potentials although a complete restoration was not achieved. 0.1 mm La³⁺ moderately shortened the electrical activity both in control and in diabetic trabeculae. Three mm 4-aminopyridine made the time course of control action potentials very similar to the diabetic ones while the action potentials from the diabetic animals were prolonged further to a smaller extent. Whole-cell clamp experiments in isolated ventricular myocytes (20–23°C) showed a considerable decrease and a somewhat accelerated inactivation of the transient outward current (I_to) in diabetes. The steady-state inactivation and the rate of recovery from inactivation of I_to did not change. No alterations in the magnitude and voltage dependence of inward rectifier (I_Kl) were found around the resting membrane potential. The diabetes-related suppression of I_to explains the decreased repolarization rate of action potentials.
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Cette revue fait le point sur les mécanismes d'action responsables des effets inotropes négatifs directs des anesthésiques halogénés (halothane, enflurane, isoflurane) au niveau du muscle cardiaque. Ces anesthésiques interviennent à toutes les étapes du couplage excitation-contraction. Au niveau des myofilaments, ils diminuent de manière dose-dépendante la sensibilité au calcium et la tension active maximale des fibres myocardiques pelées. L'effet des trois anesthésiques est quantitativement identique sur cette préparation ne contenant plus que les éléments contractiles proprement dits. Au niveau du sarcolemme, leur action principale est une diminution de l'entrée du calcium par les canaux calciques lents. L'effet de l'halothane et de l'enflurane est un peu plus important que celui de l'isoflurane pour des concentrations anesthésiques équivalentes. Les effets de ces anesthésiques sur la fonction du réticulum sarcoplasmique sont quantitativement très différents. Ces agents diminuent les stocks de calcium intracellulaire essentiellement en augmentant la perméabilité du réticulum sarcoplasmique ; néanmoins, cet effet n'est mis en évidence que pour des concentrations très élevées d'isoflurane, alors qu'il est présent pour des concentrations cliniques d'halothane ou d'enflurane. L'étude des mécanismes d'action à l'échelle cellulaire aide à comprendre les effets différents observés sur le muscle entier, ainsi que le mécanisme des interférences médicamenteuses potentielles, en particulier avec les agents pharmacologiques à action cardiaque préférentielle.
The mechanisms responsible for the direct negative inotropic effects of the three currently used volatile anesthetics (halothane, enflurane and isoflurane) are reviewed. These agents interfere at each step of excitation-contraction coupling, i.e. sarcolemmal membrane, sarcoplasmic reticulum and contractile proteins. At the myofilament level, they decrease both calcium sensitivity and maximal developed force of cardiac skinned fibers of various species, a preparation in which all functional membranes are destroyed and thus allowing to study the direct effects of volatile anesthetics on myocardial contractile proteins. The effects of the three volatile anesthetics are similar at equipotent concentrations. The site of action seems to involve the regulatory proteins of the thin myofilament, especially troponin-tropomyosin complexe. At the sarcolemmal level, all three anesthetics dicrease Ca⁺⁺ entry through the voltage-dependant calcium channels, an effect that seems slightly more important for both halothane and enflurane than for isoflurane. However, these two sites of action (contractile proteins and sarcolemmal membrane) are not sufficient to explain their overall negative inotropic effect. The third site of action involves the sarcoplasmic reticulum. Halothane and enflurane produce an initial liberation of Ca⁺⁺ from internal stores, while isoflurane does not. All three agents decrease the net uptake of Ca⁺⁺ and increase the permeability of sarcoplasmic reticulum to Ca⁺⁺, similar to the effect of caffeine. However, the resulting effect, i.e. a reduction of sarcoplasmic reticulum Ca⁺⁺ content occurs at clinical concentrations of halothane or enflurane, while much higher concentrations of isoflurane are required to produce a similar reduction. This differential effect on the sarcoplasmic reticulum function (which is quantitative but not qualitative) seems to be mainly responsible for the lesser negative inotropic effect of isoflurane as observed in intact cardiac muscles of various species including humans. The knowledge of the mechanisms of action of volatile anesthetics is important for understanding the potential consequences associated with their use in patients receiving cardiac drugs, especially calcium blockers and phosphodiesterase inhibitors.
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^∗: Present address: Laboratory of Experimental Cardiac Pathology, USSR Cardiology Research Center, 3 Cherepkovskaya Street 15a, Moscow 121552, USSR.

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Original articleEffects of halothane on contractile properties of skinned fibers from cardiomyopathic animals

Abstract

Am Heart J

Am Heart J

J Mol Cell Cardiol

J Mol Cell Cardiol

J Mol Cell Cardiol

J Moll Cell Cardiol

Br J Anaesth

J Mol Cell Cardiol

Br J Anaesth

Myocardial myosin isoenzyme shifts and the effects of halothane on cardiac contractility in non-insulin treated spontaneously diabetic rats

Anesthesiology

Regulation of tension in skinned muscle fibers. Effects of cross-bridge kinetics on apparent Ca2+ sensitivity

J Gen Physiol

Rate of force generation in muscle: Correlation with actomyosin ATPase activity in solution

Pathogenesis of cardiac dysfunction in diabetes mellitus

Can J Cardiol

Calculator program for computing the composition of the solutions containing metals and ligands used for experiments in skinned muscle cells

J Physiol (Paris)

Myoplasmic free calcium concentration reached during the twitch of an intact isolated cardiac cell and during calcium induced release of calcium from the sarcoplasmic reticulum of a skinned cardiac cell from the adult rat or rabbit ventricle

J Gen Physiol

Altered myocardial mechanics in diabetic rats

Circ Res

Potassium and ionic strength effects on the isometric force of skinned twitch muscle fibres of the rat and toad

J Physiol (Lond)

Negative inotropic effects of halothane enflurance and isoflurane in papillary muscles from diabetic rats

Anesth Analg

Heart failure and Ca2+ activation of the cardiac contractile system: Hereditary cardiomyopathy in hamsters (BIO 14.6), isoprenaline overload and the effect of APP 201–533

Basic Res Cardiol

Comparative effects of halothane enflurane and isoflurane at equipotent anesthetic concentrations on isolated ventricular myocardium of the ferret: I. Contractility

Anesthesiology

Comparative effects of halothane enflurane and isoflurane on isolated ventricular myocardium of the ferret. II. Relaxation

Anesthesiology

Hereditary polymyopathy and cardiomyopathy in the Syrian Hamster. I. Progression of heart and skeletal muscle lesions in the UM-X7.1 line

Muscle Nerve

Calcium, and myocardial cell injury. An appraisal in the cardiomyopathic hamster

Can J Physiol Pharmacol

Original article
Effects of halothane on contractile properties of skinned fibers from cardiomyopathic animals

Regulation of tension in skinned muscle fibers. Effects of cross-bridge kinetics on apparent Ca²⁺ sensitivity

Heart failure and Ca²⁺ activation of the cardiac contractile system: Hereditary cardiomyopathy in hamsters (BIO 14.6), isoprenaline overload and the effect of APP 201–533