Mechanisms of action of halogenated anesthetics on isolated cardiac muscle

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 complex. At the sarcolemmal level, all three anesthetics decrease Ca++ entry through the voltage-dependent 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.