Cellular Mechanisms of Myocardial Depression

Volatile anesthetics depress myocardial contractility through alterations of intracellular Ca²⁺ homeostasis at several subcellular targets in the normal cardiac myocyte.^{[67] [68]} Volatile agents cause dose-related inhibition of the transsarcolemmal Ca²⁺ transient^{[69] [70]} by affecting L- and T-type Ca²⁺ channels.^{[69] [71] [72] [73]} Isoflurane causes less pronounced reductions in the intracellular Ca²⁺ transient than does halothane or enflurane,^[69] although this contention remains somewhat controversial when equi-anesthetic concentrations of these agents are considered.^{[74] [75]} The structural conformation and functional integrity of the voltage-dependent Ca²⁺ channel are directly altered by volatile anesthetics, as indicated by attenuated binding of the dihydropyridine and phenylalkylamine Ca²⁺ channel blockers nitrendipine^{[76] [77]} and galopamil,^[78] respectively. The partial inhibition of Ca²⁺ influx through sarcolemmal Ca²⁺ channels has several important consequences, including declines in the availability of Ca²⁺ for contractile activation, depression of Ca²⁺ -dependent Ca²⁺ release from the sarcoplasmic reticulum (SR), and reduction of the amount of Ca²⁺ that can be subsequently stored in the SR.^{[75] [79] [80] [81] [82]} Halothane and enflurane,^{[80] [82]} but not isoflurane,^{[82] [83] [84]} also stimulate Ca²⁺ release from the SR, a caffeine-like action that may cause transient, modest increases that precede subsequent, more profound reductions in contractility.^{[80] [85] [86]} Unlike isoflurane, halothane and enflurane directly activate ryanodine-sensitive SR Ca²⁺ release channels,^{[87] [88]} thereby reducing SR Ca²⁺ storage. Volatile anesthetics also provoke a nonspecific leak of Ca²⁺ from the SR,^{[89] [90]} contributing to further decreases in accumulation of Ca²⁺ available for release during contraction. When combined with decreases in transsarcolemmal Ca²⁺ flux, these alterations in SR function represent important mechanisms by which halothane and enflurane depress the intracellular Ca²⁺ transient and reduce myocardial contractility to a greater extent than equianesthetic concentrations of isoflurane.^[69] However, later data suggest that volatile anesthetics inhibit Ca²⁺ transport from the cell through the sarcolemmal Ca²⁺ ATPase.^[91] This action may serve to partially offset reductions in SR Ca²⁺ stores. The partial preservation of the myocardial positive frequency staircase effect observed with isoflurane at physiologic excitation rates in vitro^{[75] [92]} may also be attributed to the relative maintenance of SR function by this volatile agent, in contrast to halothane and enflurane.

Evidence indicates that volatile anesthetics may also depress contractile function by inhibiting Na⁺ -Ca²⁺ exchange and reducing intracellular Ca²⁺ concentration independent of the voltage-dependent Ca²⁺ channel in vitro.^{[93] [94] [95]} This effect may be particularly important in neonatal myocardium^[93] because this tissue has been shown to be more sensitive to the negative inotropic actions of volatile anesthetics than is adult myocardium.^[96] However, the relative contribution of Na⁺ -Ca²⁺ exchanger inhibition

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The cellular mechanisms responsible for volatile anesthetic-induced depression of myocardial contractility in failing myocardium have not been extensively studied. It is likely that alterations of intracellular Ca²⁺ regulation produced by volatile anesthetics in normal myocardium also occur at similar subcellular targets in failing myocardium. Profound abnormalities in intracellular Ca²⁺ homeostasis are characteristic features of failing myocardium,^[109] and it is likely that volatile anesthetics cause further reductions in contractile function by producing additive or synergistic effects on Ca²⁺ metabolism.