Effects of isoflurane and enflurane on intracellular Ca²⁺ mobilization in isolated cardiac myocytes

Background: Enflurane and isoflurane may reduce cardiac contractility by altering mobilization and clearance of intracellular Ca²⁺ (Ca²⁺(i)). It was hypothesized that the negative inotropic actions of these agents involve limiting both membrane Ca²⁺ entry and altering intracellular Ca²⁺ release. Methods: The Ca²⁺(i) transients in rat ventricular myocytes loaded with fura-2 were recorded from a fluorescence microscope. Transients stimulated by membrane depolarization (suction electrode or elevated [K⁺](o)) or 15 mM caffeine to release Ca²⁺ from the sarcoplasmic reticulum (SR) were analyzed for net amplitude, maximal rate of rise (V(R)), average rate of decline (V(R)) in [Ca²⁺](i), and duration. Results: Enflurane and isoflurane reduced electrically stimulated Ca²⁺(i) transients in a dose- dependent manner. Enflurane depressed the Ca²⁺(i) transient amplitude more than isoflurane. Enflurane was more effective than isoflurane in reducing V(R) and V(F) in a concentration-dependent manner. At similar concentrations, both enflurane and isoflurane reduced the steady state elevation of [Ca²⁺](i) by 50 mM K⁺(o). Similarly, enflurane and isoflurane depressed caffeine-sensitive release of Ca²⁺ from the SR. The reduction in the Ca²⁺(i) transient because of SR Ca²⁺ release was greater in enflurane than in equal concentrations of isoflurane. Rates of elevation and decline in [Ca²⁺](i) were also reduced in enflurane and isoflurane. Conclusions: The negative inotropic actions of enflurane and isoflurane involve a depression of Ca²⁺ influx during membrane excitation, as well as a reduction in SR Ca²⁺ release. Slowed rates of elevation in [Ca²⁺](i) indicate that the latter mechanism may, in part, be caused by alterations in the kinetics of SR Ca²⁺ release.