Effects of Isoflurane on Intracellular Calcium and Myocardial Crossbridge Kinetics in Tetanized Papillary Muscles

BACKGROUND: Isoflurane depresses the intracellular Ca2+ transient and force development during a twitch, but its effects on crossbridge cycling rates are difficult to predict because of the transient nature of the twitch. Measurements of the effects of isoflurane on crossbridge cycling kinetics during tetanic contractions, which provide a steady state level of activation in intact cardiac muscle, have not been previously reported. METHODS: Ferret right ventricular papillary muscles were isolated, and superficial cells were microinjected with the bioluminescent photoprotein aequorin to monitor the intracellular Ca2+ concentration. The rate of tension redevelopment (kTR) was measured during steady state isometric activation (tetanic stimulation, frequency 20 Hz, 1 microM ryanodine, temperature = 30 degrees C) in the absence of isoflurane (2, 6, and 12 mM extracellular Ca2+) and in the presence of 0.5, 1.0, and 1.5 minimum alveolar concentration isoflurane (12 mM extracellular Ca2+). RESULTS: Intracellular Ca2+, isometric force, and kTR all increased when the extracellular Ca2+ increased. Isoflurane (0.5, 1.0, and 1.5 minimum alveolar concentration) caused intracellular Ca2+, isometric force, and kTR to decrease in a dose-dependent manner in the presence of 12 mM extracellular Ca2+. In the presence of increasing concentrations of isoflurane, the relation between intracellular Ca2+ and force remained unchanged, whereas the relation between intracellular Ca2+ and kTR was shifted toward higher Ca2+. CONCLUSIONS: These results indicate that isoflurane depresses myocardial crossbridge cycling rates. It appears that this effect is partially mediated by a decrease in the intracellular Ca2+. However, additional mechanisms must be considered to explain the shift of the relation between intracellular Ca2+ and kTR toward higher Ca2+.