Abstract

1, Amadou K.S. Camara2, David F. Stowe2, Zeljko J. Bosnjak2, Daniel A. Beard1, and Ranjan K. Dash1. 1Physiology, 2Anesthesiology, Medical College of Wisconsin, Milwaukee, WI Modulation of mitochondrial free Ca2+ (m[Ca2+]) is implicated as one of the possible upstream factors that initiates anesthetic-mediated cardioprotection against ischemia-reperfusion (IR) injury. To help unravel the mechanisms by which volatile anesthetics modulate m[Ca2+], experiments were conducted to spectrofluorometrically measure dose-dependent effects of isoflurane (0.5-2 mM) on the time courses of mitochondrial bioenergetics (NADH redox state, respiration, and ΔΨm) and Ca2+ uptake into the matrix. Isolated mitochondria from rat hearts were energized with 10 mM pyruvate/malate (state 2); this was followed by sequentially adding isoflurane (0.5 to 2 mM), 0.5 mM CaCl2 (with 1 mM EGTA in the buffer),and 250 μM ADP (state 3). The data showed that: (a) isoflurane dose-dependently increased m[Ca2+] in state 2 in spite of a slight ΔΨm depolarization, (b) isoflurane increased the duration of state 3 respiration as well as the duration of the ADP-induced rise in m[Ca2+], and (c) isoflurane decreased state 3 NADH oxidation (i.e., increased NADH level compared to control). These data indicate the possible roles of isoflurane (1) to modulate m[Ca2+] by directly activating the Ca2+ uniporter, independent of ΔΨm, (2) to decrease the rate of ADP phosphorylation while prolonging the duration of state 3 respiration (possibly by inhibiting complex I), and (3) to prolong the duration of ADP-induced increase in m[Ca2+] response during state 3 because of reduced electron flux and slower ADP phosphorylation.

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