TY - JOUR
T1 - Molecular mechanism of anesthetic-induced depression of myocardial contraction
AU - Meng, Tao
AU - Bu, Weiming
AU - Ren, Xianfeng
AU - Chen, Xinzhong
AU - Yu, Jingui
AU - Eckenhoff, Roderic G.
AU - Gao, Wei Dong
N1 - Publisher Copyright:
© 2016 FASEB.
PY - 2016/8
Y1 - 2016/8
N2 - Isoflurane and propofol are known to depress cardiac contraction, but the molecular mechanisms involved are not known. In this study, we determined whether decreasing myofilament Ca2+ responsiveness underlies anesthesia-induced depression of contraction and uncovered the molecular targets of isoflurane and propofol. Force and intracellular Ca2+ ([Ca2+]i) were measured in rat trabeculae superfused with Krebs-Henseleit solution, with or without propofol or isoflurane. Photoaffinity labeling of myofilament proteins with meta-Azi-propofol (AziPm) and Azi-isoflurane (Azi-iso) and molecular docking were also used. Both propofol and isoflurane dose dependently depressed force from low doses (propofol, 27 ± 6 μM; isoflurane, 1.0 ± 0.1%) to moderate doses (propofol, 87 ± 4 μM; isoflurane, 3.060.25%), without significant alteration [Ca2+]i. During steady-state activations in both intact and skinned preparations, propofol and isoflurane depressed maximum Ca2+-activated force and increased the [Ca2+]i required for 50% of activation. Myofibrils photolabeled with AziPm and Azi-iso identified myosin, actin, and myosin light chain as targets of the anesthetics. Several adducted residues in those proteins were located in conformationally sensitive regions that underlie contractile function. Thus, propofol and isoflurane decrease force development by directly depressing myofilament Ca2+ responsiveness and have binding sites in key regions for contraction in both actin and myosin.
AB - Isoflurane and propofol are known to depress cardiac contraction, but the molecular mechanisms involved are not known. In this study, we determined whether decreasing myofilament Ca2+ responsiveness underlies anesthesia-induced depression of contraction and uncovered the molecular targets of isoflurane and propofol. Force and intracellular Ca2+ ([Ca2+]i) were measured in rat trabeculae superfused with Krebs-Henseleit solution, with or without propofol or isoflurane. Photoaffinity labeling of myofilament proteins with meta-Azi-propofol (AziPm) and Azi-isoflurane (Azi-iso) and molecular docking were also used. Both propofol and isoflurane dose dependently depressed force from low doses (propofol, 27 ± 6 μM; isoflurane, 1.0 ± 0.1%) to moderate doses (propofol, 87 ± 4 μM; isoflurane, 3.060.25%), without significant alteration [Ca2+]i. During steady-state activations in both intact and skinned preparations, propofol and isoflurane depressed maximum Ca2+-activated force and increased the [Ca2+]i required for 50% of activation. Myofibrils photolabeled with AziPm and Azi-iso identified myosin, actin, and myosin light chain as targets of the anesthetics. Several adducted residues in those proteins were located in conformationally sensitive regions that underlie contractile function. Thus, propofol and isoflurane decrease force development by directly depressing myofilament Ca2+ responsiveness and have binding sites in key regions for contraction in both actin and myosin.
KW - Anesthetic agents
KW - Calcium
KW - Myofilament proteins
KW - Photolabeling
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U2 - 10.1096/fj.201600290RR
DO - 10.1096/fj.201600290RR
M3 - Article
C2 - 27170289
AN - SCOPUS:84982728970
SN - 0892-6638
VL - 30
SP - 2915
EP - 2925
JO - FASEB Journal
JF - FASEB Journal
IS - 8
ER -