TY - JOUR T1 - Effect of Isoflurane on Myocardial Energetic and Oxidative Stress in Cardiac Muscle from Zucker Diabetic Fatty Rat JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 21 LP - 28 DO - 10.1124/jpet.113.211144 VL - 349 IS - 1 AU - Xiaoxu Shen AU - Niraj Bhatt AU - Jianhong Xu AU - Tao Meng AU - Miguel A. Aon AU - Brian O’Rourke AU - Dan E. Berkowitz AU - Sonia Cortassa AU - Wei Dong Gao Y1 - 2014/04/01 UR - http://jpet.aspetjournals.org/content/349/1/21.abstract N2 - The effect of inhalational anesthetics on myocardial contraction and energetics in type 2 diabetes mellitus is unknown. We investigated the effect of isoflurane (ISO) on force and intracellular Ca2+ transient (iCa), myocardial oxygen consumption (MVo2), and energetics/redox behavior in trabecular muscles from Zucker diabetic fatty (ZDF) rats. At baseline, force and corresponding iCa were lower in ZDF trabeculae than in controls. ISO decreased force in both groups in a dose-dependent manner. ISO did not affect iCa amplitude in controls, but ISO > 1.5% significantly reduced iCa amplitude in ZDF trabeculae. ISO-induced force depression fully recovered as a result of increased iCa when external Ca2+ was raised in controls. However, both force and iCa remained low in ZDF muscle at elevated external Ca2+. In controls, force, iCa, and MVo2 increased when stimulation frequency was increased from 0.5 to 1.5 Hz. ZDF muscles, however, exhibited blunted responses in force and iCa and decreased MVo2. Oxidative stress levels were unchanged in control muscles but increased significantly in ZDF muscles after exposure to ISO. Finally, the depressive effect of ISO was prevented by 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (Tempol) in ZDF muscles. These findings suggest that ISO dose-dependently attenuates force in control and ZDF muscles with differential effect on iCa. The mechanism of force depression by ISO in controls is mainly decreased myofilament Ca2+ sensitivity, whereas in ZDF muscles the ISO-induced decrease in contraction is due to worsening oxidative stress, which inhibits iCa and force development. ER -