Abstract

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.