RT Journal Article SR Electronic T1 Reversal of Isoflurane-Induced Depression of Myocardial Contraction by Nitroxyl via Myofilament Sensitization to Ca2+ JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 825 OP 831 DO 10.1124/jpet.111.185272 VO 339 IS 3 A1 Wengang Ding A1 Zhitao Li A1 Xiaoxu Shen A1 Jackie Martin A1 S. Bruce King A1 Vidhya Sivakumaran A1 Nazareno Paolocci A1 Wei Dong Gao YR 2011 UL http://jpet.aspetjournals.org/content/339/3/825.abstract AB Isoflurane (ISO) is known to depress cardiac contraction. Here, we hypothesized that decreasing myofilament Ca2+ responsiveness is central to ISO-induced reduction in cardiac force development. Moreover, we also tested whether the nitroxyl (HNO) donor 1-nitrosocyclohexyl acetate (NCA), acting as a myofilament Ca2+ sensitizer, restores force in the presence of ISO. Trabeculae from the right ventricles of LBN/F1 rats were superfused with Krebs-Henseleit solution at room temperature, and force and intracellular Ca2+ ([Ca2+]i) were measured. Steady-state activations were achieved by stimulating the muscles at 10 Hz in the presence of ryanodine. The same muscles were chemically skinned with 1% Triton X-100, and the force-Ca2+ relation measurements were repeated. ISO depressed force in a dose-dependent manner without significantly altering [Ca2+]i. At 1.5%, force was reduced over 50%, whereas [Ca2+]i remained unaffected. At 3%, contraction was decreased by ∼75% with [Ca2+]i reduced by only 15%. During steady-state activation, 1.5% ISO depressed maximal Ca2+-activated force (Fmax) and increased the [Ca2+]i required for 50% activation (Ca50) without affecting the Hill coefficient. After skinning, the same muscles showed similar decreases in Fmax and increases in Ca50 in the presence of ISO. NCA restored force in the presence of ISO without affecting [Ca2+]i. These results show that 1) ISO depresses cardiac force development by decreasing myofilament Ca2+ responsiveness, and 2) myofilament Ca2+ sensitization by NCA can effectively restore force development without further increases in [Ca2+]i. The present findings have potential translational value because of the efficiency and efficacy of HNO on ISO-induced myocardial contractile dysfunction.