PT  - JOURNAL ARTICLE
AU  - Wengang Ding
AU  - Zhitao Li
AU  - Xiaoxu Shen
AU  - Jackie Martin
AU  - S. Bruce King
AU  - Vidhya Sivakumaran
AU  - Nazareno Paolocci
AU  - Wei Dong Gao
TI  - Reversal of Isoflurane-Induced Depression of Myocardial Contraction by Nitroxyl via Myofilament Sensitization to Ca<sup>2+</sup>
AID  - 10.1124/jpet.111.185272
DP  - 2011 Dec 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 825--831
VI  - 339
IP  - 3
4099  - http://jpet.aspetjournals.org/content/339/3/825.short
4100  - http://jpet.aspetjournals.org/content/339/3/825.full
SO  - J Pharmacol Exp Ther2011 Dec 01; 339
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.