Reversal of isoflurane-induced depression of myocardial contraction by nitroxyl via myofilament sensitization to Ca 2+

Wengang Ding, Zhitao Li, Xiaoxu Shen, Jackie Martin, S. Bruce King, Vidhya Sivakumaran, Nazareno Paolocci, Wei Dong Gao

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20 Scopus citations


Isoflurane (ISO) is known to depress cardiac contraction. Here, we hypothesized that decreasing myofilament Ca 2+ 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 Ca 2+ 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 Ca 2+ ([Ca 2+] 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- Ca 2+ relation measurements were repeated. ISO depressed force in a dose-dependent manner without significantly altering [Ca 2+] i. At 1.5%, force was reduced over 50%, whereas [Ca 2+] iremained unaffected. At 3%, contraction was decreased by ~75% with [Ca 2+] i reduced by only 15%. During steady-state activation, 1.5% ISO depressed maximal Ca 2+-activated force (F max) and increased the [Ca 2+] i required for 50% activation (Ca 50) without affecting the Hill coefficient. After skinning, the same muscles showed similar decreases in F max and increases in Ca 50 in the presence of ISO. NCA restored force in the presence of ISO without affecting [Ca 2+] i. These results show that 1) ISO depresses cardiac force development by decreasing myofilament Ca 2+ responsiveness, and 2) myofilament Ca 2+sensitization by NCA can effectively restore force development without further increases in [Ca 2+] i. The present findings have potential translational value because of the efficiency and efficacy of HNO on ISO-induced myocardial contractile dysfunction.

Original languageEnglish (US)
Pages (from-to)825-831
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
StatePublished - Dec 2011

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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