title: Reversal of isoflurane-induced depression of myocardial contraction by nitroxyl via myofilament sensitization to Ca2+.
abstract: 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+)](i) remained 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.
authors.affiliation: Department of Anesthesiology, 2nd Affiliated Hospital, Harbin Medical University, Heilongjiang, China.
authors.forename: Wengang
authors.initials: W
authors.lastname: Ding
authors.forename: Zhitao
authors.initials: Z
authors.lastname: Li
authors.forename: Xiaoxu
authors.initials: X
authors.lastname: Shen
authors.forename: Jackie
authors.initials: J
authors.lastname: Martin
authors.forename: S Bruce
authors.initials: SB
authors.lastname: King
authors.forename: Vidhya
authors.initials: V
authors.lastname: Sivakumaran
authors.forename: Nazareno
authors.initials: N
authors.lastname: Paolocci
authors.forename: Wei Dong
authors.initials: WD
authors.lastname: Gao
mesh_terms: D000085:Acetates / Q000494:pharmacology; D018685:Anesthetics, Inhalation / Q000494:pharmacology / Q000633:toxicity*; D000818:Animals; D002118:Calcium / Q000502:physiology*; D002316:Cardiotonic Agents / Q000037:antagonists & inhibitors; D004353:Drug Evaluation, Preclinical; D005609:Free Radicals / Q000378:metabolism; D005947:Glucose; D006352:Heart Ventricles / Q000187:drug effects*; D007530:Isoflurane / Q000494:pharmacology / Q000633:toxicity*; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D009210:Myofibrils / Q000187:drug effects* / Q000502:physiology; D009589:Nitrogen Oxides / Q000378:metabolism*; D009603:Nitroso Compounds / Q000494:pharmacology; D051381:Rats; D012433:Ryanodine / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology; D014325:Tromethamine; D016276:Ventricular Function / Q000187:drug effects
chemical_list: C554428:1-nitrosocyclohexyl acetate; D000085:Acetates; D018685:Anesthetics, Inhalation; D002316:Cardiotonic Agents; D005609:Free Radicals; C074097:Krebs-Henseleit solution; D009589:Nitrogen Oxides; D009603:Nitroso Compounds; D019837:Ryanodine Receptor Calcium Release Channel; D014325:Tromethamine; D012433:Ryanodine; D007530:Isoflurane; C039900:nitroxyl; D005947:Glucose; D002118:Calcium