Abstract
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.
Footnotes
This work was supported in part by the National Institutes of Health National Heart, Lung, and Blood Institute [Grants R01-HL091923, R01-HL075265]; and American Heart Association Mid-Atlantic [Grant 0855439E]. N.P. is a founder and stock owner at Cardioxyl Pharmaceutical, Inc.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.111.185272.
-
ABBREVIATIONS:
- ISO
- isoflurane
- NCA
- 1-nitrosocyclohexyl acetate
- HNO
- nitroxyl
- K-H
- Krebs-Henseleit
- ANOVA
- analysis of variance
- Fmax
- maximal Ca2+-activated force
- Ca50
- Ca2+ required to achieve 50% of Fmax
- Levo
- levosimendan
- [Ca2+]i
- intracellular Ca2+
- [Ca2+]o
- extracellular Ca2+
- Tn
- troponin
- TnC
- troponin C.
- Received June 21, 2011.
- Accepted August 23, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|