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

Research output: Contribution to journalArticle

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+] 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
Volume339
Issue number3
DOIs
StatePublished - Dec 2011

Fingerprint

Myocardial Contraction
Myofibrils
Isoflurane
Muscles
Acetates
nitroxyl
Ryanodine
Octoxynol
Heart Ventricles

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Reversal of isoflurane-induced depression of myocardial contraction by nitroxyl via myofilament sensitization to Ca 2+ . / Ding, Wengang; Li, Zhitao; Shen, Xiaoxu; Martin, Jackie; King, S. Bruce; Sivakumaran, Vidhya; Paolocci, Nazareno; Gao, Wei Dong.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 339, No. 3, 12.2011, p. 825-831.

Research output: Contribution to journalArticle

Ding, Wengang ; Li, Zhitao ; Shen, Xiaoxu ; Martin, Jackie ; King, S. Bruce ; Sivakumaran, Vidhya ; Paolocci, Nazareno ; Gao, Wei Dong. / Reversal of isoflurane-induced depression of myocardial contraction by nitroxyl via myofilament sensitization to Ca 2+ . In: Journal of Pharmacology and Experimental Therapeutics. 2011 ; Vol. 339, No. 3. pp. 825-831.
@article{874cb046c0154b018b6b3272c3e30169,
title = "Reversal of isoflurane-induced depression of myocardial contraction by nitroxyl via myofilament sensitization to Ca 2+",
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+] 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.",
author = "Wengang Ding and Zhitao Li and Xiaoxu Shen and Jackie Martin and King, {S. Bruce} and Vidhya Sivakumaran and Nazareno Paolocci and Gao, {Wei Dong}",
year = "2011",
month = "12",
doi = "10.1124/jpet.111.185272",
language = "English (US)",
volume = "339",
pages = "825--831",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "3",

}

TY - JOUR

T1 - Reversal of isoflurane-induced depression of myocardial contraction by nitroxyl via myofilament sensitization to Ca 2+

AU - Ding, Wengang

AU - Li, Zhitao

AU - Shen, Xiaoxu

AU - Martin, Jackie

AU - King, S. Bruce

AU - Sivakumaran, Vidhya

AU - Paolocci, Nazareno

AU - Gao, Wei Dong

PY - 2011/12

Y1 - 2011/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=81555207897&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=81555207897&partnerID=8YFLogxK

U2 - 10.1124/jpet.111.185272

DO - 10.1124/jpet.111.185272

M3 - Article

C2 - 21865439

AN - SCOPUS:81555207897

VL - 339

SP - 825

EP - 831

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 3

ER -