Nitroxyl increases force development in rat cardiac muscle

Tieying Dai, Ye Tian, Carlo Gabriele Tocchetti, Tatsuo Katori, Anne M. Murphy, David A. Kass, Nazareno Paolocci, Wei Dong Gao

Research output: Contribution to journalArticlepeer-review

Abstract

Donors of nitroxyl (HNO), the reduced congener of nitric oxide (NO), exert positive cardiac inotropy/lusitropy in vivo and in vitro, due in part to their enhancement of Ca2+ cycling into and out of the sarcoplasmic reticulum. Here we tested whether the cardiac action of HNO further involves changes in myofilament-calcium interaction. Intact rat trabeculae from the right ventricle were mounted between a force transducer and a motor arm, superfused with Krebs-Henseleit (K-H) solution (pH 7.4, room temperature) and loaded iontophoretically with fura-2 to determine [Ca2+]i. Sarcomere length was set at 2.2-2.3 μm. HNO donated by Angeli's salt (AS; Na2 N3O3) dose-dependently increased both twitch force and [Ca2+]i transients (from 50 to 1000 μM). Force increased more than [Ca2+]i transients, especially at higher doses (332 ± 33% versus 221 ± 27%, P < 0.01 at 1000 μM). AS/HNO (250 μM) increased developed force without changing Ca2+ transients at any given [Ca2+]o (0.5-2.0 mM,). During steady-state activation, AS/HNO (250 μM) increased maximal Ca2+- activated force (Fmax, 106.8 ± 4.3 versus 86.7 ± 4.2 mN mm -2, n =7-8, P < 0.01) without affecting Ca2+ required for 50% activation (Ca50, 0.44 ± 0.04 versus 0.52 ± 0.04 μ M, not significant)or the Hill coefficient (4.75 ± 0.67 versus 5.02 ± 1.1, not significant). AS/HNO did not alter myofibrillar Mg-ATPase activity, supporting an effect on the myofilaments themselves. The thiol reducing agent dithiothreitol (DTT, 5.0 mM) both prevented and reversed HNO action, confirming AS/HNO redox sensitivity. Lastly, NO (from DEA/NO) did not mimic AS/HNO cardiac effects. Thus, in addition to reported changes in Ca2+ cycling, HNO also acts as a cardiac Ca2+ sensitizer, augmenting maximal force without altering actomyosin ATPase activity. This is likely to be due to modulation of myofilament proteins that harbour reactive thiolate groups that are targets of HNO.

Original languageEnglish (US)
Pages (from-to)951-960
Number of pages10
JournalJournal of Physiology
Volume580
Issue number3
DOIs
StatePublished - May 1 2007

ASJC Scopus subject areas

  • Physiology

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