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This Article Full Text Full Text (PDF) All Versions of this Article: 580/3/951    most recent jphysiol.2007.129254v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dai, T. Articles by Gao, W. D. Search for Related Content PubMed PubMed Citation Articles by Dai, T. Articles by Gao, W. D. Related Collections Cardiovascular Related Article

¹ Department of Anaesthesiology and Critical Care Medicine
² Division of Cardiology, Department of Medicine
³ Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
⁴ Departments of Cardiology and Pathophysiology, Harbin Medical University, Harbin, P.R. China
⁵ Department of Clinical and Experimental Medicine, General Pathology and Immunology Section, Perugia University, Perugia, Italy

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; Na₂N₂O₃) 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 (F_max, 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 µM, 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.

(Received 26 January 2007; accepted after revision 21 February 2007; first published online 1 March 2007)
Corresponding author W. D. Gao: Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Tower 711, 600 N Wolfe Street, Baltimore, MD 21287, USA. Email: wgao3{at}jhmi.edu

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