Nitroxyl increases force development in rat cardiac muscle

• Published in: The Journal of physiology 2007-05, Vol.580 (3), p.951-960
• Main Authors: Dai, Tieying, Tian, Ye, Tocchetti, Carlo Gabriele, Katori, Tatsuo, Murphy, Anne M., Kass, David A., Paolocci, Nazareno, Gao, Wei Dong
• Format: Article
• Language: English
• Subjects: Animals; Ca(2+) Mg(2+)-ATPase - metabolism; Calcium - metabolism; Cardiovascular; Heart - physiology; Hydrazines - pharmacology; In Vitro Techniques; Intracellular Membranes - metabolism; Myocardial Contraction - drug effects; Myocardial Contraction - physiology; Myocardium - enzymology; Myocardium - metabolism; Myofibrils - enzymology; Nitric Oxide Donors - pharmacology; Nitrites - pharmacology; Nitrogen Oxides - pharmacology; Osmolar Concentration; Rats; Rats, Sprague-Dawley
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2007.129254

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 Ca 2+ 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 [Ca 2+ ] i . Sarcomere length was set at 2.2–2.3 μm. HNO donated by Angeli's salt (AS; Na 2 N 2 O 3 ) dose-dependently increased both twitch force and [Ca 2+ ] i transients (from 50 to 1000 μ m ). Force increased more than [Ca 2+ ] i transients, especially at higher doses (332 ± 33% versus 221 ± 27%, P < 0.01 at 1000 μ m ). AS/HNO (250 μ m ) increased developed force without changing Ca 2+ transients at any given [Ca 2+ ] o (0.5–2.0 m m ). During steady-state activation, AS/HNO (250 μ m ) increased maximal Ca 2+ -activated force ( F max , 106.8 ± 4.3 versus 86.7 ± 4.2 mN mm −2 , n = 7–8, P < 0.01) without affecting Ca 2+ required for 50% activation (Ca 50 , 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 m m ) 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 Ca 2+ cycling, HNO also acts as a cardiac Ca 2+ 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.