K201 (JTV-519) alters the spatiotemporal properties of diastolic Ca²⁺ release and the associated diastolic contraction during β-adrenergic stimulation in rat ventricular cardiomyocytes

Elliott, E.B., Hasumi, H., Otani, N., Matsuda, T., Matsuda, R., Kaneko, N., Smith, G.L. and Loughrey, C.M. (2011) K201 (JTV-519) alters the spatiotemporal properties of diastolic Ca²⁺ release and the associated diastolic contraction during β-adrenergic stimulation in rat ventricular cardiomyocytes. Basic Research in Cardiology, 106(6), pp. 1009-1022. (doi: 10.1007/s00395-011-0218-4)

Abstract

K201 has previously been shown to reduce diastolic contractions in vivo during beta-adrenergic stimulation and elevated extracellular calcium concentration ([Ca²⁺]_o). The present study characterised the effect of K201 on electrically stimulated and spontaneous diastolic sarcoplasmic reticulum (SR)-mediated Ca²⁺ release and contractile events in isolated rat cardiomyocytes during beta-adrenergic stimulation and elevated [Ca²⁺]_o. Parallel experiments using confocal microscopy examined spontaneous diastolic Ca²⁺ release events at an enhanced spatiotemporal resolution. 1.0 mµ mol/L K201 in the presence of 150 nmol/L isoproterenol (ISO) and 4.75 mmol/L [Ca²⁺]_o significantly decreased the amplitude of diastolic contractions to similar to 16% of control levels. The stimulated free Ca²⁺ transient amplitude was significantly reduced, but stimulated cell shortening was not significantly altered. When intracellular buffering was taken into account, K201 led to an increase in action potential-induced SR Ca²⁺ release. Myofilament sensitivity to Ca²⁺ was not changed by K201. Confocal microscopy revealed diastolic events composed of multiple Ca²⁺ waves (2-3) originating at various points along the cardiomyocyte length during each diastolic period. 1.0 mµ mol/L K201 significantly reduced the (a) frequency of diastolic events and (b) initiation points/diastolic interval in the remaining diastolic events to 61% and 71% of control levels respectively. 1.0 m#181; mol/L K201 can reduce the probability of spontaneous diastolic Ca²⁺ release and their associated contractions which may limit the propensity for the contractile dysfunction observed <i>in vivo</i>.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Smith, Professor Godfrey and Loughrey, Professor Christopher and Elliott, Dr Elspeth
• Authors: Elliott, E.B., Hasumi, H., Otani, N., Matsuda, T., Matsuda, R., Kaneko, N., Smith, G.L., and Loughrey, C.M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Basic Research in Cardiology
• ISSN: 0300-8428
• ISSN (Online): 1435-1803
• Published Online: 08 September 2011