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The role of inositol 1,4,5‐trisphosphate receptors in Ca 2+ signalling and the generation of arrhythmias in rat atrial myocytes
Author(s) -
Mackenzie Lauren,
Bootman Martin D.,
Laine Mika,
Berridge Michael J.,
Holmes Andrew,
Li WenHong,
Lipp Peter
Publication year - 2002
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2001.013411
Subject(s) - endocrinology , medicine , receptor , agonist , inositol , chemistry , myocyte , biology
Various cardio‐active stimuli, including endothelin‐1 (ET‐1), exhibit potent arrhythmogenicity, but the underlying cellular mechanisms of their actions are largely unclear. We used isolated rat atrial myocytes and related changes in their subcellular Ca 2+ signalling to the ability of various stimuli to induce diastolic, premature extra Ca 2+ transients (ECTs). For this, we recorded global and spatially resolved Ca 2+ signals in indo‐1‐ and fluo‐4‐loaded atrial myocytes during electrical pacing. ET‐1 exhibited a higher arrhythmogenicity (arrhythmogenic index; ratio of number of ECTs over fold‐increase in Ca 2+ response, 8.60; n = 8 cells) when compared with concentrations of cardiac glycosides (arrhythmogenic index, 4.10; n = 8 cells) or the β‐adrenergic agonist isoproterenol (arrhythmogenic index, 0.11; n = 6 cells) that gave similar increases in the global Ca 2+ responses. Seventy‐five percent of the ET‐1‐induced arrhythmogenic Ca 2+ transients were accompanied by premature action potentials, while for digoxin this proportion was 25 %. The β‐adrenergic agonist failed to elicit a significant number of ECTs. Direct activation of inositol 1,4,5‐trisphosphate (Ins P 3 ) receptors with a membrane‐permeable Ins P 3 ester (Ins P 3 BM) mimicked the effect of ET‐1 (arrhythmogenic index, 14.70; n = 6 cells). Inhibition of Ins P 3 receptors using 2 μM 2‐aminoethoxydiphenyl borate, which did not display any effects on Ca 2+ signalling under control conditions, specifically suppressed the arrhythmogenic action of ET‐1 and Ins P 3 BM. Immunocytochemistry indicated a co‐localisation of peripheral, junctional ryanodine receptors with Ins P 3 Rs. Thus, the pronounced arrhythmogenic potency of ET‐1 is due to the spatially specific recruitment of Ca 2+ sparks by subsarcolemmal Ins P 3 Rs. Summation of such sparks efficiently generates delayed afterdepolarisations that trigger premature action potentials. We conclude that the particular spatial profile of cellular Ca 2+ signals is a major, previously unrecognised, determinant for arrhythmogenic potency and that the Ins P 3 signalling cassette might therefore be a promising new target for understanding and managing atrial arrhythmia.