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First published online 1 August 2006
doi: 10.1242/jcs.03073

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Inositol 1,4,5-trisphosphate supports the arrhythmogenic action of endothelin-1 on ventricular cardiac myocytes

¹ Calcium Group, Laboratory of Molecular Signalling, Babraham Institute, Babraham, Cambridge, CB2 4AT, UK
² Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD, UK
³ School of Chemistry, University of St Andrews, North Haugh, St Andrews, Fife, KY16 9ST, UK
⁴ GE Healthcare, Forest Farm, Whitchurch, Cardiff, CF14 7YT, UK

^* Author for correspondence (e-mail: Llewelyn.roderick{at}bbsrc.ac.uk)

Accepted 1 June 2006

Although ventricular cardiomyocytes express inositol 1,4,5-trisphosphate [Ins(1,4,5)P₃] receptors, it is unclear how these Ca²⁺ channels contribute to the effects of Gq-coupled agonists. Endothelin-1 augmented the amplitude of pacing-evoked Ca²⁺ signals (positive inotropy), and caused an increasing frequency of spontaneous diastolic Ca²⁺-release transients. Both effects of endothelin-1 were blocked by an antagonist of phospholipase C, suggesting that Ins(1,4,5)P₃ and/or diacylglycerol production was necessary. The endothelin-1-mediated spontaneous Ca²⁺ transients were abolished by application of 2-aminoethoxydiphenyl borate (2-APB), an antagonist of Ins(1,4,5)P₃ receptors. Incubation of electrically-paced ventricular myocytes with a membrane-permeant Ins(1,4,5)P₃ ester provoked the occurrence of spontaneous diastolic Ca²⁺ transients with the same characteristics and sensitivity to 2-APB as the events stimulated by endothelin-1. In addition to evoking spontaneous Ca²⁺ transients, stimulation of ventricular myocytes with the Ins(1,4,5)P₃ ester caused a positive inotropic effect. The effects of endothelin-1 were compared with two other stimuli, isoproterenol and digoxin, which are known to induce inotropy and spontaneous Ca²⁺ transients by overloading intracellular Ca²⁺ stores. The events evoked by isoproterenol and digoxin were dissimilar from those triggered by endothelin-1 in several ways. We propose that Ins(1,4,5)P₃ receptors support the development of both inotropy and spontaneous pro-arrhythmic Ca²⁺ signals in ventricular myocytes stimulated with a Gq-coupled agonist.

Key words: Inositol 1,4,5-trisphosphate, Arrhythmia, Calcium, Ryanodine, Inotropy, Endothelin

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