The role of inositol 1,4,5-trisphosphate (InsP₃) in cardiac myocyte function is unclear and controversial, although agonists activating InsP₃ generation are positive inotropic agents in the heart and have been implicated in various cardiac pathologies. We investigated the expression and subcellular localisation of InsP₃ receptors (InsP₃Rs) in rat ventricular and atrial myocytes. In addition, the consequences of activating InsP₃Rs on spontaneous Ca²⁺ release were monitored using laser-scanning confocal microscopy. Rats were killed by cervical dislocation following CO₂ anaethesia according to Home Office regulations. PCR, Western blotting and InsP₃-binding analyses indicated that atrial and ventricular myocytes expressed InsP₃Rs. Both cell types mainly expressed type II InsP₃Rs, with atrial myocytes displaying 5-fold higher levels of InsP₃Rs than ventricular cells. We observed that stimulation of atrial myocytes with InsP₃-generating hormones increased the likelihood of pro-arrhythmogenic events such as Ca²⁺ sparks, Ca²⁺ waves and action potentials. Direct activation of InsP₃Rs by application of a membrane-permeant InsP₃ ester to the cells evoked similar responses, indicating that InsP₃R activity alone can underlie some of the established effects of hormonal stimulation. In atrial myocytes, the predominant form of Ca²⁺ release during stimulation with hormones or InsP₃ esters was an increase in Ca²⁺ spark frequency. Such increases in Ca²⁺ spark activity were most commonly observed in the cellular regions where InsP₃Rs and ryanodine receptors (RyRs) were co-localised. The activation of Ca²⁺ sparks by hormones and the InsP₃ ester suggest that cross-talk between InsP₃Rs and RyRs was responsible for the enhancement of Ca²⁺ release by InsP₃. Our data indicate that InsP₃Rs are abundantly expressed in atrial and ventricular myocytes, and that their activation can modulate cardiac function.

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