Background: Initial studies on cardiac NAADP signaling were published, but no role for NAADP in cardiac arrhythmias has been reported.
Results: NAADP affects spontaneous diastolic Ca 2+ transients in cardiac myocytes and arrhythmias in awake mice.
Conclusion: Results indicate a pivotal role for NAADP in fine-tuning of cardiac excitation-contraction coupling.
Significance: First evidence is reported for involvement of NAADP in cardiac arrhythmias evoked by β-adrenergic stimulation.
Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca 2+-releasing second messenger known to date. Here, we report a new role for NAADP in arrhythmogenic Ca 2+ release in cardiac myocytes evoked by β-adrenergic stimulation. Infusion of NAADP into intact cardiac myocytes induced global Ca 2+ signals sensitive to inhibitors of both acidic Ca 2+ stores and ryanodine receptors and to NAADP antagonist BZ194. Furthermore, in electrically paced cardiac myocytes BZ194 blocked spontaneous diastolic Ca 2+ transients caused by high concentrations of the β-adrenergic agonist isoproterenol. Ca 2+ transients were recorded both as increases of the free cytosolic Ca 2+ concentration and as decreases of the sarcoplasmic luminal Ca 2+ concentration. Importantly, NAADP antagonist BZ194 largely ameliorated isoproterenol-induced arrhythmias in awake mice. We provide strong evidence that NAADP-mediated modulation of couplon activity plays a role for triggering spontaneous diastolic Ca 2+ transients in isolated cardiac myocytes and arrhythmias in the intact animal. Thus, NAADP signaling appears an attractive novel target for antiarrhythmic therapy.