Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP)-mediated Calcium Signaling and Arrhythmias in the Heart Evoked by β-Adrenergic Stimulation* ^♦

Abstract

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.

Abstract

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.