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Background: Nitric oxide (NO) exerts a positive chronotropic effect in vitro by stimulating the pacemaker current If without affecting ICaL. If activity is modulated by [Ca2+]i and recent evidence indicates that NO can activate ryanodine receptors in cardiac sarcoplasmic (SR) vesicles. The aim of this study was to test whether exogenous NO stimulates pacemaker activity by promoting SR Ca2+ release. Methods and Results: In isolated guinea-pig atria, we evaluated the chronotropic response to increasing concentrations (from 0.1 μmol/L to 1 mmol/L) of the NO donors SIN-1 (+superoxide dismutase 100 U/mL, n=6) or DEA/NO (n=8), (i) alone, or (ii) after pre-treatment (40min) with 2μmol/L ryanodine (n=7) to block the SR Ca2+ release or 60μmol/L cyclopiazonic acid (2h) to deplete SR Ca2+ stores (n=9). Ryanodine decreased heart rate (HR) from 169±7 to 125±7 bpm (mean± SEM, p<0.05). CPA caused a transient increase in HR (from 163±6 to 196±9 bpm) followed by a reduction to 133±6 bpm (p<0.05). SIN-1 or DEA/NO alone, progressively increased HR with a peak effect of +51±5 bpm and +41±5 bpm at 0.1 mmol/L (p<0.05). In contrast, after pre-treatment with ryanodine or CPA, the peak increase in HR was only +19±4 bpm with SIN-1 and +16±3 bpm with DEA/NO (p<0.05). In addition, we evaluated the intracellular Ca2+ transient (fluorescence with 5 μmol Indo-1 AM) in guinea pig isolated sinoatrial node cells (n=6) before and after application of sodium nitroprusside (SNP, 5 μmol/L). SNP significantly augmented diastolic Ca2+ (+13±9%), peak Ca2+ (+33±21%), and the amplitude of the Ca2+ transient (+102±49%) (Fig), and increased the spontaneous beating rate by 34±12% (p<0.05). Conclusion: Exogenous NO stimulates SR Ca2+ release in sinoatrial node cells. This pathway contributes substantially to the positive chronotropic effect of NO donors. (Graph Presented).


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