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Background: Nitric oxide (NO) can modulate myocardial contractility and relaxation but it is not clear whether its effects on heart rate result from a direct action on the activity of the cardiac pacemaker or from a reflex response to the concurrent changes in arterial blood pressure. Methods and Results: In guinea pig isolated spontaneously beating atria we investigated the chronotropic effect of increasing concentrations of two NO donors (NOd): sodium nitroprusside (SNP, n=8) and 3-morpholino-sydnonimine (SIN-1, n=6). We found that exogenous NO modulates the beating rate in a concentration-dependent biphasic fashion, with a gradual increase in beating rate for low concentrations of NOd (nano- to micromolar) and a decrease in beating rate for high concentrations (millimolar). The positive chronotropic effect of 10 μmol/L SNP (n=28) or 50 μmol/L SIN-1 (n=16) was unaffected by ICaL antagonism with nifedipine (0.2 μmol/L) but was abolished after blockade of the hyperpolarization-activated inward current, If, by Cs+ (2 mmol/L) or ZD7288 (1 μmol/L). The involvement of If in the positive chronotropic response of exogenous NO was also tested in rabbit isolated patch-clamped SAN cells (n=17) where 5 μmol/L SNP caused a reversible, Cs+-sensitive, increase in this current (+ 130% at -70 mV and + 250% at -100 mV). Conclusions: Exogenous NO can directly affect pacemaker activity in a concentration-dependent biphasic fashion. The increase in beating rate with low doses of NOd is unaffected by ICaL antagonism but is abolished in the presence of If blockade. Direct recordings of If in SAN cells confirmed that this current is markedly increased by NOd. Our results suggest that stimulation of If by NO might play a part in the sinus tachycardia which accompanies pathological conditions associated with an increase in myocardial production of NO (e.g. heart failure and septic shock).


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