Zatebradine is a bradycardic agent with a selective effect on the pacemaker current in the sinus node. The effect of such drugs on heart rate variability is not known. Thirty-six patients without structural heart disease were randomly assigned to receive 10 mg of zatebradine i.v. (n = 24) or isotonic saline (n = 12). Heart rate variability (HRV) was recorded as power in the very low frequency (VLF, 0.003-0.040 Hz), low frequency (LF, 0.040-0.150 Hz), and high frequency (HF, 0.150-0.400 Hz) spectral bands as well as total power (TP, 0.003-0.400 Hz) during 5-min ECG acquisitions at baseline, 30, and 60 min following the start of the infusion. No change in heart rate variability was detected in the control group. Zatebradine significantly reduced heart rate variability at 60 min in all frequency bands: VLF (-12+/-4%, p<0.001), LF (-19+/-4%, p<0.001), and HF (-26+/-5%, p<0.001). The reduction in HRV following zatebradine is due to depression of sinus node response to all external stimuli and underscores the need for documentation of normal sinus node function in HRV research.