Abstract
[Background & Objectives] Potential adverse effects of drug candidates on the central nervous system (CNS) have been assessed in Safety Pharmacology studies with behavior analysis which performed in a relatively subjective manner. Since heart rate vary according to autonomic nervous activities which reflect CNS activities, we hypothesized that drugs effect on CNS can affect heart rate variability (HRV). The purpose of this study was to evaluate whether some frequency-domain parameters of HRV can be an objective index for detecting CNS undesirable effects.
[Materials & Methods] Rats implanted ECG telemetry system were used and their ECG data were obtained after administration of drugs 1) targeting CNS, 2) causing CNS side effects, and 3) having no obvious effect on CNS. R-R intervals were dissected to perform frequency-domain analysis obtaining the spectral power in the low frequency range (LF, 0.03 to 1.0 Hz) and the high frequency range (HF, 1.0 to 3.0 Hz), and LF/HF ratio. Data were analyzed for at least one hour before as baseline and 6 hours after drug administration every one hour.
[Results & Discussion] Drugs used in this study caused no obvious changes in heart rate. Drugs having no obvious effect on CNS hardly changed any HRV parameters, whereas drugs targeting CNS or causing CNS side effects significantly increased LF/HF from baseline in a dose-dependent manner, with changes in the latter drugs being rather evident. This study suggests that LF/HF, which represents autonomic nervous system balance, could be an indicator of drug-induced undesirable effects on the CNS.
