Progressive increase in sympathetic (SNS) nervous activity and reduction in parasympathetic (PNS) nervous activity may directly contribute to the inevitable lethal outcome of heart failure (HF) syndrome. Partial reduction of augmented SNS activity with β-adrenergic blockade prolongs survival of HF patients. However, this intervention leaves α-adrenergic overstimulation untouched and sympathetic vasoactive adrenergic co-transmitters elevated. Central sympatholysis, which blocks the whole SNS, was postulated as a more efficient approach to limit sympathetic overactivity in HF patients. Unexpectedly, moxonidine (I1- imidazoline receptor agonist) elevated HF mortality. Because alteration of fractal organization of interbeat interval (IBI) variability is associated with raised mortality (1,2), we hypothesized that differences in the effects of central sympatholytics (moxonidine & clonidine), and β1-adrenergic blocker (metoprolol) on fractal scaling coefficients may provide a clue to understanding the mechanism of moxonidine failure in the HF treatment trial. During general anesthesia (120 mg.kg-1 ketamine & 6 mg.kg-1 xylazine i.p.), 12-week old male Wistar rats (n = 8) were implanted with telemetric transmitters (HD-S11, Data Sciences, USA). Implants allowed simultaneous monitoring of aortic pressure, ECG, core body temperature, and locomotor activity. Detrended fluctuation analysis was used to assess short-term (α1) and long term (α2) scaling coefficients, which characterize the fractal organization of IBI variability. Six increasing doses of central sympatholytics (0 – 12.15 μmol.kg-1) and metoprolol (0 – 291.1 μmol.kg-1) were applied s.c. Moxonidine dose-dependently reduced the α1 coefficient; IBI intervals became uncorrelated at the highest dose (0.528 (0.116), p<0.001; Tukey HSD after multivariate (Wilks) repeated measure ANOVA; data are mean, S.D. in brackets), which reflects strong PNS activation and SNS inhibition. Sympatholytic effect of high doses of moxonidine was confirmed by the attenuation of the Brownian component in IBI fluctuations (α2=1.038 (0.118), p=0.006 at 12.15 µmol.kg-1). Clonidine reduced the α2 coefficient at all doses making IBI fluctuation less correlated at long scales also (0.657 (0.159), p<0.001), which confirms sympatholytic effects of clonidine. Short-term α1 coefficient reached white noise values (0.563 (0.1), p=0.0005) at a concentration of 1.35 µmol.kg-1. In agreement with its β1-adrenergic blocking action, metoprolol had no effect on the α1 coefficient, but weakened the Brownian component of IBI fluctuations and brought long-term IBI correlations to 1/f noise (1.059 (0.069), p=0.002). In conclusion, moxonidine and clonidine, but not metoprolol, dose-dependently activate PNS and inhibit SNS, which shift fractal organization of IBI time series toward white noise thus potentially increasing the mortality risk.