Inhibitors of hydroxymethylglutaryl-CoA reductase or statins have been shown to alleviate endothelial dysfunction. Their effects on constitutive nitric oxide synthase in the central nervous system may hypothetically affect the autonomic balance in sympathoexcitatory states, such as chronic heart failure (CHF). To address this issue, simvastatin (SIM) (0.3, 1.5, or 3 mg. kg-1. day-1 po) was given to rabbits with pacing-induced CHF over a 3-wk period. Normal and CHF vehicle-treated rabbits served as controls. Autonomic balance was assessed by measuring heart rate variability, including power spectral analysis (PSA). In addition, changes in resting heart rate were assessed before and after vagal and sympathetic autonomic blockade by atropine and metoprolol, respectively. The SD for all intervals was 8.9 +/- 0.7 ms in normal, 4.9 +/- 0.6 ms in CHF (P < 0.01), 3.8 +/- 0.6 ms in CHF with 0.3 mg. kg-1. day-1 SIM (P < 0.001), 5.7 +/- 0.9 in CHF with 1.5 mg. kg-1. day-1 SIM (P < 0.05), and 7.2 +/- 0.5 in CHF with 3.0 mg. kg-1. day-1 SIM. Similarly, total power was 40.5 +/- 6.3 ms2 in normal, 10.1 +/- 3.0 ms2 in CHF (P < 0.01), 6.0 +/- 1.6 ms2 in CHF with 0.3 mg. kg-1. day-1 SIM (P < 0.01), 13.2 +/- 3.9 ms2 in CHF with 1.5 mg. kg-1. day-1 SIM (P < 0.05), and 22.0 +/- 3.0 ms2 in CHF with 3.0 mg. kg-1. day-1 SIM. Both PSA data for low (0.625-0.1875 Hz) and high frequencies (0.1875-0.5625 Hz) showed recovery in CHF animals on medium and high SIM doses without changes in the low-to-high-frequency ratio. SIM beneficially affects autonomic tone in CHF as seen by the reversal of depressed HRV and total power of PSA. These data have important implications for the treatment of patients with autonomic imbalance.