It has been widely accepted that lidocaine has little or no effect on the autonomic nervous system. However, we have previously shown that in dogs with vagally induced atrial fibrillation, lidocaine has a pronounced parasympatholytic effect. To study the possible effect of lidocaine on autonomic cardiac control in humans, we performed spectral analysis of heart rate fluctuations in 19 healthy volunteers, who received an i.v. bolus of lidocaine (1.4 mg/kg), as well as in 13 patients suffering from acute inferior myocardial infarction (IMI) and 13 patients suffering from acute anterior myocardial infarction (AMI), who received therapeutic doses of i.v. lidocaine infusion (4 mg/min). Heart rate variability and respiratory pattern were monitored according to a predetermined protocol, with and without lidocaine. Computing the heart rate power spectrum and integrating over predetermined frequency bands, we focused mainly on the respiratory frequency band, known to predominantly reflect parasympathetic control. The administration of lidocaine resulted in a significant overall increase in mean heart rate: for the healthy control group an increase of 5.5 +/- 2.2% (mean +/- SE), for the IMI group an increase of 9.4 +/- 3.5%, and for the AMI group an increase of 8.1 +/- 2.9% (p < 0.01 for all). Simultaneously, following the administration of lidocaine, there was a decrease in the power of respiratory fluctuations: for the healthy control group a decrease of 38.4 +/- 12.5%, for the IMI group a decrease of 46.3 +/- 32.9%, and for the AMI group a decrease of 33.9 +/- 16.2% (p < 0.01 for all). These findings indicate that lidocaine has a consistent and significant parasympatholytic effect on the human heart, in healthy volunteers as well as in patients in the acute phase of myocardial infarction.