Previous animal experiments suggest that the increase in the amplitude from the R-wave to the S-wave (RSh) may be more sensitive than other ECG measures to sodium channel blocking drug actions. We measured RSh of three orthogonal leads at baseline and during intravenous pharmacologic stimulation with adenosine, ajmaline, atropine, disopyramide, isoproterenol, lidocaine, norepinephrine (NE), propranolol, and verapamil in an observer-blinded placebo-controlled study in healthy young men. The short-term reproducibility of RSh was high. Ajmaline increased RSh in the anteroposterior lead, disopyramide in the anteroposterior and vertical lead, and lidocaine in the vertical and horizontal lead, respectively. Isoproterenol increased RSh in the anteroposterior lead; atropine decreased RSh in the vertical lead. The other drugs did not affect RSh significantly. Our data do not support the concept that RSh measure is a more sensitive technique for assessing class I antiarrhythmic drug action in humans, at least in healthy subjects. In addition, our results indicate that changes in autonomic tone may influence RSh measurements.