The cardiovascular pharmacodynamics (PD) of procainamide and N-acetylprocainamide have not been well characterized in small rodents without the presence of anesthesia or restraint. This study was undertaken to examine the pharmacokinetics (PK) and PD relationship of procainamide and N-acetylprocainamide by use of electrocardiogram (ECG) telemetry in unrestrained rats. Male Sprague Dawley rats received the following treatments: vehicle, procainamide 50 and 100 mg/kg and N-acetylprocainamide 50 and 100 mg/kg via intraperitoneal (i.p.) administration. Blood samples were collected over 8 h and subsequently analyzed. PD measurements (PQ, QS, QR, QT, RR, and HR) were collected prior to dosing and over a 24 h period. Mean PK parameters after the 50 mg/kg dose were as follows: Cls/Fprocainamide = 86.42 mL min-1 kg-1, Cls/FN-acetylprocainamide = 36.62 mL min-1 kg-1, Vdprocainamide = 10.42 L/kg, and VdN-acetylprocainamide = 5.91 L/kg. The relationship between concentration (procainamide or N-acetylprocainamide) and effect (percent change QT interval) was best described by an Emax model for procainamide (EC50 = 445 ng/mL; Emax = 30.09%). These results approximate ECG changes noted in procainamide clinical studies, suggesting that telemetry can be used as a predictive tool of efficacy. Furthermore, the proposed PK-PD model describes the electrophysiological effects associated with procainamide.