In an attempt to evaluate the propranolol (P) concentration-effect relationship, percentage reduction in exercise heart rate was modeled as a function of unbound and total P concentrations using the linear, Emax, and sigmoid Emax models. Nine volunteers underwent repeated treadmill exercise tests over 48 hr during a control period, after receiving 160 mg of P orally and again after receiving 160 mg once daily for 7 days. Beta blockade was assessed as the percentage reduction in exercise heart rate compared to control. Total serum P concentrations were determined by HPLC and unbound fractions by equilibrium dialysis. Using nonlinear least-squares regression, the Emax model was best in describing the concentration-effect relationship in each subject. Mean parameters for combined single dose and steady state were Emax 33.6 +/- 4.5% and EC50 18.2 +/- 15.6 ng/ml for total P and Emax 33.5 +/- 4.3% and EC50 1.66 +/- 1.56 for unbound P. Model fits were not significantly better for unbound versus total P and EC50 values showed similar intersubject variability. The observed unbound EC50 values are consistent with reported receptor dissociation constants. Therefore the large intersubject variability in EC50 could not be accounted for by variability in P protein binding.