The dose of propranolol which produces the optimal therapeutic effect in patients with angina pectoris has been found to vary widely among patients. Because the plasma concentration of propranolol also differs markedly due to interpatient variability in absorption it seemed possible that this might be the reason for the wide range of effective doses in angina and that plasma propranolol might provide a useful guide to therapeutic response. To examine this possibility we selected ten patients with coronary artery disease complicated by angina and studied them at varying propranolol doses to a maximum of 320 mg/day. Exercise capacity was tested on a treadmill and plasma propranolol concentration was measured by gas liquid chromatography. In seven normal subjects beta-blockade was quantified precisely as inhibition of exercise tachycardia and was related to plasma propranolol levels at various doses. Maximal beta-blockade occurred at 100 ng/ml of plasma propranolol, but the dose response curve of blockade was relatively flat and the ED50 of plasma propranolol was 8+/-1 ng/ml. In the patients maximal therapeutic benefit from propranolol occurred at 30+/-7 ng/ml and at a dose of 144 mg/day. This resulted in an increase in exercise capacity from an estimated 12-7+/-0-8 ml/kg/min of oxygen consumption during control to 17-2+/-1-1 ml/kg/min on the drug. Thus, there was a wide variation of both dose and concentration among these patients at the maximum therapeutic response. However, when plasma propranolol was related to pharmacologic activity, the maximum therapeutic response was observed between 64 and 98% of total blockade. These studies indicated the extent of beta-blockade necessary to produce an effective therapeutic response in angina, but demonstrate that plasma drug levels provide no practical guide to therapy in patients with angina pectoris. A further study was conducted measuring plasma propranolol in twenty hypertensive patients to investigate the fall in blood pressure in relations to the change in plasma renin activity and the inhibition of cardiac adrenergic receptors. The inhibition of plasma renin closely resemble the response seen in heart rate inhibition in that the maximum response is seen at 100 ng/ml and the ED50 was 11 ng/ml. In contrast propranolol is shown only to begin to have a significant effect on blood pressure at a plasma level of 30 ng/ml and the effect becomes progressively greater as the plasma level increases. This suggests that the hypotensive effect of propranolol may be dissociated from the beta-blocking effects of cardiac and renin releasing receptors.