This study examined the effects of a nonselective beta-blocking agent on whole-body leucine metabolism in humans. Five normal, healthy subjects (4 male, 1 female) underwent a 6-h primed, constant-rate infusion of L-[1-13C]leucine after 5 days of twice daily oral use of 80 mg propranolol and a placebo. Leucine turnover was determined by tracer dilution and leucine oxidation by 13C enrichment of the expired CO2. Propranolol decreased the total daily energy expenditure from 1,945 +/- 177.5 to 1,619 +/- 92.5 kcal/day (P less than 0.05). A fasting associated decrease in blood glucose and an attenuated rise in free fatty acids and ketones were observed during beta-blockade. Propranolol also increased plasma leucine concentrations (73.1 +/- 8.7 to 103.4 +/- 7.3 mumol/l; P less than 0.05) and leucine oxidation (13.2 +/- 1.2 to 17.1 +/- 1.3 mumol.kg-1.h-1; P less than 0.05), although leucine turnover was not significantly altered (100.5 +/- 7.3 vs. 126.0 +/- 12.3 mumol.kg-1.h-1). In addition, the urinary urea nitrogen-to-creatinine ratio was greater during propranolol administration (0.24 +/- 0.04 vs. 0.34 +/- 0.02 mol/g; P less than 0.05). These data suggest that the beta-adrenergic system plays a role in the modulation of whole-body leucine metabolism in humans. Whether these changes are the result of a direct effect on skeletal muscle or an indirect effect mediated by altering the fuel supply to skeletal muscle cannot be discriminated by the present study.