The effects of beta-blockade on muscle utilization of glycogen and triglycerides, as well as potassium metabolism, were studied in eight healthy male subjects performing long-duration exercise to exhaustion. Subjects were studied after treatment with either placebo (PLAC), beta 1-selective (atenolol, 100 mg/day, AT), or nonselective beta-blockade (nadolol, 80 mg/day, NAD) each for 1 wk according to a randomized, double-blind, cross-over design. NAD and AT caused identical decreases in exercise heart rates, but endurance (71 +/- 8 min with PLAC) decreased significantly more with NAD (-33 +/- 4%) than with AT (-14 +/- 6%). Muscle glycogen breakdown, taking exercise time into account, was unaffected by treatment. In contrast, muscle triglyceride utilization was completely blocked by NAD whereas it was unchanged with AT as compared to PLAC. Adipose tissue lipolysis was inhibited to a similar extent by the two beta-blockers. Serum potassium increased to higher levels at exhaustion and muscle potassium decreased to lower levels with NAD than with AT or PLAC. These results suggest that decreased utilization of muscle triglycerides combined with lack of an enhanced glycogenolysis to compensate as well as alterations in potassium metabolism contribute to the decreased exercise capacity with nonselective beta-blockade compared with beta 1-selective blockade.