Twelve healthy male volunteers cycled to exhaustion at a workload corresponding to 70% of maximal aerobic power after administration of 80 mg of the beta 1+2-adrenoceptor antagonist propranolol and after administration of placebo by mouth. Exercise times until exhaustion were 39 +/- 7 and 86 +/- 7 min in the propranolol and placebo groups, respectively. Muscle inosine 5'-monophosphate content was significantly increased above resting levels at exhaustion after placebo. At exhaustion after propranolol, inosine 5'-monophosphate was not increased significantly and was lower than at exhaustion after placebo. No changes in ATP and the total adenine nucleotide content during exercise were found in the two tests. Muscle glycogen content was significantly reduced at exhaustion after placebo as well as after propranolol, but the levels were still significantly higher at exhaustion after propranolol than after placebo. No evidence for a shift in glycogen utilization among types I, IIa, and IIb fibers after propranolol was found. The results show that neither an imbalance between ATP utilization and ATP regeneration nor premature glycogen depletion, either in the whole muscle or in specific muscle fiber types, provides a satisfactory explanation for the premature fatigue during endurance exercise after propranolol.