Intense exercise causes a large loss of K⁺ from contracting muscles. The ensuing elevation of extracellular K⁺ ([K⁺]_o) has been suggested to cause fatigue by depressing muscle fiber excitability. In isolated muscles, however, repeated contractions confer some protection against this effect of elevated K⁺. We hypothesize that this excitation-induced force-recovery is related to release of the neuropeptide calcitonin gene-related peptide (CGRP), which stimulates the muscular Na⁺,K⁺-pumps. Using the specific CGRP antagonist 8-37 CGRP, we evaluated the role of CGRP in the excitation-induced force recovery and examined possible mechanisms. Intact rat soleus muscles were stimulated to evoke short tetani at regular intervals. Increasing [K⁺]_o from 4 to 11 mM decreased force to ~20% of initial force (P < 0.001). Addition of exogenous CGRP (10-9 M), release of endogenous CGRP with capsaicin, or repeated electrical stimulation recovered force to 50-70% of initial force (P < 0.001). In all cases, force recovery could be almost completely suppressed by 8-37 CGRP. At 11 mM [K⁺]_o CGRP (10-8 M) did not alter resting membrane potential or conductance but significantly improved action potentials (P < 0.001) and increased the proportion of excitable fibers from 32% to 70% (P < 0.001). CGRP was shown to induce substantial force-recovery with only modest Na⁺-K⁺ pump stimulation. We conclude that the excitation-induced force recovery is caused by a recovery of excitability, induced by local release of CGRP. The data suggest that the recovery of excitability partly was induced by Na⁺-K⁺ pump stimulation and partly by altering Na⁺ channel function.