Effects of calcitonin gene-related peptide on rat soleus muscle excitability: mechanisms and physiological significance

Will Macdonald, OB Nielsen, T Clausen

    Research output: Contribution to journalArticlepeer-review

    18 Citations (Scopus)


    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 the release of the neuropeptide calcitonin gene-related peptide (CGRP), which stimulates the muscular Na+-K+ pumps. Using the specific CGRP antagonist CGRP-(8-37), 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 extracellular K+ ([K+](o)) from 4 to 11 mM decreased force to similar 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 CGRP-(837). 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.
    Original languageEnglish
    Pages (from-to)R1214-R1223
    JournalAmerican Journal of Physiology: Regulatory, Integrative and Comparative Physiology
    Issue number4
    Publication statusPublished - 2008


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