During exercise, loss of K+ from active muscles causes an increase in the extracellular K+ concentration ([K+]o). When exercise intensity is high, the concentration of K+ may increase to above 10 mM in the interstitium of the working muscles (see e.g. Sejersted & Sjogaard, 2000). Since exposure of isolated muscles to such concentrations of K+ leads to loss of muscle excitability and depression of excitation-induced force production, the exercise-induced increase in [K+]o has been proposed to contribute to muscle fatigue (Sejersted & Sjogaard, 2000). The loss of muscle excitability at high [K+]o is most likely related to slow inactivation of voltage gated Na+ channels (Ruff, 1996). When Na+ channels inactivate, the inward depolarising Na+ current they carry becomes to weak to overcome the re-polarising or inhibitory K+ and Cl- currents, resulting in failure of the initiation and of the propagation of action potentials. Since skeletal muscle has a large Cl- conductance, this vulnerability of membrane function to increased [K+]o may be of particular importance for the excitability of this tissue. Lately we have found that in acidified rat muscles, excitability and force production can be maintained at a higher [K+]o than in muscles at normal pH (Nielsen et al. 2001). Thus, when isolated soleus muscles from humanely killed rats were incubated at a [K+]o of 10 mM, which reduced tetanic force and excitability (as judged from the area of compound action potentials, M-waves) by around 75%, subsequent addition of 20 mM lactic acid led to an almost complete recovery of force production and excitability. The increased tolerance of acidified muscles to elevated [K+]o could also be induced by increasing the CO2 tension and seems to be related to a reduction in intracellular pH. In search for a mechanism for the improved excitability of acidified muscles we found that a similar increase in the tolerance to elevated [K+]o could be induced in muscles at normal pH by adding 9-AC (an inhibitor of the major muscle Cl- channel, ClC1) or by replacing buffer Cl- by methanesulfonate, which do not penetrate through the Cl- channels (Pedersen et al. 2005). Since both treatments reduces the Cl- conductance of the muscle fibres, this indicated that the improved excitability in acidified muscles could be related to an inhibition of Cl- channels leading to a lowered Cl- conductance. To examine this, the effect of acidosis on the membrane conductance of single muscle fibres was measured in muscles incubated at 11 mM K+ in normal and in Cl- free buffer at 5 or 24% CO2. Membrane conductance was measured by injecting hyperpolarizing constant current pulses into muscle fibres through one intracellular microelectrode while recording the membrane voltage response by another electrode. From these measurements, membrane conductance was calculated according to Boyd & Martin (1959). These experiments showed that in muscles at 11 mM K+, the recovery of compound action potentials and force with muscle acidification was associated with a reduction in the chloride conductance from 1731 to 938 S/cm2 (P < 0.01). No change was observed in the potassium conductance (405 to 455 S/cm2 (P < 0.16). From this study it is concluded that the recovery of excitability induced by acidification in K+-depressed muscles is related to a reduction in the inhibitory Cl- currents, possibly through an inhibition of ClC-1 channels, and that acidosis thereby reduces the Na+ current needed to generate and propagate an AP. Together, these findings indicate that the development of muscle acidosis during intense exercise causes an up-regulation of muscle excitability, which may help muscles to maintain their excitability when [K+]o is increased. Thereby, the development of muscle acidosis may delay possible fatigue caused by loss of muscle excitability.