Experiments have been designed to investigate the physiological factors influencing the interrelationship between excitation and force generation that may counteractt he processesle ading to a decline in force (fatigue) during stimulatedi sometric contractions of the human adductor pollicis in vivo. Indices of isometric force, relaxation and contraction rates and evoked compound muscle action potentials (CMAP) were measured during defined patterns of stimulated activity (via the motor nerve). A computerized stimulator controller for precise generation of trains of electrical impulses was developed for this purpose. Forces generated at different frequencies were reproducible on separate occasions. Using an ascending frequency stimulation protocol (1-100Hz) the relationship between force decline and excitation (measured as the amplitude of the surface evoked CMAP) appeared to be dependent on stimulation frequency during ischaemic and nonoccluded activity. At high frequencies (50-100Hz), a `safety factor' was apparent, allowing preservation of force despite a marked fall in excitation, whereas at low frequencies (1-10Hz) force initially potentiated and then declined in excess of excitation. Maximum relaxation rate was reduced at all stimulation frequencies and was independent of stimulation frequency. Contractile activity performed was shown to be linearly related to maximum relaxation rate over a frequency range of 20-100Hz for up to 30max. seconds. Contractile activity performed was therefore used as a measure of the metabolic cost of a contraction. Force failure appeared to depend upon the numbers of stimuli delivered, independent of frequency, rather than on contractile activity performed, suggesting that electrophysiological factors are of importance in contributing to fatigue. Further studieso n CMAP characteristicsd emonstrateda broadeningo f the action potential, reflecting a slowing of conduction velocity, which is thought to lead to `runin' of action potentials, and hencet he reduction of CMAP amplitude associatedw ith the high-frequency `safety factor'. The broadening of the action potential recovered immediately during ischaemic conditions at 100Hz following 2400 stimuli but did not recover following prolonged activity at 20Hz until circulation was restored, whereas CMAP amplitude recovered immediately at both frequencies, suggesting that slowing of conduction velocity may be dependent on metabolic factors at low stimulation frequencies which in turn may depend on the contractile history of the muscle. Patients with myophosphorylase deficiency (and thus unable to utilize glycogen), were studied to investigate the importance of energy supply. A failure of ischaemic recovery of the CMAP amplitude and no broadening of the CMAP after stimulated activity at 20Hz was observed, suggesting a failure of excitation of individual muscle cells occurs resulting in force failure in these individuals. Reversing the pattern of stimulation resulted in an initial enhancement of low frequency (10Hz) force and a prolonged maintenance of this force throughout the period of contraction studied. This was independent of slowing of relaxation or excitation. The initial force enhancement may result from the increased slowing of relaxation, and in addition, a form of post-tetanic twitch potentiation operates to counteract the decline in force despite a loss in excitation. In conclusion, during stimulated contractile activity of the adductor pollicis, mechanisms act to maintain or increase force generated per action potential distal to the sarcolemmal membrane, at both high and low frequencies of stimulation, thereby counteracting mechanisms that lead to fatigue. It is postulated that the alterations in intramuscular processes may allow voluntary isometrically contracting muscle to optimize force production at the onset of a contraction where high motor unit discharge rates are initially developed, delaying or eliminating the influence of excitation failure which would lead to contractile failure once maximal force is achieved, and subsequently to optimize contractile activation in the light of possible excitation failure as motor unit discharge rates decline. These findings may have important functional implications and may form the basis of physiological strategies for optimizing force production in the development of stimulation regimes for `functional electrical stimulation' or to any area of skeletal muscle research in which fatigue resistance is of importance.