The non-steroidal anti-inflammatory drugs (NSAIDs) are a widely used group of drugs in clinical medicine. However, their propensity to cause gastrointestinal damage limits their clinical utility. The pathogenesis of this toxicity is not well established. It has been postulated that an early event in the development of damage is an effect of these drugs on mitochondrial function. The present paper sets out to evaluate the effects of indomethacin, a commonly used NSAID, on energy metabolism in vivo . Indomethacin was administered to male Sprague-Dawley rats, either intrajejunally or orally, and indices of mitochondrial function were determined. The parameters chosen for this purpose were oxygen uptake by, lactate levels in and the energy charge of jejunal tissue. Oxygen uptake by and energy charge in jejunal tissue were unaffected at 1 and 3h after dosing by gavage with indomethacin. The drug significantly affected the tissue lactate/pyruvate ratio at 3h (but not at 1h) after oral dosing. Effects of indomethacin on jejunum incubated ex vivo were found to be reversible. The data suggest that indomethacin affects mitochondrial function in vivo , but that compensatory changes in glycolytic rate maintain energy charge.

1. To examine metabolic correlates of insulin resistance in skeletal muscle, we used 31 P magnetic resonance spectroscopy to study glycogenolytic and oxidative ATP synthesis in leg muscle of lean and obese Zucker rats in vivo during 6 min sciatic nerve stimulation at 2 Hz. 2. The water content of resting muscle was reduced by 21 ± 7% in obese (insulin-resistant) animals compared with lean animals, whereas the lipid content was increased by 140 ± 70%. These results suggest that intracellular water content was reduced by 17% in obese animals. 3. During exercise, although twitch tensions were not significantly different in the two groups, rates of total ATP synthesis (expressed per litre of intracellular water) were 48 ± 20% higher in obese animals, suggesting a 50 ± 8% reduction in intrinsic ‘metabolic efficiency’. Changes in phosphocreatine and ADP concentration were significantly greater in obese animals than in lean animals, whereas changes in intracellular pH did not differ. 4. These results imply that oxidative ATP synthesis during exercise is activated earlier in obese animals than in lean animals. This difference was not fully accounted for by the greater increase in the concentration of the mitochondrial activating signal ADP. Neither the post-exercise recovery kinetics of phosphocreatine nor the muscle content of the mitochondrial marker enzyme citrate synthase was significantly different in the two groups. The increased oxidative ATP synthesis in exercise must therefore be due to altered kinetics of mitochondrial activation by signals other than ADP. 5. Thus, the insulin-resistant muscle of obese animals may compensate for its decreased efficiency (and consequent increased need for ATP) by increased reliance on oxidative ATP synthesis.

1. We set out to define abnormalities of oxidative ATP synthesis, cellular proton efflux and the efficiency of ATP usage in gastrocnemius muscle of patients with claudication due to peripheral vascular disease, using data obtained by 31 P magnetic resonance spectroscopy during aerobic exercise and recovery. 2. Eleven patients with moderate claudication were studied and results were compared with 25 age-matched control subjects. Changes in pH and phosphocreatine concentration during recovery were used to calculate the maximum rate of oxidative ATP synthesis ( Q max .) and the capacity of net proton efflux. Changes in pH and phosphocreatine concentration were used to estimate rates of non-oxidative and (indirectly) oxidative ATP synthesis throughout exercise, taking account of abnormalities in proton efflux during exercise. 3. In patients with claudication, slow post-exercise phosphocreatine recovery showed a 42 ± 9% decrease in Q max. , and the slow ADP recovery was consistent with this. pH recovery was slow, showing a 77 ± 9% decrease in the capacity for proton efflux. Both abnormalities are compatible with a substantial reduction in muscle blood flow. 4. During exercise, increased phosphocreatine depletion and intracellular acidification were a consequence of impaired oxidative ATP synthesis and the consequent increase in non-oxidative ATP synthesis, compounded by reduced proton efflux. The acidification prevented an increase in ADP concentration which could otherwise partially compensate for the oxidative defect. All these abnormalities are compatible with a reduced muscle blood flow. 5. In addition, initial-exercise changes in pH and phosphocreatine concentration implied a 44 ± 5% reduction in ‘effective muscle mass’, necessitating an ATP turnover (per litre of muscle water) twice as high for given power output as in control muscle. Some of this is probably due to a localized loss of muscle fibres, but the rest appears to reflect reduced metabolic efficiency of the muscle. This is not a direct consequence of reduced blood flow, and may be related to change in muscle fibre type.