The long-term goal of this proposal is a better understanding of the adaptation of the mechanisms of acid-base regulation to conditions of prolonged oxygen deprivation. Prolonged hypoxia is frequently associated with cardiopulmonary disease, and is a feature of healthy individuals exposed to altitude. The changes in plasma acid-base status of mammals, including humans, exposed to prolonged hypoxia are well known. However, less is known concerning the effect of prolonged hypoxic exposure on the ability of intact animals to regulate plasma and cellular acid-base composition when challenged with an acid load. This is an important gap because acid-base status directly or indirectly influences virtually every aspect of cellular function. The specific aim of the present project is to study the acid-base consequences of physical exercise in rats that have been exposed to simulated high altitude for three weeks. Exercise will be used as a challenge to the acid-base balance since the processes which provide energy for muscle contraction result in acid formation. In addition, increased physical activity is a frequent occurrence in everyday life. Prolonged hypoxia may alter the acid-base effects of exercise by altering the net acid load generated during muscle contraction, by influencing the effectiveness of the mechanisms of acid removal, or by a combination of both mechanisms. These possibilities will be investigated using two complementary models: intact rats and isolated skeletal muscles. The goals of the experiments in intact rats will be to establish the relationship between exercise intensity, oxygen uptake and plasma and intracellular acid-base balance, and to determine the effect of hypoxic exercise on circulatory, ventilatory and metabolic adjustments to exercise. These adjustments influence plasma and tissue acid-base changes with exercise. The studies in intact animals will be carried out in chronic hypoxic rats exercising in hypoxic conditions and in normoxic controls exercising in either normoxic or acute hypoxic conditions. The experiments in isolated muscles will be directed to study the cellular acid-base effects of muscle contraction, and the mechanisms responsible for these effects. The interplay between net acid load generation, chemical buffer value and rate of proton equivalent extrusion on cell acid-base balance will be studied in muscles obtained from rats exposed to prolonged hypoxia and from normoxic controls. The results of these experiments should improve our understanding of the adaptations to oxygen deprivation and may provide ways to improve these adaptations.