We have reported that a submaximal exercise stress causes a prolonged elevation in cardiac cyclic AMP. In addition, this elevation is associated with an increased activity in the enzyme involved in the hydrolysis of the cyclic nucleotide, cyclic AMP phosphodiesterase (PDE). Characterization of the elevation in enzyme activity suggests that induction takes place rather than enzyme activation. It is the purpose of the experiments outlined in this proposal to 1) further characterize the parameters that will produce the exercise stimulated induction of myocardial cyclic AMP and PDE by investigating the influence of exercise intensity and duration on these events; 2) study alternative methods from promoting PDE induction through the injection of agents into the whole animal that elevate the tissue level of cyclic AMP; 3) investigate intracellular changes associated with the prolonged elevation of cyclic AMP by measuring the activation states of the cyclic AMP-dependent protein kinase, phosphorylase b kinase, phosphorylase, and glycogen synthase; 4) determine factors that influence the post-exercise time-course of changes in heart PDE activity and cyclic AMP content by dietary and hormonal modifications; and 5) perform a detailed characterization of the elevated enzyme activity through kinetic activity analysis, chromatographic separation of different enzyme species, and determination of enzyme sensitivity to various effectors. The heart responds to stress in various ways. The data we have presented suggests that cardiac tissue responds to prolonged exposure to elevated levels of cyclic AMP by inducing an enzyme that will remove the nucleotide. Taken one step farther, chronic stress-induced increases in hormone titers may promote a decrease in the tissue sensitivity to hormones through the induction of cyclic AMP phosphodiesterase. It is anticipated that the experiments proposed here will not only fully characterize the exercise-induced response, but determine if the phenomenon is specific to the exercise stress. Stress is a key factor in diseases such as coronary heart disease and hypertension. A desensitization of the tissue to hormones may be valuable in counteracting or delaying the onset of disease. The studies described here contribute to our understanding of the relationship between exercise and the endocrine system.