The effect of one bout of intense swimming caused significant increases in the cyclic AMP content of fast-twitch white skeletal muscle, liver, and heart. Further investigation of the exercise-induced increase in myocardial cyclic AMP indicates that the nucleotide content remained elevated long after (24 h) termination of exercise. This increase in cyclic AMP was time dependent, with the level increasing gradually throughout the work bout. The increase in cardiac cyclic AMP seemed to be independent of work intensity, provided that work time was of sufficient duration (greater than or equal to 30 min). Increases in cardiac cyclic AMP were also seen when rats were exposed to 2 degrees C for 1-7 d. The increases in cyclic AMP seen following exercise and cold exposure were accompanied by an increase in cardiac cyclic AMP phosphodiesterase (PDE) activity. Our working hypothesis was that prolonged elevations in cyclic AMP produced an induction and/or activation of one or more of the PDE isozymes. When we administered dibutyryl cyclic AMP to rats, cardiac PDE activity was increased. This increase was inhibited by cycloheximide, suggesting that the elevated enzyme activity is mediated by the synthesis of new protein. These data support the concept that cyclic AMP is involved in the regulation of its own metabolism during physiological stress.