Rabbit isolated right and left atria were exposed to theophylline and to selected doses of histamine agonists. Right atrial rate and left atrial tension were increased by theophylline (3 x 10(-4) M), the H1 agonist 2-pyridylethylamine (PEA) (1 x 10(-4) M), and the H2 agonists 4-methylhistamine (1 x 10(-4) M) and impromidine (1 x 10(-8) M). In the right atria the combined effect of theophylline (3 x 10(-4) M) and any of the histamine agonists was greater than the response to either agonist alone. However, the combined effects were not significantly greater than the sum of the individual right atrial responses. In the left atria the combined effect of theophylline (3 x 10(-4) M) with any one of the histamine agonists was not only greater than the response to either agonist alone but was also significantly greater than the sum of the individual responses. The potentiation of the left atrial response to the H2 agonists by theophylline was significantly decreased by the H2 antagonist cimetidine (1 x 10(-5) M). However, the potentiation of the left atrial response to the H1 agonist (PEA) by theophylline was not significantly altered by the H1 antagonist promethazine (2 x 10(-6) M). Reports that the cardiac effects of H1 and H2 receptor agonists are potentiated by phosphodiesterase inhibitors such as theophylline as a result of increased cyclic AMP levels are not supported by the present study.