An earlier study demonstrated an increase in dopamine and a decrease in norepinephrine in the failing myopathic hamster heart. There was evidence to suggest that this abnormal distribution of catecholamines was secondary to a marked increase in cardiac sympathetic nerve traffic rather than a peculiarity of hamster cardiomyopathy. In this study the hamster model was used to dissect further the step limiting the conversion of dopamine into norepinephrine. In heart failure, cardiac norepinephrine was reduced from a mean value (± standard error of the mean) of 1,192 ± 176 to 441 ± 61 ng/g (probability [p] < 0.005) and cardiac dopamine was increased from 51 ± 5 to 458 ± 70 ng/g (p < 0.001). Cardiac decompensation also induced increases in both cardiac tyrosine hydroxylase (84 percent, p < 0.001) and cardiac dopamine-beta-hydroxylase (46 percent, p < 0.001) relative to values In the control hearts. In preparations of noradrenergic granules 44 percent of norepinephrine stores and 33 percent of dopamine stores were associated with the vesicular pellet of normal hearts. Congestive heart failure led to a significant decrease in norepinephrine, particularly in the intravesicular compartment, whereas dopamine exhibited an approximately 20-fold rise, reflected exclusively by the supernatant (extravesicular) fraction. Ganglionic blockade restored catecholamine content and distribution to normal. Inhibition of monoamine oxidase doubled the norepinephrine content of failing hearts (p < 0.01) in the absence of a change in dopamine. Catecholamine histofluorescence observations revealed a marked reduction in the number of nerves in apposition to the muscle of myopathic hearts In addition to a sprouting of new adrenergic fibers into connective tissue and in the lipofuscin pigment debris. It is concluded that an increase in sympathetic activity, at least in the myopathie hearts, can lead to a shift in the rate-limiting step for norepinephrine synthesis from the hydroxylation of tyrosine to the transport of dopamine across the membrane of the noradrenergic granule. Furthermore, it appears that one or more deaminated metabolites of dopamine in the extravesicular space contribute to this shift by inhibiting the dopamine uptake system.