Although it is clear that cardiac norepinephrine stores are often markedly reduced in congestive heart failure, the mechanism responsible for this depletion has not been elucidated. The objective of this study was to investigate cardiac synthesis of norepinephrine in experimental right-sided heart failure by measuring the activity of tyrosine hydroxylase, the rate-limiting enzyme in the biosynthesis of norepinephrine. In homogenates of the right ventricles of 6 dogs with congestive heart failure and 2 with chronic cardiac denervation, myocardial tyrosine hydroxylase activity was severely reduced, averaging 0.4 ±0.1 (SE) and 0.2 iryunole/g per hour respectively as compared to a normal value of 3.3 ± 0.7 m/tmole/g per hour. Tyrosine hydroxylase activity was normal in reserpine-treated, norepinephrine-depleted dogs. These data provide evidence for a mechanism severely limiting norepinephrine biosynthesis in congestive heart failure.