Reduction of Cardiac Tyrosine Hydroxylase Activity in Experimental Congestive Heart Failure ITS ROLE IN THE DEPLETION OF

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 measur-ing the activity of tyrosine hydroxylase, the rate-limiting enzyme in the bio-synthesis 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. ADDITIONAL KEY WORDS biosynthesis catecholamines reserpine denervation enzyme activity anesthetized dogs • Cardiac norepinephrine stores are mark-edly reduced in congestive heart failure in humans (1, 2) and in experimentally pro-duced congestive heart failure in the dog, cat, and guinea pig (3, 4). Moreover, it has been shown that in experimental heart failure there is a reduction in the response of the heart to sympathetic nerve stimulation, and it has been postulated that the heart failure state may be intensified by loss of intrinsic neurotransmitter stores (5). Cardiac stores of norepinephrine are pri-marily synthesized from tyrosine in the heart (6, 7), although up to 20 % may be de-rived from the uptake of exogenous norepi-nephrine (8). The objective of this study was to investigate cardiac synthesis of norepineph