A possible change in the rate-limiting step for cardiac norepinephrine synthesis in the cardiomyopathic Syrian hamster.

Abstract

The development of heart failure in the cardiomyopathic hamster is associated with a decrease in norepinephrine stores and parallel increases in cardiac sympathetic tone and tyrosine hydroxylase activity. Despite the increase in tyrosine hydroxylase, cardiac norepinephrine synthesis does not increase in heart failure. In this study, we have shown that an accumulation of cardiac dopamine accompanies the decline of cardiac norepinephrine. The abnormal content of norepinephrine and of dopamine in the decompensating hamster heart is restored to normal by peripheral ganglionic blockade. The acute increase in cardiac sympathetic tone induced by immobilization stress in control hamsters mimics the alterations in cardiac catecholamine distribution found in heart failure. Other investigators have demonstrated similar alterations in the catecholamine content of the rat submaxillary gland and adrenal medulla following an increase in sympathetic input to these organs. We conclude that the increase in cardiac sympathetic tone in the late stages of hamster cardiomyopathy appears to lead to a shift in the rate-limiting step for norepinephrine synthesis from the hydroxylation of tyrosine to the hydroxylation of dopamine. There is evidence that this shift which results in an accumulation of dopamine in the noradrenergic nerve terminals of the heart is a general manifestaion of augmented sympathetic nerve traffic rather than a peculiarity of hamster cardiomyopathy.

Decreased adrenergic neuronal uptake activity in experimental right heart failure. A chamber-specific contributor to beta-adrenoceptor downregulation.

“…The lack of correlation between NE uptake activity and myocardial NE depletion in the left ventricles of RHF dogs in our present study, however, suggests that NE depletion cannot be accounted for by abnormal NE uptake alone. Alternatively, myocardial NE depletion could have resulted from decreased NE synthesis, as heart failure has been shown to be associated with a decrease in cardiac tyrosine hydroxylase activity (48)(49)(50), or other ratelimiting steps for cardiac NE synthesis (51).…”

Cardiac noradrenergic nerve terminal abnormalities in dogs with experimental congestive heart failure.

“…32 On the other hand, dopamine 8-hydroxylase activity was reduced in the cardiomyopathic Syrian hamster. 33 We know of no published studies that applied the immunohistochemical technique to investigate cardiac innervation in our animal models of congestive heart failure. Nevertheless, a recent study by Wharton et al,34 using an immunohistochemical technique similar to ours did show a moderate number of tyrosine hydroxylase immunostained nerve fibers in the ventricular muscles in cardiac transplant recipient hearts.…”

Tracer norepinephrine kinetics in coronary circulation of patients with heart failure secondary to chronic pressure and volume overload.

“…Tissue levels of norepinephrine are reduced (1)(2)(3)(4) in cardiac muscle and plasma levels are increased (5,6). From studies on the cardiomyopathic Syrian hamster it has been surmised that cardiac tissue depletion in humans with chronic heart failure due to mechanical overload is due to increased sympathetic stimulation (7,8). Indeed, Swedberg et al (9,10) sinus norepinephrine balance in human heart failure of various etiologies.…”