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A possible change in the rate-limiting step for cardiac norepinephrine synthesis in the cardiomyopathic Syrian
Insights
In heart failure, cardiac norepinephrine synthesis is impaired due to increased sympathetic tone, leading to dopamine accumulation. Ganglionic blockade restores normal catecholamine levels in hamsters.
Area of Science:
- Cardiovascular Physiology
- Neuroendocrinology
- Biochemistry
Background:
- Heart failure in cardiomyopathic hamsters shows decreased norepinephrine and increased cardiac sympathetic tone.
- Despite elevated tyrosine hydroxylase activity, norepinephrine synthesis does not increase during heart failure.
Purpose of the Study:
- To investigate the role of dopamine accumulation in heart failure pathophysiology.
- To determine if increased sympathetic tone alters norepinephrine synthesis regulation.
- To examine the effect of peripheral ganglionic blockade on cardiac catecholamine levels.
Main Methods:
- Analysis of cardiac catecholamine content (norepinephrine and dopamine) in failing and control hamsters.
- Pharmacological intervention using peripheral ganglionic blockade.
- Induction of acute sympathetic stress in control hamsters via immobilization.
Main Results:
- Cardiac dopamine accumulation correlates with norepinephrine decline in heart failure.
- Peripheral ganglionic blockade normalized abnormal norepinephrine and dopamine levels.
- Immobilization stress in control hamsters mimicked the catecholamine alterations seen in heart failure.
Conclusions:
- Increased cardiac sympathetic tone in heart failure shifts norepinephrine synthesis regulation, favoring dopamine accumulation.
- This shift in the rate-limiting step of norepinephrine synthesis is a response to augmented sympathetic nerve activity.
- The observed catecholamine alterations are a general manifestation of increased sympathetic traffic, not unique to hamster cardiomyopathy.
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.