Dioxygen activation at mononuclear nonheme iron active sites: enzymes, models, and intermediates.

Tyrosine hydroxylase. the initial step in norepinephrine biosynthesis.

To define the state of the parasympathetic nervous system in heart failure, parasympathetic blockade with atropine was induced after adrenergic blockade with propranolol in 12 normal subjects and in nine patients with heart disease. Atropine elevated heart rate by 55 ± 9 per cent in normal subjects, but by only 23 ± 8 per cent in patients with heart disease (p less than 0.05). In 23 control subjects and 22 patients, transient elevations in arterial pressure were produced by intravenous injections of phenylephrine, and successive R-R intervals were plotted as a function of systolic pressure. The slowing of heart rate per unit rise in systolic arterial pressure averaged 16.0 ±1.8 msec per millimeter of mercury in normal subjects but only 3.70 ± 0.8 msec per millimeter of mercury in the patients (p less than 0.001). Baroreceptor-induced slowing of heart rate in normal subjects was shown to be mediated by the parasympathetic nervous system since it could be abolished with atropine. These findings poi...

https://www.nejm.org/doi/pdf/10.1056/NEJM197110142851602?listPDF=true

Defective cardiac parasympathetic control in patients with heart disease.

Intracellular and extracellular electrophysiology of nigral dopaminergic neurons—1. Identification and characterization

This article provides an update about catecholamine metabolism, with emphasis on correcting common misconceptions relevant to catecholamine systems in health and disease. Importantly, most metabolism of catecholamines takes place within the same cells where the amines are synthesized. This mainly occurs secondary to leakage of catecholamines from vesicular stores into the cytoplasm. These stores exist in a highly dynamic equilibrium, with passive outward leakage counterbalanced by inward active transport controlled by vesicular monoamine transporters. In catecholaminergic neurons, the presence of monoamine oxidase leads to formation of reactive catecholaldehydes. Production of these toxic aldehydes depends on the dynamics of vesicular-axoplasmic monoamine exchange and enzyme-catalyzed conversion to nontoxic acids or alcohols. In sympathetic nerves, the aldehyde produced from norepinephrine is converted to 3,4-dihydroxyphenylglycol, not 3,4-dihydroxymandelic acid. Subsequent extraneuronal O-methylation consequently leads to production of 3-methoxy-4-hydroxyphenylglycol, not vanillylmandelic acid. Vanillylmandelic acid is instead formed in the liver by oxidation of 3-methoxy-4-hydroxyphenylglycol catalyzed by alcohol and aldehyde dehydrogenases. Compared to intraneuronal deamination, extraneuronal O-methylation of norepinephrine and epinephrine to metanephrines represent minor pathways of metabolism. The single largest source of metanephrines is the adrenal medulla. Similarly, pheochromocytoma tumor cells produce large amounts of metanephrines from catecholamines leaking from stores. Thus, these metabolites are particularly useful for detecting pheochromocytomas. The large contribution of intraneuronal deamination to catecholamine turnover, and dependence of this on the vesicular-axoplasmic monoamine exchange process, helps explain how synthesis, release, metabolism, turnover, and stores of catecholamines are regulated in a coordinated fashion during stress and in disease states.

Catecholamine Metabolism: A Contemporary View with Implications for Physiology and Medicine

Guinea-pig hearts were perfused with varying concentrations of the norepinephrine precursors, tyrosine, 3,4-dihydroxyphenylalanine (dopa) and 3,4-dihydroxyphenethylamine (dopamine). With all three precursors the rate of norepinephrine synthesis increased as the concentration in the perfusion fluid increased. However, only with tyrosine were maximal rates achieved (0.2 µg/g/hr) at concentrations below 5 x 10 -4 M. The apparent Km for the overall reaction (tyrosine → norepinephrine) was found to be comparable to that observed for conversion of tyrosine to dopa by purified tyrosine hydroxylase ( 2 x 10 -5 M). These and other factors indicate that conversion of tyrosine to dopa is the rate-limiting step in the formation of norepinephrine in the sympathetic nervous system.

Although ascorbic acid has been shown to be a requirement for purified dopamine-β-oxidase activity severe seurvy did not diminish the ability of isolated heart to form norepinephrine from tyrosine or dopamine.

Elucidation of the rate-limiting step in norepinephrine biosynthesis in the perfused guinea-pig heart

A rapid and simple radioassay for tyrosine hydroxylase activity.

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 mµmole/g per hour respectively as compared to a normal value of 3.3 ± 0.7 mµmole/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.

Reduction of Cardiac Tyrosine Hydroxylase Activity in Experimental Congestive Heart Failure: Its Role In The Depletion Of Cardiac Norepinephrine Stores

Morton Levitt

Papers

Tyrosine hydroxylase. the initial step in norepinephrine biosynthesis.

Elucidation of the rate-limiting step in norepinephrine biosynthesis in the perfused guinea-pig heart

A rapid and simple radioassay for tyrosine hydroxylase activity.

Reduction of Cardiac Tyrosine Hydroxylase Activity in Experimental Congestive Heart Failure: Its Role In The Depletion Of Cardiac Norepinephrine Stores

Conversion of L-tyrosine to 3,4-dihydroxyphenylalanine by cell-free preparations of brain and sympathetically innervated tissues