Is There a Third Peripheral Catecholaminergic System? Endogenous Dopamine as an Autocrine/ Paracrine Substance Derived from Plasma DOPA and Inactivated by Conjugation

Abstract

In mammals, the sympathetic neurotransmitter is norepinephrine (NE), and the main adrenomedullary hormone is epinephrine (EPI). The sources and physiological roles of the third endogenous catecholamine, dopamine (DA), outside the brain have been obscure. Several lines of evidence suggest that in the periphery, rather than DA serving only as the precursor for the active compounds, released from sympathetic nerves and the adrenal medulla, DA may also act as an autocrine/paracrine regulator of local organ function. Thus, in the kidneys, most of DA formation appears to be from proximal tubular uptake of plasma DOPA, and binding of locally formed DA to dopaminergic receptors decreases Na/K ATPase activity and thereby accentuates natriuresis. In the gastric mucosa, DA may modulate sodium absorption and acid secretion. Recent clinical and laboratory animal evidence has indicated that the lungs and mesenteric organs contribute substantially to total body production and metabolism of DA. Generation of DA in non-noradrenergic, non-adrenergic cells can explain why human urine contains higher concentrations of DA and its metabolites than of NE and its metabolites. The vast preponderance of plasma DA in humans is sulfoconjugated. Since patients with sympathoneural failure have normal plasma levels of DA sulfate, one may speculate that the sulfoconjugating mechanism is relatively independent of sympathetic nerves and acts to localize DA effects and inactivate DA entering the circulation. These considerations lead to the concept of a third peripheral catecholaminergic system, where DA derived from plasma DOPA acts as an autocrine/paracrine substance and is inactivated by conjugation.

Diagnostic accuracy of free and total metanephrines in plasma and fractionated metanephrines in urine of patients with pheochromocytoma

“…In the case of renal failure, the screening algorithm proposed by Sawka (adjustment of the cut-off ratio for a positive result of plasma free metanephrines and combination with 24-h urinary metanephrines) seems to be most appropriate and cost-effective for detecting pheochromocytoma (30). The sulfotransferase SULT1A3 is very active in the gastrointestinal tract, and may produce conjugated metanephrines after consumption of foods (31). Dietary influences have been reported not to influence plasma total metanephrines (32), whereas a recent publication has established that a standardized meal rich in metanephrines (including six bananas) may induce an increase of plasma-deconjugated normetanephrine, plasma-deconjugated and free methoxytyramine, and urine-deconjugated normetanephrine (33).…”

Peripheral dopamine in hypertension and associated conditions

“…Because of a short half-life of free DA (2-3 min) which is rapidly conjugated upon release, the magnitude of the DA release is better appreciated by determining, in addition to free DA, also the long half-life (3 h) DA sulfate. 2,3 As an example of repetitive physical stress, people who regularly exercise have higher DA than untrained sedentary subjects. 24 With plasma DA (and NA) sulfates reflecting the degree of training, 25 acute physical exercise-induced changes in free and sulfated DA (and NA) 24 are compatible with DA release from its sulfate as a possible source of free DA increase additional to the exerciseand training-induced increase in the DA precursor plasma DOPA.…”

“…Many other than neuronal and adrenomedullary tissues (gastrointestinal system, kidney, heart, lung, adrenal cortex, carotid bodies) represent this third catecholamine generating compartment. 2 There is a generous DA synthesis in this compartment due to a wide alimentary and intrinsic availability of the DA precursors tyrosine and dihydroxyphenylalanine (DOPA) and of both tissue enzymes necessary to synthesise DA (tyrosine hydroxylase, aromatic acid decarboxylase). This makes rapid inactivation of considerable homeostatic balance-threatening DA surges (such as following a meal) absolutely essential.…”

“…Extraneuronal sulfoconjugation of DA evolved as one of the most efficient extraneuronal means to inactivate circulating free DA. 2 Its product DA sulfate may become a complementary or surrogate marker of the overall free DA release 2,3 provided that a postprandial DA increase is eliminated by several hours of fasting. Sulfoconjugation of DA is also the only reversible metabolic pathway of DA contrasting with its irreversible oxidation and O-methylation.…”

“…Most of DA originates in its autocrine paracrine synthesis. 2 The peripheral neuronal free DA release (prior to its NA synthesis by dopamine ␤-hydroxylase) and its eventual spillover dependent on the neuronal free DA release-reuptake balance, represents a small contribution to the circulating free DA pool acting at receptor sites. The other side of the balance is dependent on free DA excretion and metabolism which is partly irreversible (Omethylation via catechol-O-methyltransferase COMT and oxidation via mono-amine-O-oxydae MAO) partly reversible (sulfoconjugation via sulfotransferase and deconjugation via sulfatase).…”