Regional 5-hydroxyindoleacetic acid production in humans

doi:10.1016/0024-3205(95)00269-C

Life Sciences

Volume 57, Issue 3, 9 June 1995, Pages 255-267

https://doi.org/10.1016/0024-3205(95)00269-C Get rights and content

Abstract

Veno-arterial plasma concentration differences and regional organ plasma flowwere used to quantify the relative amounts of 5-hydroxyindoleacetic acid (5-HIAA) contributed by various sites into the peripheral circulation. Positive venoarterial concentration gradients were found in the hepatosplanchnic, forearm, cardiac and jugular vessels in the healthy subjects. The renal circulation was determined to be the principal site of 5-HIAA clearance, extracting 18 ± 2 nmol/min. The gut was the greatest contributor to the total 5-HIAA plasma pool with the relative contributions of the various organs being as follows: hepatosplanchnic organs 58 %, skeletal muscle 26 %, brain 6 % and the heart 3 %. The source of 5-HIAA stemming from these regional beds remains unknown, it may derive from serotonin taken up by and deaminated in ubiquitous endothelial cells, enterochromaffin cells of the gut, peripheral serotonergic nerves, serotonin turnover in platelets or perhaps the metabolism of serotonin taken up by sympathetic nerves. To test the latter hypothesis we examined 23 patients with chronic congestive heart failure and 9 patients with pure autonomie failure to investigate the possible effects of sympathetic nervous system overactivity and underactivity on peripheral 5-HIAA production and plasma 5-HIAA concentration. The resting arterial plasma 5-HIAA concentration in the heart failure patients was increased three-fold. This elevated plasma 5-HIAA concentration was attributable to an increased rate of whole body 5-HIAA production. The arterial 5-HIAA plasma concentration in the autonomic failure patients was paradoxically elevated, being 70 % greater than that of the healthy subjects. The increased 5-HIAA plasma concentration in these patients was accounted for by a reduction in 5-HIAA plasma clearance. In all subjects studied there was a weak relationship only between total body norepinephrine spillover to plasma and the arterial 5-HIAA plasma concentration. We found that in healthy subjects the overflow of 5-HIAA into the hepatic vein was significantly related to the underlying degree of sympathetic activity. It can be concluded that 5-HIAA is produced at a number of sites throughout the body with the arterial plasma concentration being dependant on both the level of production and plasma clearance. By far the majority of 5-HIAA in plasma is derived from the gut with only minimal contribution from the brain.

References (57)

B.M Twarog
Comp Biochem Physiol
(1988)
J Ortiz et al.
Life Sci
(1988)
G.W Lambert et al.
Life Sci
(1993)
G.W Lambert et al.
Life Sci
(1991)
M Esler et al.
Life Sci
(1979)
M Picard et al.
J Chromatogr
(1985)
A Minegishi et al.
J Chromatogr
(1984)
P.M.M Van Haard et al.
J Chromatogr
(1988)
H Schworer et al.
Neuroscience
(1987)
G Bertaccini et al.
Lancet
(1960)

T.F Burks et al.

Journal of Pharmaceutical Science

(1966)

J Hagege et al.

Kidney Int

(1985)

M.J Sole et al.

Kidney Int

(1986)

J Odink et al.

J Chromatogr

(1988)

T Hannedouche et al.

Kidney Int

(1989)

M.J Sole et al.

J Mol Cell Cardiol

(1985)

I Blum et al.

Metabolism

(1992)

S.F Leibowitz

TINS

(1992)

I.H Page

Perspect Biol Med

(1976)

V Erspamer et al.

J Pharm Pharmacol

(1959)

B.H Resnick et al.

Gastroenterology

(1961)

A Sjoerdsma et al.

Annals New York Acad Sci

(1990)

T.J Verbeuren

Synthesis, storage, release and metabolism of 5-hydroxytryptamine in peripheral tissues

C.N Gillis

Peripheral metabolism of serotonin

G.M Tyce

Biochemistry of serotonin

M.A Anderson et al.

Life Science

(1987)

K.M Dhasmana et al.

Life Sci

(1994)

I.T Meredith et al.

Clin Auton Res

(1991)

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Regional 5-hydroxyindoleacetic acid production in humans

Abstract

Comp Biochem Physiol

Life Sci

Life Sci

Life Sci

Life Sci

J Chromatogr

J Chromatogr

J Chromatogr

Neuroscience

Lancet

Journal of Pharmaceutical Science

Kidney Int

Kidney Int

J Chromatogr

Kidney Int

J Mol Cell Cardiol

Metabolism

TINS

Perspect Biol Med

J Pharm Pharmacol

Gastroenterology

Annals New York Acad Sci

Synthesis, storage, release and metabolism of 5-hydroxytryptamine in peripheral tissues

Peripheral metabolism of serotonin

Biochemistry of serotonin

Life Science

Life Sci

Clin Auton Res