Norepinephrine metabolism in humans. Kinetic analysis and model (original) (raw)
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Journal of the Autonomic Nervous System, 1995
Circulatory metabolic and cardiovascular responses to 1-h-long infusions of norepinephrine (NE) (approx. 0.2 and 0.4 nmol/kg body weight per min) were measured on two separate occasions in six subjects. The infusions increased circulating NE concentrations 6-and 13-fold, respectively. Blood flow to adipose tissue, measured with the ~33Xe clearance technique, increased from a basal value of about 3 ml/100 g per min, to about twice this value at 60 min with both doses of NE. In contrast muscle blood flow was unaffected. The higher dose of NE produced significant increments at 60 rain in whole body oxygen consumption (approx. 9%), and circulating concentrations of glucose (approx. 18%), non-esterified fatty acids (approx. 200%) and glycerol (approx. 32%)which were greater than those observed with the low-dose infusion. Changes in blood pressure, pulse and CO2 exchange were observed within 5-10 min after the start of the infusion, whilst changes in adipose tissue blood flow were observed after 15-30 rain. It is concluded that in humans (i) a dose of NE as low as 0.2 nmol/kg per rain is sufficient to evoke both circulatory and metabolic responses; (ii) the pattern in the adipose tissue blood flow response to NE may help explain some of the conflicting reports about the haemodynamic effects of this hormone in adipose tissue; and (iii) blood flow and vascular resistance in different tissues may be affected in different ways by norepinephrine.
Human norepinephrine metabolism
Journal of Clinical Investigation, 1971
subject during physiologic variations and pathologic states associated with abnormalities in catecholamine metabolism, but may serve as a technique whereby drugs that affect human norepinephrine metabolism may undergo precise pharmacologic evaluation.
Journal of Neurochemistry, 2002
This study used regional differences in plasma concentrations of norepinephrine and its metabolites to examine how production of the transmitter by sympathetic nerves, in particular, those innervating mesenteric organs, is integrated with metabolism by the liver and elimination by the kidneys. Higher concentrations of norepinephrine, its glycol metabolites 3,4-dihydroxyphenylglycol and 3-methoxy-4-hydroxyphenylglycol and their sulfate conjugates in portal venous than arterial plasma indicate substantial production of norepinephrine by mesenteric organs (15.5 nmol/min). Much lower concentrations of norepinephrine and its glycol metabolites in plasma leaving than entering the liver indicate their efficient hepatic removal (20 nmol/min). Higher concentrations of vanillylmandelic acid in the hepatic outflow than inflow indicate that this metabolic end product is produced largely from the norepinephrine and glycol metabolites removed by the liver. Renal elimination of vanillylmandelic acid (18-20 nmol/min), produced mainly by the liver(17 nmol/min), and of 3-methoxy-4-hydroxyphenylglycol sulfate (7-9 nmol/min), produced largely by mesenteric organs (7 nmol/min), comprised 86-91% of the total renal elimination of norepinephrine metabolites. The results show that mesenteric organs produce about one-half of the norepinephrine formed in the body. The liver removes substantial amounts of circulating norepinephrine and its glycol metabolites and converts these compounds to vanillylmandelic acid, which is then eliminated from the body by the kidneys. The sulfate conjugates are also metabolic end products eliminated by the kidneys. However, these metabolites are produced by extrahepatic tissues, in particular, mesenteric organs, which represent a significant source of sulfate-conjugated norepinephrine and 3,4-dihydroxyphenylglycol, and the main source of sulfate-conjugated 3-methoxy-4hydroxyphenylglycol.
Estimation of intrasynaptic norepinephrine concentrations in humans
Hypertension, 1986
Levels of synaptic cleft norepinephrine associated with pressor responses were estimated in humans by measuring blood pressure and arterial plasma norepinephrine during norepinephrine infusion and during yohimbine-induced release of endogenous norepinephrine. Linear pressor response-log norepinephrine concentration relationships were observed during the infusions. At a pressor response of 20 mm Hg, arterial norepinephrine averaged 3647 pg/ml. The pressor-log norepinephrine relationship was shifted more than fivefold to the left during combined ganglionic, alpha 2-adrenergic receptor, and Uptake1 (neuronal norepinephrine uptake) blockade: arterial norepinephrine averaged 684 pg/ml at a 20 mm Hg pressor response. During yohimbine-induced release of endogenous norepinephrine in desipramine-pretreated subjects, arterial norepinephrine averaged 467 pg/ml at a 20 mm Hg pressor response. Since the norepinephrine concentration in the synaptic clefts must have been between the values for pla...
Metabolism, 1989
responses to similar doses of norepinephrine appear to be different when repeatedly administered. This hypothesis was tested by three consecutive go-minute infusions of a fixed dose of norepinephrine separated by a rest period of one hour between infusions. There was a significant increase or potentiation of the metabolic response as measured by oxygen consumption to the third dose of norepinephrine, while the cardiovascular responses showed no change. It is therefore important to make allowances for this phenomenon when assessing intergroup differences in regulatory thermogenesis using dose-response protocols for norepinephrine administration. 0 k99 b; W.9. Sainders Con&y.
Clinical pharmacology and therapeutics, 1993
The renal effects of incremental infusions of norepinephrine (placebo, 0.025 mu/kg/min), 0.075 micrograms/kg/min, phenylephrine (placebo, 0.5 micrograms/kg/min, 2.5 micrograms/kg/min), and tyramine (placebo, 2 micrograms/kg/min, 15 micrograms/kg/min) were examined in three respective groups (n = 9, 8, and 8) of normotensive male subjects undergoing water diuresis. Tyramine is an indirect sympathetic agent that causes neuronal release of endogenous norepinephrine. Increases in mean arterial pressure during each high-dose infusion were comparable in all three groups. Both norepinephrine and phenylephrine caused a decrease in urinary sodium excretion and effective renal plasma flow, with no changes in glomerular filtration rate. Proximal tubular sodium reabsorption, as assessed by both lithium clearance and solute-free water clearance methods, was increased by pressor doses of norepinephrine and phenylephrine. In contrast, a similar pressor dose of tyramine was associated with a pressu...