Demonstration of neuronal and extraneuronal uptake of circulating norepinephrine in the forearm.

Chang, P. C.; Krogt, J. A. Van Der; Brummelen, P. Van

doi:10.1161/01.hyp.9.6.647

Cited by 26 publications

(8 citation statements)

References 28 publications

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“…The increase in leg NA spillover during bladder percussion was in the same magnitude as the increase during mental stress in control subjects (see Figure 2). Several factors such as increased blood ow, 54 nerve ®ring rate or nerve density 55 are known to increase NA spillover. None of these seem to have contributed to the NA spillover rise in decentralised leg, since blood¯ow actually decreased, and nerve ®ring rate is reported to be low even during bladder stimulation.…”

Section: Sympathetic Functionmentioning

confidence: 99%

Insulin resistance and sympathetic function in high spinal cord injury

Karlsson

1999

Spinal Cord

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Objective: Cardiovascular disease (CVD) is today one of the main causes of death and aects spinal cord injured (SCI) earlier than able-bodied. Risk factors for CVD, such as decreased glucose tolerance, insulin resistance and increased fat mass, are all reported among SCI subjects and may be related to changes in sympathetic nervous system (SNS) function. Methods: In order to test our hypothesis of a relationship between metabolic disturbances and alterations in SNS function, glucose and adipose tissue metabolism was investigated by the hyperinsulinaemic normoglycaemic clamp and microdialysis. Body composition was determined by DEXA-scanning. The SNS function was evaluated in total body as well as above and below lesion level by radiolabelled noradrenaline (NA) isotope dilution technique. A 24 h continuous plasma-NA monitoring was performed in seven SCI subjects. Results: Following an oral glucose load the SCI group demonstrated normal glucose tolerance but impaired insulin sensitivity with a maximum insulin value of 83 mU.1 71 in SCI compared to 50 in siblings, while adipose tissue metabolism was normal compared to siblings. Fat tissue mass constituted 34% of body mass in SCI group compared to 21% in weightmatched controls. Peripheral aerent activation resulted in increased blood pressure, decreased heart rate and reduction in muscle and skin blood¯ow. Furthermore, lipolysis below lesion level was activated by peripheral stimulation (89 ± 135 mmol.l 71 ). The 24 h continuous monitoring revealed p-NA levels 41.40 nmol.l 71 sucient to induce lipolysis in 20% of the registrations. NA spillover below lesion level increased substantially following peripheral aerent stimulation (0.06 ± 0.90 pmol.min.71 .100 g 71 ), whereas spillover above lesion level increased during central activation. Conclusions: We found signs of decreased insulin sensitivity and increased fat tissue mass. Peripheral activation of SNS was visualised in the SCI group by increased transmitter spillover as well as increased lipolysis and vasoconstriction. The diurnal registration of NA levels indicated frequent episodes of peripheral sympathetic activation in the group. This may compensate for the inability of central activation of SNS and may contribute to maintain lipolysis activity as well as to generate insulin resistance in the group

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Section: Sympathetic Functionmentioning

confidence: 99%

Insulin resistance and sympathetic function in high spinal cord injury

Karlsson

1999

Spinal Cord

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“…There are few reports, however, that describe uptake2 in human tissues. This finding is based on noradrenaline transport studies in the human umbilical artery [5], on the finding that corticosterone delays the removal of noradrenaline from the forearm circulation [6], and on the expression of extraneuronal transport for noradrenaline in the human renal carcinoma cell line Caki-1 [71. In vitro studies demonstrate the affinity of numerous antiarrhythmic drugs for uptake2 [7].…”

Section: Introductionmentioning

confidence: 99%

Extraneuronal uptake of noradrenaline in human tissue (uptake2)

Babin‐Ebell

Gliese

1995

Heart Vessels

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The neurotransmitter, noradrenaline, is inactivated by active transport out of the synaptic cleft, either back into the adrenergic neurons (uptake1) or into extraneuronal cells (uptake2). Although experimental models clearly demonstrate uptake2 in various animal tissues, there are few reports of studies that demonstrate uptake2 in human tissue. Furthermore, uptake2 has never been described in human heart tissue. We demonstrated a reduction of 3H-noradrenaline uptake in human atrial and venous tissue and in rat atrial and ventricular tissue by O-methyl isoprenaline-a known inhibitor of uptake2. These results indicate that uptake2, as has been described in previous experimental models, does exist in humans and further, the results emphasize the importance of uptake2, since about 50% of exogenous noradrenaline is inactivated by uptake2 in the rat heart.

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“…Inhibition of extraneuronal uptake by these compounds requires concentrations in the gM range, a factor, that combined with complications of low solubility or actions on other systems, limits the utility of these compounds to isolated tissue preparations. In fact, the in vivo administration of these conventional inhibitors results in little or no effects on the circulatory clearance of catecholamines (Esler et al 1981b;Zimlichman et al 1986;Chang et al 1987). …”

Section: Discussionmentioning

confidence: 99%

Disprocynium24, a novel inhibitor of the extraneuronal monoamine transporter, has potent effects on the inactivation of circulating noradrenaline and adrenaline in conscious rat

Eisenhofer

McCarty

Pacák

et al. 1996

Naunyn-Schmiedeberg's Arch Pharmacol

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The role of extraneuronal uptake in terminating the actions of catecholamines has been difficult to evaluate in vivo, largely because of lack of suitable inhibitors. The compound, 1,1'-diisopropyl-2,4'-cyanine iodide or disprocynium24 (D24), is a novel inhibitor of extraneuronal uptake with a high degree of potency in vitro. This study examined the actions of D24 on the inactivation and metabolism of circulating noradrenaline and adrenaline in conscious rats. Animals received i.v. infusions of 3H-labelled noradrenaline and adrenaline, and their extraneuronal O-methylated metabolites, normetanephrine and metanephrine. Plasma concentrations of endogeneous and 3H-labelled catecholamines and metanephrines were measured before and after D24. D24 caused large increases in plasma concentrations of noradrenaline and adrenaline, effects due to both decreases in their plasma clearances and increases in their rates of release into plasma. Plasma concentrations of normetanephrine and metanephrine also increased due to their decreased clearance from plasma. Increased release of normetanephrine into plasma did not contribute to increased plasma concentrations of normetanephrine. In fact, the contribution of extraneuronal O-methylation to noradrenaline clearance decreased substantially after D24. The data indicate that D24 is a potent inhibitor of the extraneuronal catecholamine transporter in vivo and that this process contributes importantly to the removal of circulating catecholamines and their O-methylated amine metabolites. Increased release of noradrenaline into plasma may reflect an increase in the proportion of transmitter that escapes from sites of release into the circulation. However, increased adrenaline release indicates that the drug also causes sympathoadrenal activation.

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Demonstration of neuronal and extraneuronal uptake of circulating norepinephrine in the forearm.

Cited by 26 publications

References 28 publications

Insulin resistance and sympathetic function in high spinal cord injury

Insulin resistance and sympathetic function in high spinal cord injury

Extraneuronal uptake of noradrenaline in human tissue (uptake2)

Disprocynium24, a novel inhibitor of the extraneuronal monoamine transporter, has potent effects on the inactivation of circulating noradrenaline and adrenaline in conscious rat

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