Roles of uptake1 and catechol-O-methyltransferase in removal of circulating catecholamines in the rabbit

Abstract

Anesthetized rabbits were simultaneously infused with [3H]norepinephrine (NE), [3H]epinephrine (Epi), [3H]dopamine (DA), and [3H]isoproterenol (Iso), and their plasma clearances and fractional extractions across the systemic (ERS), as well as pulmonary (ERP), circulation were determined before and after blockade of uptake1 by desipramine (2 mg/kg). Desipramine reduced the clearance of NE, Epi, and DA by 39, 13, and 14%, respectively, but did not affect Iso clearance. Similar results were obtained with respect to the effects of desipramine on ERS. By contrast, desipramine reduced ERP of NE and DA (which for both amines was markedly lower than ERS) by > 70%; its effect on the very low ERP of Epi was not determinable. Comparison of the desipramine-sensitive components of ERS and ERP indicated that for uptake1 NE was the preferred substrate in the systemic circulation and DA was preferred in the pulmonary circulation. In the absence and presence of desipramine, catechol-O-methyltransferase inhibition had no effect on the clearance of NE, Epi, and DA and decreased Iso clearance by 25%. Hence the contribution by uptake1 to the removal of circulating catecholamines depends on the type of amine and on whether the systemic or pulmonary circulation is considered. Moreover catechol-O-methyltransferase does not appear to contribute to the clearance of NE, Epi, and DA but plays a definite role in the removal of circulating Iso.

BIA 3-202, a Novel Catechol-O-Methyltransferase Inhibitor, Reduces the Peripheral O-Methylation of <i>L</i>-DOPA and Enhances Its Availability to the Brain

“…Another aspect worthwhile to mention concerns the observation that BIA 3-202 did not affect plasma levels of both norepinephrine and dopamine either in vehicle-treated or L-DOPA plus benserazide treated rats. This would agree with the view that COMT does not appear to contribute to the clearance of circulating catecholamines [23].…”

Sympathetic Neural Regulation of Heart Rate Is Robust against High Plasma Catecholamines

“…NA released from the sympathetic nerve terminals is removed from the synaptic cleft by two catecholamine uptake mechanisms: a high-affinity, low-capacity neuronal uptake (uptake 1 ) and a lowaffinity, high-capacity extraneuronal uptake (uptake 2 ) [5, 18, 19]. The uptake 1 mechanism also contributes to plasma clearance of NA [20]. High plasma NA might occupy the uptake 1 process to some extent and slow the NA removal from the synaptic cleft during SNS.…”

Adrenaline and Noradrenaline: Partners and Actors in the Same Play"

“…It has been shown that NET inhibitors (e.g., cocaine, imipramine, and desipramine) potentiate the effects of the neurotransmitters, while inhibitors of MAO and COMT have relatively little immediate effect (Gonçalves et al, 1989, Eisenhofer, 1994, Eisenhofer and Finberg, 1994, Friedgen et al, 1994, Blaha et al, 1996, Friedgen et al, 1996. Early studies in isolated tissues showed that the inhibition of MAO or COMT could limit the ability of neuronal and extraneuronal uptake to clear extracellular catecholamines (Furchgott andGarcia, 1968, Belfrage et al, 1977).…”

“…Early studies in isolated tissues showed that the inhibition of MAO or COMT could limit the ability of neuronal and extraneuronal uptake to clear extracellular catecholamines (Furchgott andGarcia, 1968, Belfrage et al, 1977). More recent in vivo studies however indicate that inhibition of one enzyme under normal physiological conditions has little effect on the overall catecholamine clearance and on their extracellular or circulating levels (Eisenhofer, 1994, Eisenhofer and Finberg, 1994, Friedgen et al, 1994, Blaha et al, 1996, Friedgen et al, 1996. Only when MAO and COMT are both inhibited or subjected to saturating concentrations of substrate, the clearance of catecholamines is significantly impaired (Eisenhofer, 1994, Friedgen et al, 1996.…”