Isolated perfused lungs of guinea-pig, in contrast with rat, lack an uptake process for noradrenaline

Bryan-Lluka, Lesley J.; O’Donnell, Stella R.

doi:10.1016/0952-0600(91)90004-m

Cited by 6 publications

(3 citation statements)

References 14 publications

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“…The pulmonary artery and left atrium were quickly cannulated in situ. The preparation was then removed from the thorax and ventilated in a heated, sealed chamber as described previously (Bryan-Lluka and O'Donnell 1991), The lungs were perfused via the pulmonary artery cannula and the perfusion solution was allowed to drain through a cannula in the left atrium (venous effluent). The perfusion pressure was monitored via a manometer attached to the pulmonary artery cannula.…”

Section: Methodsmentioning

confidence: 99%

Evidence for uptake1-mediated efflux of catecholamines from pulmonary endothelial cells of perfused lungs of rats

Westwood

Scarcella

Bryan-Lluka

1996

Naunyn-Schmiedeberg's Arch Pharmacol

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Previous pharmacological studies have demonstrated that pulmonary endothelial cells and noradrenergic neurones possess the same transporter for inward transport of catecholamines, uptake1. In noradrenergic neurones, it has been shown that uptake1 is also involved in the carrier-mediated outward transport, or efflux, of noradrenaline and dopamine. The aim of the present study was to examine the efflux of noradrenaline and dopamine from perfused lungs of rats to determine whether uptake1, in addition to diffusion, mediates efflux of catecholamines from pulmonary vascular endothelial cells. The effects of reducing the cellular sodium gradient and of substrates and inhibitors of uptake1 on the efflux of 3H-noradrenaline and 3H-dopamine from rat lungs were measured. Isolated perfused lungs of rats (monoamine oxidase and catechol-O-methyltransferase inhibited) were loaded with 3H-(-)-noradrenaline or 3H-dopamine for 10 min followed by perfusion with either (1) a low sodium, amine-free Krebs solution, in which NaCl was replaced by either Tris.HCl or LiCl, for 15 or 10 min, respectively or (2) amine-free Krebs solution for 30 min in the absence or presence of a substrate or inhibitor of uptake1 for the last 15 min. The rate constants for spontaneous efflux of noradrenaline and dopamine from the lungs were 0.0163 min-1 and 0.0466 min-1, respectively. When NaCl was replaced by Tris.HCl during efflux, the rate constants for efflux of noradrenaline and dopamine were increased 2.5-fold and 3-fold, respectively, whereas, when NaCl was replaced by LiCl, the rate constants were increased 8-fold and 4-fold, respectively. The uptake1 substrates, dopamine (1 and 3 mumol/l) and adrenaline (40 mumol/l), both caused a rapid and marked increase in the efflux of noradrenaline, while noradrenaline (4 mumol/l) had a similar effect on the efflux of dopamine. The uptake1 inhibitors, imipramine (3 and 10 mumol/l) and nisoxetine (50 nmol/l), caused small and gradual increases in the efflux of noradrenaline and dopamine from rat lungs. These results demonstrate that efflux of noradrenaline and dopamine from rat lungs is affected by alterations in the normal sodium gradient across the cell and by drugs that interact with the uptake1 transporter. Thus, it can be concluded that the spontaneous efflux of catecholamines from pulmonary vascular endothelial cells is mediated predominantly by uptake1. In addition, efflux of catecholamines from the lungs has a diffusional component, which, combined with inhibition of reuptake, accounts for the small increase in amine efflux by inhibitors of uptake1.

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Section: Methodsmentioning

confidence: 99%

Evidence for uptake1-mediated efflux of catecholamines from pulmonary endothelial cells of perfused lungs of rats

Westwood

Scarcella

Bryan-Lluka

1996

Naunyn-Schmiedeberg's Arch Pharmacol

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“…During efftux, continuous l-rain samples of perfusion solution were collected from the cannula in the left atrium (venous effluent). At the end of each experiment, the preparation was removed from the ventilation chamber and treated as described previously (Bryan-Lluka and O'Donnell 1991). Venous effluent, 3H-noradrenaline infusion solution and lung homogenate supernatant samples were assayed for 31t by liquid scintillation counting.…”

Section: Methodsmentioning

confidence: 99%

“…5-5.5, 9.5-10.5, 14.5 15.5, 16.5-17.5 and 18.5 19.5 rain. At the end of each experiment, the preparation was removed from the ventilation chamber and treated as described previously (Bryan and O'Donnell 1991) and an arterial sample (i.e. perfusion solution from the pulmonary artery cannula) was coliected.…”

Section: Methodsmentioning

confidence: 99%

Amezinium and debrisoquine are substrates of uptake1 and potent inhibitors of monoamine oxidase in perfused lungs of rats

Bryan-Lluka

Seers

Sharpe

1996

Naunyn-Schmiedeberg's Arch Pharmacol

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Previous studies have resulted in the classification of amezinium as a selective inhibitor of neuronal monoamine oxidase (MAO), because it is a much more potent MAO inhibitor in intact tissues, in which it is accumulated in noradrenergic neurones by uptake1, than in tissue homogenates. In the present study, the effects of amezinium on the deamination of noradrenaline were investigated in intact lungs of rats, since the pulmonary endothelial cells are a site where the catecholamine transporter is non-neuronal uptake1. In addition, another drug that is both a substrate of uptake1 and a MAO inhibitor, debrisoquine, was investigated in the study. The first aim of the study was to show whether amezinium and debrisoquine are substrates of uptake1 in rat lungs. After loading of isolated perfused lungs with 3H-noradrenaline (MAO and catechol-O-methyltransferase (COMT) inhibited), the efflux of 3H-noradrenaline was measured for 30 min. When 1 mumol/l amezinium or 15 mumol/l debrisoquine was added for the last 15 min of efflux, there was a rapid and marked increase in the fractional rate of loss of 3H-noradrenaline, which was reduced by about 70% when 1 mumol/l desipramine was present throughout the efflux period. These results showed that both drugs were substrates for uptake1 in rat lungs. In lungs perfused with 1 nmol/l 3H-noradrenaline (COMT inhibited), 10, 30 and 300 nmol/l amezinium caused 58%, 76% and 74% inhibition of noradrenaline deamination, respectively, and 30, 300 and 3000 nmol/l debrisoquine caused 56%, 89% and 96% inhibition of noradrenaline deamination, respectively. When MAO-B was also inhibited, 10 nmol/l amezinium caused 84% inhibition of the deamination of noradrenaline by MAO-A in the lungs. In contrast, in hearts perfused with 10 nmol/l 3H-noradrenaline under conditions where the amine was accumulated by uptake2 (COMT, uptake1 and vesicular transport inhibited), 10 nmol/l amezinium had no effect and 300 nmol/l amezinium caused only 36% inhibition of deamination of noradrenaline. The results when considered with previous reports in the literature show that amezinium is about 1000 times more potent and debrisoquine is about 20 times more potent for MAO inhibition in rat lungs than in tissue homogenates, and the reason for their high potencies in the intact lungs is transport and accumulation of the drugs in the pulmonary endothelial cells by uptake1. Amezinium is much less potent as a MAO inhibitor in cells with the uptake2 transporter, such as the myocardial cells of the heart. The results also confirmed previous reports that amezinium is highly selective for MAO-A.

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The effects of type 1 diabetes mellitus and of tobacco smoke on dissipation of catecholamines in pulmonary endothelial cells — a non-neuronal site of uptake1

Bryan-Lluka

McKee

1991

Recent Advances in Neuropharmacology

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Isolated perfused lungs of guinea-pig, in contrast with rat, lack an uptake process for noradrenaline

Cited by 6 publications

References 14 publications

Evidence for uptake1-mediated efflux of catecholamines from pulmonary endothelial cells of perfused lungs of rats

Evidence for uptake1-mediated efflux of catecholamines from pulmonary endothelial cells of perfused lungs of rats

Amezinium and debrisoquine are substrates of uptake1 and potent inhibitors of monoamine oxidase in perfused lungs of rats

The effects of type 1 diabetes mellitus and of tobacco smoke on dissipation of catecholamines in pulmonary endothelial cells — a non-neuronal site of uptake1

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