51. α2C-Adrenoceptors modulate L-DOPA uptake in opossum kidney cells and in the mouse kidney.
- Author
-
Moura E, Silva E, Serrão MP, Afonso J, Kozmus CE, and Vieira-Coelho MA
- Subjects
- Acridines pharmacology, Adrenergic alpha-2 Receptor Agonists pharmacology, Adrenergic alpha-2 Receptor Antagonists pharmacology, Animals, Cell Line, Dopamine urine, Dose-Response Relationship, Drug, Kidney drug effects, MAP Kinase Kinase 1 metabolism, Medetomidine pharmacology, Mice, Mice, Knockout, Opossums, Piperazines pharmacology, Signal Transduction drug effects, Signal Transduction physiology, Sodium Chloride, Dietary metabolism, Dopamine metabolism, Dopamine Agents pharmacokinetics, Kidney metabolism, Levodopa pharmacokinetics, Receptors, Adrenergic, alpha-2 metabolism
- Abstract
Targeted deletion or selective pharmacological inhibition of α(2C)-adrenoceptors in mice results in increased brain tissue levels of dopamine and its precursor l-3,4-dihydroxyphenylalanine (l-DOPA), without significant changes in l-DOPA synthesis. l-DOPA uptake is considered the rate-limiting step in dopamine synthesis in the kidney. Since α(2C)-adrenoceptors may influence the transport of l-DOPA, we investigated the effect of α(2C)-adrenoceptor activation on l-DOPA uptake in a kidney cell line (opossum kidney cells). l-DOPA and dopamine kidney tissue levels in α(2C)-adrenoceptor knockout (α(2C)KO) mice and in mice treated with the selective α(2C)-adrenoceptor antagonist JP-1302 were also evaluated. The α(2)-adrenoceptor agonist medetomidine (0.1-1,000 nM) produced a concentration-dependent decrease in l-DOPA uptake in opossum kidney cells (IC(50): 2.5 ± 0.5 nM and maximal effect: 28 ± 5% of inhibition). This effect was abolished by a preincubation with JP-1302 (300 nM). Furthermore, the effect of medetomidine (100 nM) was abolished by a preincubation with U-0126 (10 μM), a MEK1/2 inhibitor. Kidney tissue levels of l-DOPA were significantly higher in α(2C)KO mice compared with wild-type mice (wild-type mice: 58 ± 2 pmol/g tissue and α(2C)KO mice: 81 ± 15 pmol/g tissue, P < 0.05) and in mice treated with JP-1302 (3 μmol/kg body wt) compared with control mice (control mice: 62 ± 2 pmol/g tissue and JP-1302-treated mice: 75 ± 1 pmol/g tissue, P < 0.05), both without significant changes in dopamine kidney tissue levels. However, mice treated with JP-1302 on a high-salt diet presented significantly higher dopamine levels in the kidney and urine compared with control animals on a high-salt diet. In conclusion, in a kidney cell line, α(2C)-adrenoceptor activation inhibits l-DOPA uptake, and in mice, deletion or blockade of α(2C)-adrenoceptors increases l-DOPA kidney tissue levels.
- Published
- 2012
- Full Text
- View/download PDF