Effect of L-threo-3,4-dihydroxyphenylserine (L-DOPS), an immediate precursor of norepinephrine, on the cerebral blood flow in rats.

Abstract

Abstract-L-threo-3,4-Dihydroxyphenylserine (L-DOPS), a norepinephrine (NE) precursor, 3 mg/kg, i.v., increased the cerebral blood flow (CBF) in both the striatum and hippocampus as well as the mean arterial blood pressure (MABP) in urethane-anesthetized rats, as NE infusion did. The L-DOPS induced increase in CBF was inhibited by benserazide (3 mg/kg/hour), a peripheral aromatic L-amino acid decarboxylase inhibitor, and propranolol (3 mg/kg, i.p.), a 19-adrenoceptor blocker as well. These results suggest that the effects of L-DOPS may be at tributed to the action of NE formed from L-DOPS, and the action may be mediated by stimulation of i9-adrenoceptor.A synthetic amino acid, L-threo-3,4 dihydroxyphenylserine (L-DOPS) has been known to be decarboxylated by aromatic L amino acid decarboxylase to yield norepine phrine (NE) in vitro (1) and in vivo (2-4). It has also been reported that L-DOPS produced a positive chronotropic effect in rat atrial preparations (5) as well as an inotropic effect in open-chest rats (6), a slow onset and long-lasting hypertensive effect in rats (7) and a diuretic effect in rats and mice (8). In clinical studies, DL or L DOPS has recently been reported to improve postual hypotension and dizziness in par kinsonian patients (9), and the patients with familial amyloid polyneuropathy (10) or Shy Drager syndrome (11), and also to show beneficial effect on akinesia or freezing phenomenon in advanced parkinsonian patients (12). In the present study, the effect of L-DOPS on the cerebral blood flow (CBF) was studied in rats in comparison with that of NE.The experiments were carried out in male Sprague-Dawley rats weighing between 240 and 310 g. The animals were anesthetized with urethane (1.25 g/kg, i.p.). Polyethylene catheters were inserted into the femoral artery and vein for continuous measurement of blood pressure and for administration of drugs. After tracheotomy, the animals were paralyzed with intravenous infusion of 6.19 8 mg/kg pancuronium bromide and were ventilated using a respirator. The CBF was measured by the hydrogen clearance method. Briefly, an epoxy-coated platinum electrode, 300 aim in diameter, with a 1 mm portion at its tip uncoated and plated with platinum black, was placed stereotaxically in the striatum and another one in the hippocampus. The reference electrode was an Ag-AgCI electrode inserted under the skin. The rectal temperature of animals was maintained close to 37 °C.As shown in Fig. 1, administration of L DOPS (3 mg/kg, i.v.) produced a statistically significant increase in striatal blood flow as well as an elevation in mean arterial blood pressure (MABP), whereas 1 mg/kg of L DOPS produced no significant effect on CBF. These effects were long-acting. Similar results were also observed in the hip pocampus, but the flow increment was somewhat less than that in the striatum (not shown in the figure). The increases in CBF and MABP produced by L-DOPS were inhibited by about 85 and 70%, respectively, by i.v. infusion of a peripheral aromatic L

Regulation of MCP‐1 production in brain by stress and noradrenaline‐modulating drugs

“…The effects of raising CNS NA levels on MCP-1 expression were tested by treating 3-month-old female C57Bl6 mice with the synthetic NA precursor L-DOPS, which is converted by the enzyme L-AAAD to NA (Sato et al 1987;Kikuchi et al 2000). Mice were treated for 10 days with a daily injection of L-DOPS (200 mg/kg i.p.)…”

“…By administering desipramine, the endogenous NA reuptake system is inhibited. Another approach was to administer the synthetic NA precursor L-threo-3,4-dihydroxyphenylserine (L-DOPS) which is converted to NA by L-aromatic amino acid decarboxylase (L-AAAD) (Sato et al 1987;Kikuchi et al 2000). To confine this conversion to the brain, L-DOPS was used in combination with benserazide (an inhibitor of L-AAAD) that does not cross the blood brain barrier.…”

“…By administering desipramine, the endogenous NA reuptake system is inhibited. Another approach was to administer the synthetic NA precursor l ‐threo‐3,4‐dihydroxyphenylserine (L‐DOPS) which is converted to NA by l ‐aromatic amino acid decarboxylase (L‐AAAD) (Sato et al. 1987; Kikuchi et al.…”

The protective effect of L-threo-3,4-dihydroxyphenylserine on ischemic hippocampal neuronal death in gerbils.

“…4 ' 5 Benserazide, an extracerebral decarboxylase inhibitor, at a high dose (1 mg/kg or more) may penetrate the blood-brain barrier and inhibit the decarboxylation of DOPS to norepinephrine. 5 An addition of DOPS increases nerve growth factor (NGF) synthesis in cultured mouse L-M fibroblast and astroglial cells, and this effect is not blocked by treatment See Editorial Comment, page 1432 with decarboxylase inhibitor.…”

Midodrine Hydrochloride and l‐threo‐3,4‐dihydroxy‐Phenylserine Preserve Cerebral Blood Flow in Hemodialysis Patients With Orthostatic Hypotension

“…L-DOPS is known to activate β-adrenergic receptors (33) and dilate brain blood vessels (34). Furthermore, Sato et al (35) reported that L-DOPS increased CBF in urethane-anesthetized rats, and suggested that such effects might be mediated by the action of NE formed from L-DOPS in the brain, through stimulation of βadrenoceptors. Our results confirmed that serum NE concentrations increased significantly following oral administration of L-DOPS, which might contribute to the improvement in CBF.…”