Norepinephrine precursor therapy in neurogenic orthostatic hypotension.

Abstract

BACKGROUND:

In patients with neurogenic orthostatic hypotension (NOH), the availability of the sympathetic neurotransmitter norepinephrine (NE) in the synaptic cleft is insufficient to maintain blood pressure while in the standing posture.

METHODS AND RESULTS:

We determined the effect of oral administration of the synthetic amino acid L-threo-3,4-dihydroxyphenylserine (L-DOPS), which is decarboxylated to NE by the enzyme L-aromatic amino acid decarboxylase (L-AADC) in neural and nonneural tissue, on blood pressure and orthostatic tolerance in 19 patients with severe NOH (8 with pure autonomic failure and 11 with multiple-system atrophy). A single-blind dose-titration study determined the most appropriate dose for each patient. Patients were then enrolled in a double-blind, placebo-controlled, crossover trial. L-DOPS significantly raised mean blood pressure both supine (from 101+/-4 to 141+/-5 mm Hg) and standing (from 60+/-4 to 100+/-6 mm Hg) for several hours and improved orthostatic tolerance in all patients. After L-DOPS, blood pressure increases were closely associated with increases in plasma NE levels. Oral administration of carbidopa, which inhibits L-AADC outside the blood-brain barrier, blunted both the increase in plasma NE and the pressor response to L-DOPS in all patients

CONCLUSIONS:

Acute administration of L-DOPS increases blood pressure and improves orthostatic tolerance in patients with NOH. The pressor effect results from conversion of L-DOPS to NE outside the central nervous system.

• Authors: Horacio Kaufmann, Daniela Saadia, Andrei Voustianiouk, David S Goldstein, Courtney Holmes, Melvin D Yahr, Rachel Nardin, Roy Freeman
• Journal: Circulation (Circulation) Vol. 108 Issue 6 Pg. 724-8 (Aug 12 2003) ISSN: 1524-4539 [Electronic] United States
• PMID: 12885750 (Publication Type: Clinical Trial, Controlled Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antiparkinson Agents
• Aromatic-L-Amino-Acid Decarboxylases
• Droxidopa
• Carbidopa
• Norepinephrine

Topics

• Administration, Oral
• Aged
• Antiparkinson Agents (adverse effects, pharmacokinetics, therapeutic use)
• Aromatic-L-Amino-Acid Decarboxylases (drug effects, metabolism)
• Blood Pressure (drug effects)
• Carbidopa (pharmacology)
• Cross-Over Studies
• Double-Blind Method
• Droxidopa (adverse effects, pharmacokinetics, therapeutic use)
• Female
• Hemodynamics (drug effects)
• Humans
• Hypotension, Orthostatic (drug therapy, etiology, physiopathology)
• Male
• Middle Aged
• Neurodegenerative Diseases (complications)
• Norepinephrine (biosynthesis, blood, physiology)
• Posture
• Single-Blind Method
• Treatment Outcome