The discovery of the pressor effect of DOPS and its blunting by decarboxylase inhibitors

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H. Kaufmann

Mount Sinai School of Medicine, New York, NY, USA

Summary. In the 1950s it was found that an artificial aminoacid, 3,4-threo-dihydroxy-phenylserine (DOPS), was converted to nor-epinephrine (NE) in a single step by the enzyme L-aromatic amino acid decarboxy-lase (AADC), bypassing the need for the rate limiting enzyme dopamine beta hydroxylase. Trying to replicate the success of dihydroxy-phenylalanine (DOPA) in the treatment of Parkinson disease, treatment with DOPS was attempted in patients with autonomic failure who have impaired NE release. DOPS improved orthostatic hypotension in patients with familial amyloid polyneuropathy, congenital deficiency of dopamine beta hydroxy-lase, pure autonomic failure and multiple system atrophy. DOPS pressor effect is due to its conversion to NE outside the central nervous system because concomitant administration of carbidopa, an inhibitor of AADC that does not cross the blood-brain barrier, blunted both the increase in plasma NE and the pressor response. DOPS pressor response is not dependent on intact sympathetic terminals because its conversion to NE also occurs in non-neuronal tissues.

Introduction

Melvin Yahr played a pioneering role in the use of levodopa to restore dopamine neurotransmission in patients with Parkinson disease (PD). Trying to replicate that re markable therapeutic success, he was also involved in a less well-known, still unfolding story, using a similar pharmacological paradigm to restore noradrenergic neurotransmission in patients with autonomic failure.

Orthostatic hypotension, the most disabling feature of autonomic failure, is due to deficient release of norepinephrine (NE) by postganglionic sympathetic neurons. As shown in Fig. 1, this defect in NE release can be due to degeneration of peripheral postgan-glionic sympathetic neurons, as it occurs in the Lewy body disorders (pure autonomic failure, PD and dementia with Lewy bodies), and in some peripheral neuropathies (e.g. amyloid and diabetic polyneuropathy); or may be caused by lesions in central autono-mic neurons, as it occurs in patients with multiple system atrophy (MSA) (Kaufmann and Biaggioni, 2003). Rarely, the defect in NE release is caused by congenital deficiency of the enzyme dopamine beta hydroxylase (Kim et al., 2002). Finally, in autoimmune au-tonomic neuropathy, autoantibodies against ganglionic nicotinic cholinergic receptors prevent neurotransmission at the autonomic ganglia and block NE release (Vernino et al., 1998).

Normally, NE is synthesized from levo-dopa (Fig. 2), which is first decarboxylated to dopamine by L-aromatic amino acid dec-arboxylase (AADC) and then hydroxylated to norepinephrine by dopamine beta hydro-xylase (DBH). The rate-limiting enzyme for

Fig. 1. Site of involvement in the sympathetic efferent pathway in different types of autonomic failure. AAN autoimmune autonomic neuropathy, MSA multiple system atrophy, FAP familial amyloid polyneuropathy, DA dopamine, DBH dopamine beta hydroxylase, NE norepinephrine, atb antibody, NiAChR nicotinic cholinergic receptor

Fig. 1. Site of involvement in the sympathetic efferent pathway in different types of autonomic failure. AAN autoimmune autonomic neuropathy, MSA multiple system atrophy, FAP familial amyloid polyneuropathy, DA dopamine, DBH dopamine beta hydroxylase, NE norepinephrine, atb antibody, NiAChR nicotinic cholinergic receptor this reaction is DBH. Thus, oral administration of levodopa leads to an increase in dopamine but no significant increase in nor-epinephrine. However, a synthetic amino acid identical to levodopa but with an added beta hydroxyl group (Fig. 2), dyhidroxypheny-lserine, DOPS, was found, in the 1950s, by Blaschko et al. (1950) and Schmiterlow (1951) to be converted, in vivo, to norepinephrine after a single decarboxylation step by AADC, bypassing the need for DBH.

DOPS has four steroisomers (Bartholini et al., 1975). Early studies used a racemic mixture that contained both the D and L iso-forms of DOPS but only the L-isoform is converted to biologically active L-norepine-phrine. Furthermore, the D-stereoisomer of DOPS might competitively inhibit the decarboxylation of the L stereoisomer to L-nore-pinephrine. (Inagaki et al., 1976) Thus, the pure L isoform of DOPS is the preferred formulation for treatment.

Administration of DOPS could increase the synthesis of NE in sympathetic neurons and in other tissues as well (Fig. 3). Using the neutral aminoacid transporter, DOPS could be taken up by sympathetic neurons, converted to norepinephrine, stored and released during sympathetic activation, thus acting as a neurotransmitter. DOPS may also be con-

DOPA

AADC

DOPAMINE

AADC

DOPS

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NOREPINEPHRINE

Fig. 2. The pathway for the physiological synthesis of norepinephrine from DOPA and non-physiological synthesis of norepinephrine from DOPS. DOPS 3,4,-L-threo-dihydroxyphenyserine, DOPA Dihydroxyphenyl-alanine, AADC L-aromatic aminoacid decarboxylase, DBH dopamine beta hydroxylase

Fig. 3. Sites of decarboxylation of DOPS to NE. Central, pre and postganglionic sympathetic neurons and a blood vessel are depicted. CNS central nervous system, NE norepinephrine, DOPS 3,4-threo-dihydroxy-phenylserine, E ephinephrine, AADC L-aromatic aminoacid decarboxylase, PNMT phenylethanolamine N-methyltransferase

Fig. 3. Sites of decarboxylation of DOPS to NE. Central, pre and postganglionic sympathetic neurons and a blood vessel are depicted. CNS central nervous system, NE norepinephrine, DOPS 3,4-threo-dihydroxy-phenylserine, E ephinephrine, AADC L-aromatic aminoacid decarboxylase, PNMT phenylethanolamine N-methyltransferase verted to NE outside sympathetic neurons, because AADC is widely expressed in the cytoplasm of different tissues including kidney, gut and liver, and these cells also express the neutral aminoacid transporter in their surface. NE synthesized from DOPS in nonneural tissues is rapidly released into the bloodstream where it acts as a circulating vasoconstrictor hormone. Finally, DOPS crosses the blood-brain barrier (Kato et al., 1987) and it has been suggested that its pressor effect could be due to central activation of sympathetic outflow (Kachi et al., 1988). This, however, proved not to be the case (see below).

Clinical uses of DOPS

DBH deficiency

DOPS proved extremely useful in patients with DBH deficiency. These patients have severe orthostatic hypotension, their serum dopamine levels are high and they have unde-

tectable plasma NE. In 1987, Biaggioni and Roberstson (1987) and Man in't Veld (Man in't Veld et al., 1987) showed that administration of DOPS had a dramatic normalizing effect on the blood pressure of these patients. DOPS was directly converted to norepine-phrine, bypassing the need for dopamine beta hydroxylase. They also showed that DOPS was taken up by postganglionic neurons where it was converted to NE stored and released when appropriate. After treatment with DOPS, NE increased upon standing, and infusion of tyramine produced release of NE, whereas before treatment, tyramine had induced release of dopamine.

Other types of autonomic failure

In 1980, Suzuki et al. reported that administration of DOPS had a pronounced pressor effect and induced a marked increase in urinary excretion of norepinephrine in patients with familial amyloid polyneuropathy, a dis order with orthostatic hypotension due to destruction of sympathetic fibers (Suzuki et al., 1980). In 1981, Araki and collaborators (Araki et al., 1981) reported that in rats oral administration of DOPS increased blood pressure but the pressor effect was much more pronounced in rats made hypotensive by chemical sympathectomy with the neuro-toxin 6-hydroxydopamine. Interestingly, L-threo-DOPS produced the same increase in plasma NE concentrations in sympathecto-mized rats as in the controls, indicating that norepinephrine was synthesized from DOPS in places other than sympathetic nerves. The pressor effect was markedly reduced by inhibition of peripheral decarboxylase and by blockade of alpha-adrenoceptors.

In 1983, Birkmayer et al. (1983) reported successful use of DOPS in a small study of parkinsonian patients with orthostatic hypotension. In the last decade, with few exceptions (Hoeldtke et al., 1984), several small studies have reported success using DOPS in the treatment of orthostatic hypotension in patients with different types of autonomic failure (Kaufmann et al., 1991; Freeman et al., 1999) including a recent report of its use in a patient with autoimmune autonomic neuropathy (Gibbons et al., 2005). Recent work has clarified the mechanism of the pressor effect of DOPS in patients with autonomic failure (Kaufmann et al., 2003) and confirmed the earlier findings in rats (Araki et al., 1981). Better understanding of its mechanism of action and pharmacokinetics should allow proper clinical use of this compound in patients with autonomic failure.

Mechanism of action of DOPS

Central vs. peripheral

Although DOPS crosses the blood-brain barrier (Karai et al., 1987; Kachi et al., 1988) its pressor effect is only due to its conversion to norepinephrine outside the brain. Concomitant administration of DOPS with carbidopa, an inhibitor of AADC that does not cross the blood-brain barrier and thus inhibits NE synthesis only outside the CNS, blocked both the pressor effect and the increase in plasma norepinephrine (Fig. 4). This is important because many patients with orthostatic hypotension have parkinsonism and are treated with a combination of DOPA and a decar-boxylase inhibitor, which will prevent nor-epinephrine formation from DOPS outside the brain, blunting its pressor effect.

Neurotransmitter vs. circulating hormone

Rather than being taken up by postganglionic sympathetic neurons, converted to NE intra-neuronally, as it occurs in patients with DBH deficiency, and released when sympathetic fibers discharge during orthostasis, in degenerative autonomic disorders, DOPS appears to exert its pressor effect mostly by conversion to NE outside sympathetic neurons (in the kidney, gut and liver), acting as a circulating vasoconstrictor hormone. This is suggested by the finding that administration of DOPS increased blood pressure and venous plasma NE levels both in the supine and upright position and that the magnitude of the increase did not change during orthostasis (Fig. 4).

This peripheral extraneuronal mechanism of action of DOPS renders it very effective in patients with PAF, a disorder with widespread loss of sympathetic terminals (Goldstein et al., 1997; Hague et al., 1997) and markedly exaggerated pressor responses to circulating norepinephrine (Polinsky et al., 1981). Indeed, Kaufmann et al. (2003) found that the pressor response to DOPS in patients with PAF was more pronounced than in patients with MSA, despite a lower dose of DOPS being taken by PAF patients. Thus, non-neural tissue most likely stomach, liver or kidney, where AADC is extensively expressed, appears to be the major site of NE generation from DOPS. There was a clear relationship between the pressor response and venous plasma norepinephrine levels.

Time (hours)

Fig. 4. The effect of 3,4-threo-dihydroxyphenylserine (DOPS), carbidopa, DOPS + carbidopa and placebo on mean blood pressure (MBP) when supine and after 3 minutes standing. Data = mean ± SE. * denotes p < 0.05

Time (hours)

Fig. 4. The effect of 3,4-threo-dihydroxyphenylserine (DOPS), carbidopa, DOPS + carbidopa and placebo on mean blood pressure (MBP) when supine and after 3 minutes standing. Data = mean ± SE. * denotes p < 0.05

In patients with autonomic failure, the peak blood pressure effect occurred around 4 hours after DOPS administration. Blood pressure remained higher than placebo for another 3 hours, for a total of 7 hours. Plasma NE levels increased progressively. As shown in Fig. 5, the threshold NE venous plasma level required to exert a pressor effect was 700 pg/mL.

Pharmacokinetics

The peak DOPS plasma levels occurred around 3 hours after oral administration of

DOPS (Fig. 6), a similar time frame and levels to those reported for DOPA (Nutt and Woodward, 1986). NE peaked at 6 hours after DOPS ingestion.

Patients with PAF had significantly lower plasma NE and DHPG levels than did the patients with MSA, both at baseline and after DOPS administration. The volume of distribution was smaller in PAF than in MSA, possibly reflecting neuronal uptake in MSA, and lack of it in PAF.

The peak levels of NE were only about one-thousandth the peak level of DOPS. This might be interpreted as indicating low

Fig. 5. Plasma concentration of norepinephrine (NE) vs. changes in systolic blood pressure (SBP). Data = mean ± SE. Solid curve represents the best fit (r2 = 0.903). From Kaufmann et al. (2003)

efficiency of conversion of DOPS to NE; however, the difference is mostly explained by much longer half-time of DOPS in the plasma - about 140 minutes - which exceeded by about a hundred-fold the known half-time of NE in the plasma, which is 1.5 minutes or less (Goldstein et al., 1983). Therefore, even if DOPS were converted completely and instantaneously to NE, from the large difference in half times of clearance from the plasma, the peak DOPS level in venous plasma would exceed the peak NE level several fold (Goldstein et al., 2004).

Intracellular storage, neuronal vs. extraneuronal

The slow decline in plasma NE from the peak level probably reflects ongoing production of NE from DOPS and ongoing entry of the produced NE into the bloodstream from a cellular storage site. Cells that express the

Fig. 6. Levels of DOPS and norepinephrine after DOPS administration. Data = mean ± SE. DOPS = 3,4,-L-

threo-dihydroxyphenyserine

Fig. 6. Levels of DOPS and norepinephrine after DOPS administration. Data = mean ± SE. DOPS = 3,4,-L-

threo-dihydroxyphenyserine neutral amino acid transporter and also contain AAAD, including sympathetic nerves and parenchymal cells in the liver and kidneys, would be expected to take up DOPS and convert it to NE. In patients with PAF, storage of DOPS and NE is likely to occur in non-neuronal tissue as sympathetic terminals are severely affected but in MSA patients both sympathetic nerves and extraneuronal production of NE from DOPS is likely.

In conclusion

DOPS increases blood pressure and alleviates the symptoms of orthostatic hypotension in patients with multiple system atrophy and pure autonomic failure. After oral administration, DOPS is converted to NE even in patients with severe destruction of peripheral sympathetic nerves, through decarboxylation to norepinephrine in non-neural tissues, in the kidney, gut and the liver, where AADC is widely expressed. The pressor effect of DOPS is due to its conversion to NE outside the central nervous system because concomitant administration of carbidopa, an inhibitor of AADC that does not cross the blood-brain barrier, blunted the pressor response. This finding has implications for the use of DOPS in parkinsonian patient already taking DOPA and a decarboxylase inhibitor.

References

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Schmiterlow CG (1951) The formation in vivo of noradrenaline from 3:4-dihydroxyphenylserine (noradrenaline carboxylic acid). Br J Pharmacol 6(1): 127-134 Suzuki T, Higa S, et al. (1980) Effect of infused L-threo-3,4-dihydroxyphenylserine on adrenergic activity in patients with familial amyloid poly-neuropathy. Eur J Clin Pharmacol 17(6): 429-435 Vernino S, Adamski J, et al. (1998) Neuronal nicotinic ACh receptor antibody in subacute autonomic neuropathy and cancer-related syndromes. Neurology 50(6): 1806-1813

Author's address: H. Kaufmann, MD, Mount Sinai School of Medicine, Box 1052, New York, NY 10029, USA, e-mail: [email protected]

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