Oxidant stress secondary to dopamine metabolism has been proposed as a pathogenic factor in the development of Parkinson's disease. Biochemical abnormalities extending beyond the central nervous system have been identified in patients with this condition. Previous investigators have found abnormally elevated concentrations of the lipid peroxidation product, malondialdehyde, in the plasma and serum of patients with Parkinson's disease. We attempted to replicate these findings but controlled for other factors that could influence malondialdehyde levels. We detected no significant elevations in mean serum malondialdehyde concentrations in either levodopa-treated or untreated patients with Parkinson's disease, compared to normal controls; similarly, no elevation was found in a group of patients with dementia of Alzheimer's type. On the other hand, a group of subjects with diabetes mellitus but no neurodegenerative disease had significantly elevated mean serum malondialdehyde levels, consistent with previous studies of diabetic patients. Autoxidation is one of the two major routes by which dopamine and dopa metabolism may generate oxygen free radicals. We analyzed the autoxidation product of dopa, 5-S-cysteinyl-dopa, in the plasma of these same groups of patients with neurodegenerative disease and normal controls; no significant differences were identified. Serum concentrations of two other antioxidant substances, alpha-tocopherol and uric acid, were also statistically similar in these groups. In conclusion, analysis of several blood products relevant to oxidant stress, including malondialdehyde, 5-S-cysteinyl-dopa, alpha-tocopherol, and uric acid, failed to distinguish patients with Parkinson's disease or dementia of Alzheimer's type from controls.

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Infusion of ANP to rats results in an inhibition of Na(+)-H+ antiport and Na(+)-Pi symport in brush border membrane vesicles (BBMV) prepared from kidneys of these animals (J Clin Invest 75:1983). iIn the present study we investigated the intrarenal mechanism by which infused ANP elicits these changes in proximal tubular transport systems. As in rats, infusion of ANP to rabbits resulted in a diuresis, natriuresis, and increase in GFR; however, unlike in rats, the fractional excretion of phosphate (Pi) was not changed. In BBMV prepared from cortices of ANP-infused rabbits, the rate of Na(+)-H+ antiport was decreased (delta -27%), but Na+ gradient-dependent uptakes of Pi and L-proline were not different from controls. Incubation of rabbit cortical tubule suspension in vitro with ANP 10(-7) M alone had no inhibitory effect on Na(+)-H+ antiport in BBMV prepared from these tubules, whereas incubation with other hormonal agents, 1 U/ml PTH (delta 61%) or with dopamine (DA) 10(-4) M (delta -34%), did inhibit the rate of Na(+)-H+ antiport in BBMV from the same pool of tubules. However, when tubules were incubated in the presence of (10(-5) M) DA, the addition of 10(-7) M ANP did cause a significant (delta -21%) decrease in Na(+)-H+ antiport activity in BBMV. In contrast, ANP did not show similar inhibitory effect in the presence of submaximal inhibitory doses of PTH. To explore whether ANP may act on proximal tubules in vivo indirectly, via mediation of DA, we evaluated the effect of ANP on some parameters of catecholamine system in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

SUMMARY1. High pressure liquid chromatography with electrochemical detection was used to quantify the efflux, in the same sample, of endogenous 5-hydroxytryptamine (5-HT), noradrenaline (NA), and 5-hydroxyindoleacetic acid (5-HIAA) into superfusates of the rat spinal cord in vivo. The efflux of these three agents was measured prior to, and during, electrical stimulation of the nucleus raphe magnus (n.r.m.) and nucleus reticularis paragigantocellularis (n.r.p.g.), two medullary nuclei implicated in antinociception.2. In untreated rats, basal efflux of 5-HT and NA was 0-21 and 0-12 ng/ml of superfusate respectively; the basal efflux of 5-HIAA was 18-17 ng/ml. Stimulation of the n.r.m. and n.r.p.g. in these animals increased the efflux of 5-HT and 5-HIAA, but did not alter the efflux of NA.3. 60 min after administration of fluoxetine (10 mg/kg, i.P.), a 5-HT uptake inhibitor, basal efflux of 5-HT and NA was unaltered, but the basal efflux of 5-HIAA was decreased. In these rats, stimulation of the n.r.m. and n.r.p.g. increased the efflux of 5-HT and of NA. The efflux of 5-HIAA was not altered.4. In rats pre-treated with both fluoxetine and desipramine (10 mg/kg, I.P.), the basal efflux of NA was increased while that of 5-HIAA was decreased; the basal efflux of 5-HT was not affected. The efflux of NA, but not of 5-HT, was increased in these animals during stimulation of the n.r.m. and n.r.p.g. The efflux of 5-HIAA was not changed by stimulation.5. Addition of fluoxetine alone or with desipramine to the superfusate in high concentrations greatly increased basal efflux of 5-HT. Failure of stimulation of the ventromedial medulla to increase the efflux of 5-HT in these animals may be related to feed-back inhibition of release by the high concentration of 5-HT initially present in the superfusate.6. These results indicate that electrical stimulation of the n.r.m. and n.r.p.g. increases the efflux of endogenous 5-HT and NA from the spinal cord.

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SUMMARY1. Superfusates taken from spinal cords of cats anaesthetized with chloralose and urethane were assayed for endogenous serotonin and noradrenaline by high-pressure liquid chromatography with electrochemical detection.2. Stimulating the dorsolateral funiculus, caudal to a spinal transaction, enhanced in a frequency-dependent manner the levels of monoamines in the spinal superfusate.3. Tyramine added to the superfusate enhanced the release of noradrenaline and serotonin. 4. In cats with intact neuraxes, stimulation of the sciatic nerve at high, but not low intensities produced a 2-to 3-fold increase in the levels of monoamines in the spinal superfusate. This evoked monoamine efflux was attenuated by cold block of the cervical spinal cord.5. Stimulation of the infraorbital branch of the trigeminal nerve evoked the release of noradrenaline and serotonin from the lumbar cord in animals with intact neuraxes. Cold block of the cervical cord blocked trigeminal-evoked release of lumbar serotonin and noradrenaline.6. That the monoamine efflux was not due to elevations in blood pressure was indicated by the failure of vasoxyl, an a-agonist producing hypertension, to evoke any changes in spinal monoamine levels. 7. The monoamine release was not dependent upon either an opiate-sensitive link or upon the activation of the sympathetic ganglia, because systemic administration of naloxone (an opiate antagonist) and chlorisondamine (a ganglionic blocking agent) failed to antagonize the evoked release of amines.8. These results suggest the existence of a spinopetal monoamine system which is activated by peripheral stimuli. The modulatory influence associated with increasing monoamine tone in the spinal cord clearly indicated that somatic stimuli may activate a descending monoamine pathway which serves to modulate the magnitude of the ascending sensory message.

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