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Biomedical subjects

J J Warsh

Publications and source records attributed to J J Warsh.

108 records · Page 6Linked to original sources
PubMed1977

A gas chromatographic-mass spectrometric (GC-MS) assay for 3-methoxy-4-hydroxyphenethyleneglycol and vanilmandelic acid in human serum.

Procedure for the quantification of 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) and vanilmandelic acid (VMA) in human serum are described. MHPG was selectively acetylated then determined as its 4-acetyl-di-trifluoroacetyl derivative and VMA as its di-pentabluoropropionyl-methyl ester. Deuterium-labeled MHPG and VMA were used as internal standards. Each of these metabolities and the resprective internal standards was recorded by double ion monitoring respectively, and the ratios were determined for specificity. Assay sensitivities of 1.0 ng/ml for MHPG and 2.0 ng/ml for VMA were achieved using 0.5 ml of serum. Total and free MHPG concentrations in human serum were determined to be 16.5 ng/ml +/- 4.4 (S.D.) and 4.6 ng/ml +/- 1.0 respectively from 10 normal male subjects. Free VMA concentrations were 7.0 ng/ml +/- 1.5; thus the ratio of MHPG/VMA was calculated to be 2.4 +/- 0.7 in these subjects. Of these two major normal metabolites of norepinephrine, MHPG is regarded to be largely derived from the central nervous system while VMA is from the periphery. The procedures are highly specific as well as simple and sensitive enough to permit simultaneous measurement of these two metabolites in a series of multiple samples from an individual.

Adult↗
PubMed1977

CNS monoamine metabolism in bipolar affective disorder. Evaluation using a peripheral decarboxylase inhibitor.

Carbidopa, a decarboxylase inhibitor that does not cross the blood-brain barrier, inhibits the peripheral synthesis of nor-adrenaline, serotonin, and tryptamine. By reducing the peripheral component of end-products of these amines in urine, a more accurate assessment of central nervous system (CNS) amine metabolism is provided. Urinary 5-hydroxyindoleacetic acid (5-HIAA), tryptamine, and 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured over ten days in ten normal controls and eight bipolar depressives. After a three-day baseline period, carbidopa, 100 mg three times a day, was given for seven days. While the patients tended to excrete less MHPG in the baseline period, these differences became somewhat larger, and statistically significant when peripheral contributions were reduced with carbidopa. While carbidopa resulted in striking inhibition of tryptamine excretion, and smaller decreases in the excretion of 5-HIAA and MHPG, evidently from storage pools, there were no significant differences in degree of inhibition between patients and controls. Absolute values of 5-HIAA and tryptamine were similar for both groups, during the baseline and again with carbidopa. These results after carbidopa are compatible with a central catecholaminergic deficit in bipolar depressives and the use of urinary MHPG as an index of CNS catecholamine function.

Adolescent↗
PubMed1977

The effect of a peripheral decarboxylase inhibitor (carbidopa) on monoamine and neuroendocrine function in man.

Carbidopa, a selective extracerebral decarboxylase inhibitor, was given to 10 normal volunteers to determine its effects on endogenous catecholamine, indoleamine, and endocrine function. Tryptamine, which is largely extracerebral in origin, was inhibited markedly (80 percent) by the carbidopa; 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenolglycol (MHPG) excretion also were inhibited by the drug but not to the same degree as tryptamine. These differential results may be due partly to the higher central nervous system origin of the 5-HIAA and MHPG but also to a peripheral "stores" effect. In addition, carbidopa resulted in significant increases in plasma prolactin and a small but significant decrease in plasma glucagon.

Adult↗
PubMed1976

Total and free plasma tryptophan levels in patients with affective disorders: effects of a peripheral decarboxylase inhibitor.

Previous reports of decreased cerebrospinal fluid tryptophan levels and decreased free plasma tryptophan levels, as well as a reduction in the volume of distribution of tryptophan, suggest that alterations in the disposition of plasma tryptophan may occur in depressives. We examined the disposition of plasma tryptophan in ten normal controls and ten depressed patients. These measures were made on two drug-free baseline days and on two days when the subjects had been receiving the peripheral decarboxylase inhibitor, carbidopa, which inhibits tryptophan metabolism via extracerebral indoleamine pathways.

Adolescent↗
PubMed1976

Spinal reflexes and the concentrations of 5-HIAA, MHPG, and HVA in lumbar cereborspinal fluid after spinal lesions in man.

Descending bulbospinal pathways that employ specific neurotransmitter substances are known to be capable of modulating segmental reflex activity in the experimental animal. To determine whether this might also occur in man correlations have been sought between the activity in spinal reflex pathways and the lumbar cerebrospinal fluid (CSF) concentrations of 5-hydroxyindolacetic acid (5-HIAA), 3 methoxy-4-hydroxyphenylglycol (MHPG), and homovanillic acid (HVA) in 12 patients with complete or virtually complete spinal lesions. The concentrations of 5-HIAA and MHPG in lumbar CSF ARE REDUCED AFTER COMPLETE OR VIRTUALLY COMPLETE SPINAL LESIONS IN MAN. This may occur within 18 days of the lesion. MHPG concentrations appear to be inversely related to the level of the lesion. The HVA concentration in lumbar CSF is reduced when there is obstruction of the CSF pathways. No relationship could be demonstrated between the concentrations of 5-HIAA or MHPG in lumbar CSF and the activity in the spinal monosynaptic pathway (estimated from the proportion of the motoneurone pool activated by the Achilles tendon reflex or H reflex) or the activity of a spinal inhibitory mechanism (estimated by the degree of vibratory inhibition of the monosynaptic reflex). Patients with a tonic vibration reflex (TVR) tended to have higher MHPG levels. There appeared to be an association between low CSF HVA and enhanced vibratory inhibition of the monosynaptic reflex in the nine patients whose spinal lesions were complete.

Adolescent↗
PubMed1976

Effect of carbidopa on prolactin, growth hormone and cortisol secretion in man.

Serum prolactin, growth hormone and cortisol levels were examined in normal volunteers following administration of carbidopa, a peripheral decarboxylase inhibitor. 24-hour urinary tryptamine levels dropped markedly indicating that inhibition of decarboxylase was effective. Prolactin levels rose while growth hormone and cortisol remained unchanged. Since the tuberoinfundibular dopamine nerve terminals lie outside the blood brain barrier, this study suggests that these neurons are involved in prolactin but not in growth hormone or cortisol regulation. Findings are compatible with two alternate hypotheses--either that dopamine is a physiologic prolactin inhibiting factor (PIF) or that tuberoinfundibular dopamine neurons regulate the release of PIF.

Adult↗
PubMed1976

Brain and peripheral metabolism of 5-hydroxytryptophan-14C following peripheral decarboxylase inhibition.

Following selective peripheral decarboxylase inhibition, a greater fraction of peripherally measured monoamine metabolites should derive from central nervous system monoamine metabolism. In rats pretreated with the peripheral decarboxylase inhibitor L-alpha-(3,4-dihydroxybenzyl)-alpha-hydrazinopropionic acid (MK-486) (50 mg/kg i.p. or i.v.), the peripheral formation of 5-hydroxytryptamine-14C (5-HT-14C) from the precursor DL-5-hydroxytryptophan-14C (5-HTP-14C) was reduced by 82 to 100% over a 4-hour interval. There was a marked increase in the penetration of 5-HTP-14C into brain and in the appearance in brain of 5-HT-14C and 5-hydroxyindoleacetic acid-14C (5-HIAA-14C). The cerebral metabolism of 5-HTP-14C in vehicle-pretreated animals appeared to occur mainly in the brain vascular compartment. Following MK-486 pretreatment, the in vivo metabolism of 14C-5-hydroxyindoles in the extracerebral compartment obeys linear kinetics as does the uptake and decarboxylation of 5-HTP-14C in brains. The cerebral turnover of 5-HT-14C appeared to increase as a function of the dose of 5-HTP injected. This phenomenon may be a result of either saturation of brain 5-HT storage sites or nonspecific metabolism of 5-HTP in brain catecholamine neurons. A highly signigificant correlation was found between the brain and blood 5-HIAA-14C levels following MK-486. The adrenal formation of 5-HT, which was not inhibited by MK-486, did not appear to contribute significantly to the blood 5-HIAA-14c levels. These results suggest the possibility that following peripheral decarboxylase inhibition a larger fraction of peripherally measured 5-HIAA may derive from central nervous system 5-HT metabolism.

5-Hydroxytryptophan↗
PubMed1975

The origin of blood k-hydroxyindoleacetic acid following L-hydrazino-alpha-methyldopa (MK-486).

Blood 5-HIAA-14C levels derived from exogenous D,L-5-HTP-14C were investigated in normal, sham-operated and nephrectomized rats pretreated with MK-486 and probenecid (200 mg/kg i.p.). Blood 5-HIAA-14C levels decreased in nephrectomized rats following probenecid. Peripheral decarboxylase inhibition by MK-486 was enhanced by both probenecid and nephrectomy. Increased penetration of 5-HTP into brain occurred following probenecid. The results indicate that following MK-486 about 20% of the blood 5-HIAA-14C derived from 5-HTP-14C in rats originates in the CNS.

5-Hydroxytryptophan↗
PubMed1975

The origin of blood 5-hydroxyindoleacetic acid following L-hydrazine-alpha-methyldopa (MK-486).

Blood 5-HIAA-14C levels derived from exogenous D,L-5-HTP-14C were investigated in normal, sham-operated and nephrectomized rats pretreated with MK-486 and probenecid (200 mg/kg i.p.). Blood 5-HIAA-14C levels decreased in nephrectomized rats following probenecid. Peripheral decarboxylase inhibition by MK-486 was enhanced by both probenecid and nephrectomy. Increased penetration of 5-HTP into brain occurred following probenecid. Thr results indicate that the following MK-486 about 20% of the blood 5-HIAA-14C derived from 5-HTP-14C in rats originates in the CNS.

5-Hydroxytryptophan↗
PubMedDate not supplied

Inositol 1,4,5-trisphosphate receptor in developing and senescent rat cerebellum.

Numerous process associated with intracellular calcium homeostasis have previously been found to vary with age. To determine whether the binding sites for the calcium-mobilizing second messenger, inositol 1,4,5-trisphosphate (InsP3), also displays such variation, [3H]InsP3 binding was investigated in cerebellar or cerebral cortical membranes prepared from rats at different ages from birth up to 24 months of age. In the cerebellum, the InsP3 receptor density was very low during the first week after birth, increased markedly between days 8 and 28 and then reached an apparent plateau between 28 to 56 days of age. The InsP3 receptor binding affinity was comparable at different developmental stages. No age-related differences were found in InsP3 receptor density or affinity in the cerebral cortex of 3-, 6-, 9-, 12-, and 24-month-old rats. In the cerebellum, InsP3 receptor density but not affinity was significantly reduced in 24-month-old compared only to 3-month-old animals. Our data suggest that the changes in InsP3 receptor binding during early development might reflect the growth and maturation of neurons containing these receptors (i.e., Purkinje cells). Furthermore, the age-dependent reduction in InsP3 receptor density, together with the recent report of senescent changes in protein kinase C activity, indicate that disruption of phosphoinositide second messenger system may be of importance to the impairment of neuronal responsiveness and behavioral deficits observed with aging.

Aging↗
PubMedDate not supplied

Effect of midbrain raphé lesions or intracisternal 6-hydroxydopamine administration on D, L-5-hydroxytryptophan-14C metabolism after peripheral decarboxylase inhibition.

Brain and blood 14C-5-hydroxyindole metabolism was studied in normal, raphé-lesioned and 6-hydroxydopamine (60HDA)-treated rats given L-(-)-alpha-hydrazino-3, 4-dihydroxy-alpha-methylhydrocinnamic acid (MK-486) (50 mg/kg) intraperitoneally and 5-hydroxytryptophan (5-HTP)-14C (5 muCi, 0.51 mCi/mmol) intravenously. Raphé lesioning and 60HDA treatment caused significant decrements in brain 5-hydroxytryptamine (5-HT)-14C and 5-hydroxyindoleacetic acid (5-HIAA)-14C levels and 5-HT concentrations compared to those in normal controls. In normal and 60HDA-treated rats there were decreased brain dopamine levels, possibly a consequence of non-specific metabolism of 5-HTP in brain. Blood 5-HIAA-14C levels were significantly decreased in 60HDA-treated but not raphé-lesioned rats. As increased brain 5-HT turnover was observed in raphé-lesioned rats, this may have prevented a decrease in blood 5-HIAA-14C levels. The results suggest that changes in blood 5-HIAA-14C following MK-486 and 5-HTP-14C may be related to changes in brain 5-HT-14C metabolism.

5-Hydroxytryptophan↗
PubMedDate not supplied

CNS 3-methoxy-4-hydroxyphenylglycol: its peripheral assessment by isotopic dilution and theoretical significance.

An isotope dilution model for the peripheral measurement of CNS catecholamine metabolism was examined in rabbits. 3H-norepinephrine (3H-norepinephrine (3H-NE) infusions were performed on rabbits before and after central sympathectomy via intraventricular 6-hydroxydopamine (6-OHDA) treatment. Urine samples were obtained 72 hr after 3H-NE infusion and analysed for specific activities (SAs) of 3-methoxy-4-hydroxyphenylglycol (MHPG) and 3-methoxy-4-hydroxymandelic acid (VMA). The SA of MHPG was lower than that of VMA in all animals suggesting a source of unlabelled MHPG. The difference between the SAs of VMA and MHPG was abolished when the brain MHPG was markedly lowered by 6-OHDA injections. In animals which received 6-OHDA but retained moderate levels of brain MHPG, the difference between SAs of VMA and MHPG was maintained. The proposed model is able to predict and differentiate between rabbits that have severe depletion of CNS catecholamines and normal controls. The results suggest important relationships between CNS and peripheral NE metabolism and the compensatory capacity of the CNS to insult.

Animals↗
PubMedDate not supplied

Determination of picogram levels of brain serotonin by a simplified liquid chromatographic electrochemical detection assay.

A simplified assay is described for measurement of picogram amounts of serotonin (5-HT) by high pressure liquid chromatography with electrochemical detection (LCEC). The procedure involves pre-purification of brain 5-HT by adsorption on Amberlite CG-50. Serotonin is subsequently resolved and detected by LCEC on Zipax SCX resin. The present method gives working sensitivities of at least 100 pg, tissue recoveries of 95% and very low interassay variability (coefficient of variation = 3%). Determination of rat brain area 5-HT by this LCEC method is described and compared to other high sensitivity methods.

Animals↗
PubMedDate not supplied

Unchanged regional norepinephrine glycol metabolite levels in rat brain two months after amygdala kindling.

Concentrations of the norepinephrine (NE) glycol metabolites MHPG (3-methoxy-4-hydroxyphenylethyleneglycol) and DHPG (3,4-dihydroxyphenylethyleneglycol) were examined in 13 brain regions of amygdala-kindled and yoked control rats. The subjects were killed 2 months after the kindled rats had exhibited their sixth 'stage 4-5' generalized seizure. In experiment 1, small but statistically significant decreases in total MHPG levels were found in the right hippocampus (91.6% of control) and hypothalamus (90.7% of control). When the study was repeated with 2 additional control groups, non-kindled, electrically stimulated controls and maximal electroshock convulsion controls, however, these small changes were not seen. The data suggest that since amygdala kindling does not produce any consistent, long-lasting alterations in brain regional NE glycol metabolite levels, there are no consistent, long-term changes in central NE neuronal activity.

Amygdala↗