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Biomedical subjects

J Z Fields

Publications and source records attributed to J Z Fields.

At least 55 records · Page 3Linked to original sources
PubMed1995

Modulation of neutrophil function by novel colonic factors: possible role in the pathophysiology of ulcerative colitis.

Tissue damage in acute ulcerative colitis (UC) may be triggered by neutrophils (PMNs) and their inflammatory mediators such as reactive oxygen species (ROS). Because circulating PMNs appeared normal in subjects with UC, we hypothesized that the critical abnormality that attracts and activates PMNs in UC is a local colonic factor. Accordingly, the colonic milieu was sampled by using in vivo rectal dialysis (mol wt < or = 12 kd). Normal PMNs were exposed in vitro to rectal dialysates (RD) from control subjects (cRD) or subjects with active UC (aRD) or inactive UC (IRD). PMN-derived ROS were measured by chemiluminescence. cRD did not increase ROS production by unstimulated PMNs; aRD significantly and concentration-dependently increased ROS; IRD gave intermediate results. cRD inhibited the PMN-stimulating effects of both the bacterial peptide formyl-methionyl-leucyl-phenylalanine (fMLP) and phorbol myristate acetate (PMA). aRD and IRD blunted the effect of fMLP and PMA significantly less than did cRD. Rectal dialysates from 44% of subjects with active UC exaggerated the fMLP effect, whereas potentiation occurred for only 13% of cRDs and 18% of iRDs. cRD preconditioned with either activated or nonactivated PMNs was not significantly different than unconditioned cRD. We thus infer the existence of colonic factors in UC that (1) can trigger PMNs to produce ROS and (2) have a proinflammatory modulatory effect on bacterial peptide-induced, PMN-mediated ROS production, thereby initiating or perpetuating inflammation and eventually causing tissue damage.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Prevention and reversal of dopamine receptor supersensitivity by cyclo(leucyl-glycyl) (CLG): biphasic dose-response curves.

Chronic administration (21 days) of haloperidol (HAL) (IP, 1.0 mg/kg/day) induced a behavioral supersensitivity (stereotypic sniffing) to dopamine (DA) agonists (apomorphine) and upregulation (increased Bmax for sulpiride-inhibitable [3H]spiroperidol binding) of striatal and limbic D2 DA receptors (DAr). Coadministration of cyclo(leucyl-glycyl) (CLG; 8mg/kg, SC; every third day, every other day, but not every day) with HAL attenuated the behavioral supersensitivity. D2-DAr binding assays showed 1) that CLG-induced changes in Bmax parallel these behavioral changes and 2) that the biphasic CLG dose-response curve may involve CLG failure at high cumulative doses to lower Bmax. CLG also reversed an already established D2 DAr supersensitivity/upregulation (i.e., when CLG was injected daily for four days after the withdrawal of HAL). CLG alone did not alter behavior or binding. CLG's ability to both prevent and reverse D2 DAr upregulation/supersensitivity in animal models suggests that CLG may be useful, within a therapeutic window, in clinical disorders that are thought to involve upregulated DAr (e.g., tardive dyskinesia, L-DOPA-induced dyskinesias, and schizophrenia).

Amino Acid Sequence↗
PubMed1994

The differing effects of acute and chronic alcohol on gastric and intestinal permeability.

OBJECTIVE: Acute and chronic alcohol intake cause GI symptoms because of either alcohol-induced structural or functional abnormalities. In theory, the disruption of the integrity of the gut mucosa should be reflected by changes in the absorption of molecular probes, such as lactulose, mannitol, and sucrose. Accordingly, we investigated the effects of acute and chronic ethanol on the permeability of the gastric and small intestinal mucosa. METHODS: We measured the absorption of sucrose, mannitol, and lactulose in 20 controls and 18 alcoholics within 3 days after their last drink. We evaluated the reversibility of the abnormalities in alcoholics by repeat testing after 7 to 14 days of sobriety. The acute effects of ethanol in normal controls and abstinent alcoholics were also studied after the administration of ethanol by both the oral and IV routes. RESULTS: The absorptions of lactulose and sucrose in chronic alcoholics were normal. However, the alcoholics demonstrated a significant decrease in mannitol absorption and a corresponding increase in the lactulose/mannitol ratio. Both parameters returned to normal after a period of sobriety. Acute ethanol did not significantly affect mannitol or lactulose absorption, whereas oral ethanol significantly increased sucrose absorption. CONCLUSIONS: Chronic ethanol reversibly affects the integrity of small intestinal villi without significantly affecting gastrointestinal permeability. In contrast, a single oral dose of ethanol increases gastroduodenal permeability but has no effect on the lactulose or mannitol permeability of the small intestine. These regional changes in gut permeabilities may contribute to alcohol-induced GI symptoms.

Adolescent↗
PubMed1994

Increased gastrointestinal symptoms in chronic alcoholics.

Although chronic alcoholics frequently present with gastrointestinal (GI) symptoms, the precise prevalence of GI symptoms in this group is unknown. Accordingly, we compared the frequency and severity of GI symptoms in 48 male alcoholics with those of 48 nonalcoholic controls. A standardized questionnaire was administered on two separate occasions to all subjects, and 14 GI symptoms were evaluated for three periods (during active drinking, early withdrawal, and sobriety). Symptom severity was assessed with a visual analog scale (1-10). Both actively drinking and withdrawing alcoholics had more frequent heartburn, nausea, vomiting, diarrhea, and flatulence, and more severe chest pain, milk intolerance, and postprandial fullness. These symptoms were transient and did not correlate with the quantity of alcohol consumed. Thus, alcoholics have more frequent and more severe GI symptoms which resolve quickly during abstinence and which predominantly occur while actively drinking rather than during withdrawal.

Adult↗
PubMed1993

Alterations in striatal neurotrophic activity induced by dopaminergic drugs.

The administration of dopaminergic drugs induces a variety of compensatory responses ostensibly designed to reinstate normal dopamine (DA) tone. We have hypothesized that drug-induced alterations in striatal-derived neurotrophic activity contributes to these compensatory processes. This phenomenon has been studied by examining the growth of mesencephalic cultures incubated with cell-free extracts of striatal tissue taken from patients or rats treated with various drugs. Our results reveal that reducing striatal DA tone by administering the DA antagonist haloperidol, the DA neurotoxin 6-hydroxydopamine, or as occurs naturally in Parkinson's disease, increases striatal trophic activity. Conversely, increasing striatal DA tone by administering the indirect DA agonists amphetamine or levodopa reduces trophic activity in the striatum. Kainic acid lesions of the striatum similarly reduce this trophic activity. The implications of these drug-induced alterations in trophic activity are discussed and reviewed.

Animals↗
PubMed1993

Increased production of luminol enhanced chemiluminescence by the inflamed colonic mucosa in patients with ulcerative colitis.

Reactive oxygen species have been implicated as mediators of inflammation in ulcerative colitis. Chemiluminescence is a reliable means of estimating reactive oxygen species in biological media. Increased reactive oxygen species values in the inflamed colonic mucosa in rats were seen by chemiluminescence. The aims of the study were to find out if chemiluminescence is raised in the colonic mucosa of patients with ulcerative colitis and correlates with disease activity, and to elucidate the sources of the chemiluminescence. It was found that reactive oxygen species, as measured by the chemiluminescence technique, are raised in inflamed colonic mucosa and correlates with symptom score, sigmoidoscopic score, disease activity, and activity of the neutrophil enzyme myeloperoxidase. Chemiluminescence was inhibited by a myeloperoxidase inhibitor (azide) and an H2O2 scavenger (catalase) but not by allopurinol, an inhibitor of the enzyme xanthine oxidase. Chemiluminescence was also inhibited by indomethacin, but this did not seem to be related to inhibition of cyclo-oxygenase. These findings suggest that a likely cellular source of reactive oxygen species in the inflamed colon of patients with ulcerative colitis is the neutrophil and that myeloperoxidase conversion of H2O2 to hypochlorous acid, contributes to the chemiluminescence signal and possibly, to the tissue injury. Neither cyclo-oxygenase nor lipoxygenase seem to play a part as sources for the chemiluminescence.

Adult↗
PubMed1992

Inhibition of mitochondrial succinate oxidation--similarities and differences between N-methylated beta-carbolines and MPP+.

N-Methylated beta-carbolinium compounds (N-Me-BCs), including 2-N-methyl and 2,9-N,N-dimethyl analogs, structural analogs of 1-methyl-4-phenylpyridinium (MPP+), may be endogenously bioactivated, MPP(+)-like toxins, capable of inducing parkinsonism. Both MPP+ and selected N-Me-BCs inhibit NADH-linked mitochondrial respiration (Complex I). We now show that both also inhibit succinate-supported (Complex II) respiration, the greatest inhibition (80%) being seen for 2,9-dimethylharmanium. Complex I inhibition occurs at MPP+ concentrations (IC50 = 0.17 mM) about one order of magnitude lower than Complex II inhibition (greater than 1.2 mM). In contrast, Complex I and Complex II inhibition by the N-Me-BCs tested occurred at similar concentrations (I, 0.1 mM; II, 0.25 mM) and concentrations similar to Complex I inhibition by MPP+. 2,9-N,N-Dimethyl-BCs, which are the permanently charged BC analogs of MPP+, show inhibitory characteristics similar to MPP+: slow onset of inhibition, potentiation by TPB, and reversal by DNP. The fact that succinate oxidation cannot bypass the Complex II inhibition by N-Me-BCs could enhance any chronic neurotoxicity of N-Me-BCs.

1-Methyl-4-phenylpyridinium↗
PubMed1992

Lack of [3H]quinuclidinyl benzylate binding to biologically relevant binding sites on mononuclear cells.

We analyzed the binding characteristics of [3H]quinuclidinyl benzylate ([3H]QNB), a muscarinic cholinergic ligand, to rat and human mononuclear cells (MNC). Under various assay conditions, atropine-sensitive, saturable binding occurred with an apparent Kd of 10 nM. Conditions which disrupted the MNC membrane reduced total binding and eliminated specific binding. Muscarinic agonists were unable to inhibit [3H]QNB binding to MNC at concentrations up to 10(-2) M. Stereoisomers dexetimide and levetimide were equipotent inhibitors of binding (IC50 2 x 10(-5) M). We conclude that, although atropine-sensitive binding of [3H]QNB to MNC occurs, the binding is not consistent with the presence of a biologically relevant muscarinic cholinergic receptor.

Adult↗
PubMed1992

Chronic ethanol feeding produces a muscarinic receptor upregulation, but not a muscarinic supersensitivity in lower esophageal sphincter muscle.

Muscarinic acetylcholine receptors (mAChR) are important in esophageal physiology, and mAChR alterations may be involved in ethanol-induced esophageal dysfunction. We previously demonstrated that acute ethanol decreases lower esophageal sphincter pressure (LESP), whereas withdrawal from chronic ethanol results in pressure increases which are reversible by acute ethanol. To see if this increase in LESP is due to upregulation of mAChR, we evaluated both mAChR binding and dose-response curves for bethanechol and atropine-induced changes in LESP before and after acute and chronic ethanol exposure. The number of mAChR sites (Bmax) in LES (3.4 fmol/mg tissue) was lowered by acute ethanol (1.72, -50%); withdrawal from chronic ethanol raised Bmax (5.2, +54%). Acute injection of ethanol into cats in withdrawal reversed this increase in mAChR density (3.1, -10%). These changes correlated with our earlier data on ethanol-induced changes in LESP. However, the dose-response curve for bethanechol-induced pressure increases shifted to the right [ED25 (micrograms/kg); control, 8.6; withdrawal, 21.3], paralleled by an increase in the number of low-affinity agonist binding sites. Thus, 1) the withdrawal-associated increase in Bmax (up-regulation) is more likely to be a compensatory response to deficits (functional subsensitivity) distal to the receptor recognition site than to proximal deficits; 2) the increase in Bmax does not cause LESP hyperactivity; and 3) receptor binding changes do not necessarily translate into physiological changes.

Animals↗
PubMed1991

Long-lasting dopamine receptor up-regulation in amphetamine-treated rats following amphetamine neurotoxicity.

Amphetamine (A) (9.2 mg/kg, IP), in combination with iprindole (I) (10.0 mg/kg, IP), caused long-lasting dopamine (DA) depletions in striatum (-49%, 4 weeks) but not in nucleus accumbens following one A/I injection. Striatal DA had recovered by 4 months. DA receptors (DAr) were up-regulated: 1) behavioral responses to a DA receptor agonist (apomorphine) were significantly elevated. These included apomorphine-induced locomotor activity (+103% and +160%, on weeks 3 and 10) and apomorphine-induced stereotypy (day 10). 2) Bmax for [3H]spiroperidol binding to striatal D2 DAr (12 weeks) increased (+53%, week 12). Injection of the DAr neuromodulator cyclo(leucyl-glycyl) (8 mg/kg/day x 4 days, SC) reversed the Bmax increase. Thus toxicity (DA depletion) following high-dose amphetamine appears to induce compensatory changes in DAr. This DAr upregulation may explain the lack of abnormal movements despite enduring DA depletion. Additionally, the A/I paradigm as an animal model of long-lasting DAr up-regulation, could be used to screen neuromodulatory agents, like CLG, that might treat disorders (e.g., tardive dyskinesia and schizophrenia) thought to involve up-regulated DAr.

Animals↗
PubMed1991

Permanent haloperidol-induced dopamine receptor up-regulation in the ovariectomized rat.

One of the confounding problems associated with the study of tardive dyskinesia in rodent models has been the inability to produce a permanent supersensitivity to dopamine (DA) following neuroleptic drugs. We recently observed that ovariectomy (OVX) results in a permanent dopamine receptor (DA-R) up-regulation in the striatum of the rat. This permanent up-regulation of striatal D2 DA-R required three months to fully develop and lasted for at least 12 months post-OVX. In the present study we further characterized this model by examining the development of both apomorphine-induced stereotypy and D2 DA-R density in the striatum of OVX and Sham-operated rats following haloperidol (16 days at 1.0 mg/kg/day, IP). Following the chronic haloperidol treatment, both the OVX and the Sham-operated animals increased both their behavioral responses (stereotypic sniffing) to apomorphine, and the density of striatal D2 DA-R. However, by 30 days posthaloperidol, the Sham animals had reverted to normal behavioral responses to apomorphine and normal levels of striatal DA-R, while both the behavioral responses and the density of D2 DA-R in the OVX animals treated with haloperidol remained up-regulated. These data indicate that 1) the time required to develop this unique animal model of a permanent DA-R up-regulation in the ovariectomized (OVX) rat can be considerably shortened; 2) there is probably a unique neurochemical change induced by haloperidol in the OVX but not in Sham rats that leads to the DA-R up-regulation becoming permanent.

Animals↗
PubMed1991

Neurochemical basis for the absence of overt "stereotyped" behaviors in rats with up-regulated striatal D2 dopamine receptors.

Because of substantial evidence for the hyperdopaminergic hypothesis of tardive dyskinesia (TD), animal models, especially rats, treated chronically with neuroleptics continue to be used to study this disorder. The rat model has been criticized because, unlike TD, in rats there is an apparent lack of spontaneous abnormal movements even when striatal D2 dopamine receptor (DAr) density is substantially increased. Our data suggest a mechanism by which rats suppress these abnormal movements normally associated with elevated DAr levels. We correlated neurochemical with behavioral changes using several animal models, including nonneuroleptic ones, which elicit varied levels of DAr upregulation. There was (as expected) a robust, significant, positive correlation between striatal DAr density and apomorphine-induced stereotypic behaviors. In contrast, there was a significant negative correlation between increased DAr density and synthesis capacity for striatal DA (Vmax for tyrosine hydroxylase). We conclude that this decrease in Vmax is a compensatory adjustment of the nigrostriatal DA tract for the increased DAr density induced in our animal models. Our data further suggest the generalization that an observed increase in receptor density doesn't necessarily predict a functional change (spontaneous behavior, neuropathology) because compensatory neural mechanisms exist. In TD these compensatory neural mechanisms may fail, leading to spontaneous behaviors.

Animals↗
PubMed1990

Canine gastric muscarinic receptors up-regulate after vagotomy.

Postvagotomy (PV) gastroparesis is an infrequent but troublesome problem. To test the hypothesis that the rarity of the PV syndrome is due to compensatory up-regulation of muscarinic cholinergic receptors (mAChR), we measured changes in stomach mAChR and gastric acid secretion in dogs before and three weeks after truncal vagotomy. Maximum acid output dropped significantly one week PV and then partially recovered by three weeks PV. mAChR density changed in parallel and was significantly increased in body mucosa, body muscle, and antrum mucosa. In the body, changes in mAChR in mucosa correlated positively with changes in muscle, suggesting that mAChR binding in pinch biopsies of gastric mucosa might become useful in evaluating patients for postvagotomy syndrome. PV up-regulation of mAChR in the mucosa of the canine gastric body might explain PV recovery of gastric acid secretion.

Animals↗
PubMed1990

The effects of cyclo(leucyl-glycyl) on nigrostriatal dopaminergic supersensitivity--inhibition of apomorphine-induced climbing.

In a previous study we showed that cyclo(leu-gly) (CLG) prevents the behavioural supersensitivity induced in the mesolimbic dopamine (DA) tract (in mice) by chronic haloperidol (HAL). In the current study, we evaluated the effects of CLG on supersensitivity to DA agonists in the nigrostriatal DA tract induced by chronic HAL (1.0 mg/kg, i.p. x 21 days--Experiment 1) or by acute injection of a high dose of apomorphine (APO) (Experiment 2). In Experiment 1 CLG was given at doses of either (a) 0 mg/kg/day (b) 1 mg/kg every third day (30 minutes prior to HAL), (c) 1 mg/kg every day, or (d) 8 mg/kg every third day. In Experiment 2 the dose of CLG was 8 mg/kg, s.c., given 24h after APO. Co-administration of CLG with HAL attenuated the development of HAL-induced supersensitivity in both paradigms (b) and (c) above, although the attenuation was significantly greater in (c) compared to (b). This biphasic dose response (D-R) curve for CLG in Experiment 1 indicates that a therapeutic window exists for CLG (bell-shaped D-R curve) and is similar to previous curves for CLG effects on the mesolimbic DA tract. In Experiment 2, CLG attenuated the DA receptor supersensitivity caused by acute high dose APO. The capacity of CLG to down-regulate DA receptors and attenuate dopaminergic supersensitivity in these experiments suggests a potential therapeutic use in the prevention of tardive and/or L-dopa-induced dyskinesias.

Animals↗
PubMed1990

Mitochondrial respiratory inhibition by N-methylated beta-carboline derivatives structurally resembling N-methyl-4-phenylpyridine.

Mitochondrial accumulation and respiratory inhibition are critical steps in the actions of N-methyl-4-phenylpyridinium ion (MPP+), the toxic metabolite of the parkinsonism-inducing agent, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. We examined the respiratory characteristics of 2-methylated beta-carbolines (2-Me beta Cs) and 2-methylated 3,4-dihydro-beta-carbolines (2-MeDH beta Cs), which encompass the MPP+ structure. As indoleamine derivatives, they could have endogenous roles in idiopathic parkinsonism. With rat liver mitochondria, the order for inhibition of NAD(+)-linked O2 consumption (6-min preincubations) was as follows: MPP+ = 2-methylharmine greater than 2-methylharmol = 2-methylharmaline much greater than 2-methylharmalol greater than 2-methylnorharman greater than 6-OH-2-methylharmalan much greater than 2-methylharman. Similar to MPP+, 2-MeDH beta C/2-Me beta C inhibition was potentiated by tetraphenylboron and reversed by dinitrophenol, consistent with the involvement of cationic forms. However, the participation of neutral forms was indicated by the 2-MeDH beta C/2-Me beta C inhibitory time courses, which were unlike MPP+. The neutral forms probably arise via indolic nitrogen deprotonation because the characteristics of a cationic beta-carboline that cannot N-deprotonate, 2,9-dimethylnorharman, mirrored MPP+ rather than 2-Me beta Cs. Succinate-supported respiration was also significantly blocked by 2-MeDH beta Cs/2-Me beta Cs, but results with tetraphenylboron and 2,9-dimethylnorharman indicated that cationic forms were less important than in the inhibition of NAD(+)-linked respiration. We suggest that the relatively potent inhibition by certain 2-MeDH beta Cs/2-Me beta Cs involves neutral forms for passive mitochondrial entry and cationic as well as neutral forms that act at several respiratory sites. Respiratory inhibition could reasonably underlie the reported neurotoxicity of 2-Me beta Cs.

1-Methyl-4-phenylpyridinium↗
PubMed1990

Gastroduodenal ulcers in rats induced by 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP): requirement for gastric acid secretion and the role of prostaglandins.

To better study the neuropathophysiology of duodenal and gastric ulcers (DU & GU) an appropriate animal model is needed. One such model was recently provided by 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP), a neurotoxin, which reliably induces DU and GU in rats that are macroscopically similar to human ulcers. However, the underlying ulcerogenic mechanism is not known. Accordingly, we investigated the roles of prostaglandins (PG) (cytoprotective factors) and omeprazole and atropine (inhibitors of gastric acid secretion) in DU, with GU as the secondary outcome measure. Compounds known to effectively inhibit gastric acid secretion in rats, omeprazole or atropine, totally prevented DU and GU. Doses of misoprostol, a PGE1 analog, that are known to be cytoprotective but not anti-secretory in rats decreased the frequency of DU but not GU. Meclofenamate or BW755c, compounds known to inhibit both cyclo-oxygenase and lipo-oxygenase and thus eicosanoid formation, worsened DU & GU. In order to further evaluate the role of PGs, levels of PGE2-alpha in gastric and duodenal mucosa were measured using an RIA assay. Following 4 days of MPTP injections, PGE2-alpha levels were significantly lowered in duodenal but not gastric mucosa. Thus, as in human ulcer disease, 1) MPTP-induced ulcers in rats also appears to require at least some gastric acid; 2) prostaglandins have an anti-ulcer effect against MPTP-induced DU but not GU. In addition, the mechanisms of DU and GU appear to be different even though there is a single etiology namely, MPTP.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1990

MPTP-induced duodenal ulcers in rat. Prevention by reuptake blockers for serotonin and norepinephrine, but not dopamine.

Abnormal activity of dopamine, serotonin, and norepinephrine may contribute to the pathophysiology of duodenal ulcers. We therefore studied the effects of neuropharmacological manipulations on 1-methly-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP)-induced duodenal ulcers. Duodenal ulcers were produced in rats by 12 subcutaneous injections of a neurotoxin, MPTP, over 4 days. At an MPTP dose of 20 mg.kg. injection, duodenal ulcers developed in 91% (43 of 47) of animals with low mortality. When neuropharmacological agents were preadministered before MPTP, the following effects on duodenal ulcers incidence were obtained. MAO-B inhibitors (pargyline [55%], deprenyl [43%]) but not MAO-A inhibitors (clorgyline [91%]) significantly decreased the frequency of duodenal ulcers suggesting that, like MPTP-induced parkinsonism, formation of a toxic metabolite, probably 1-methyl-4-phenyl-pyridinium is involved. Reuptake blockers for serotonin (fluoxetine [18%], indalpine [25%]) also decreased the frequency of duodenal ulcers. Reuptake blockers for norepinephrine (desmethylimipramine [17%], tomoxepine [31%], but not amfonelic acid [82%]) decreased the frequency of duodenal ulcers. Reuptake blockers for dopamine (benztropine [73%], amfonelic acid [82%], GBR-12909 [80%]) did not protect against duodenal ulcers. However, GBR-12909 significantly decreased the severity of those duodenal ulcers that were produced. These data suggest that abnormally low levels of synaptic transmission in serotonergic and possibly noradrenergic neurons play an important role in the pathogenesis of duodenal ulcer while the role of dopamine may be limited to modulation of ulcer severity.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗