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Biomedical subjects

W H Wu

Publications and source records attributed to W H Wu.

At least 37 records · Page 2Linked to original sources
PubMed1998

The effects of serotonin biosynthesis inhibition on nicotine and nifedipine-induced analgesia in rats.

UNLABELLED: The calcium channel blocker nifedipine has analgesic properties that are enhanced by nicotine. Although it is not known how this analgesic state might affect the awareness of anginal pain and impending myocardial infraction, recent studies have shown an increased mortality associated with the use of large doses of nifedipine. Because both nifedipine- and nicotine-induced analgesia involve serotonergic mechanisms, we studied the effects of the serotonin biosynthesis inhibitor parachlorophenylalanine (pCPA) on nifedipine- and nicotine-induced analgesia. Nociception was assessed by tail-flick method. Rats pretreated with pCPA (300 mg/kg intraperitoneally [IP]) followed by either nifedipine (15 mg/kg IP) or nicotine (1 mg/kg subcutaneously) had a increase in tail-flick latency of 41% (P = 0.09) and 50% (P = 0.05), respectively, compared with animals that did not receive pCPA. Additionally, rats pretreated with pCPA followed by a combination of nicotine and nifedipine doubled their tail-flick latency (P = 0.0001) compared with animals that were not treated with pCPA. These data further support the involvement of the serotonergic system in both nifedipine- and nicotine-induced analgesia and suggest that drugs that affect serotonin levels, including tricyclic antidepressants and serotonin-specific reuptake inhibitors, may also affect the analgesia induced by nifedipine and nicotine. IMPLICATIONS: This study examines the effect of serotonin depletion on nicotine- and nifedipine-induced analgesia. Nifidipine is a calcium channel blocker used to treat high blood pressure. It also has pain-relieving properties that are enhanced by nicotine. Because both nifedipine- and nicotine-induced analgesia involve the neurotransmitter serotonin, it is important to know how changes in serotonin concentration might affect both nicotine- and nifedipine-induced analgesia. This study not only supports the involvement of the serotonergic system in both nifidipine- and nicotine-induced analgesia, but also suggests that drugs that affect serotonin levels may also affect analgesia induced by nifidipine and nicotine.

Analgesics, Non-Narcotic↗
PubMed1997

Ondansetron modulates GABA(A) current of rat central nervous system neurons.

We examined the effect of ondansetron, a 5-HT3 receptor antagonist, on the whole cell current response of freshly isolated hypothalamic and hippocampal neurons of rats to gamma-aminobutyric acid (GABA). The nystatin perforated patch technique was used to minimize run-down of the GABA current. While 1-150 microM ondansetron had no effect on membrane conductance, co-application with agonist reversibly depressed the maximal end GABA current. The concentration-response relation of GABA reveals a non-competitive mechanism. However, the inhibitory effect was more potent when ondansetron was co-applied with lower concentrations of GABA: i.e., the ondansetron concentration needed to depress the current induced by 5 microM GABA to half amplitude was 7 microM compared to 28 microM for the current induced by 10 microM GABA. Analysis of the current-voltage relationship with and without ondansetron indicated that the effect of ondansetron is not voltage dependent. Current-voltage relations also showed that the effect of ondansetron was not due to activation of a GABA-independent current because the reversal potentials were the same with and without ondansetron. The present data suggest that ondansetron's suppression of GABA-activated current may be the molecular basis of ondansetron-induced seizures observed in vivo.

Animals↗
PubMed1997

Cocaine depresses GABAA current of hippocampal neurons.

Although blockade of dopamine re-uptake and the resulting elevation of excitatory agonists is commonly thought the primary mechanism of cocaine-induced seizures, it is possible that other neurotransmitters such as gamma-aminobutyric acid (GABA) are involved. To examine this possibility, the effects of cocaine on the whole cell GABA current (IGABA) of freshly isolated rat hippocampal neurons were investigated with the patch-clamp technique. Preincubation or acute application of cocaine reversibly suppressed IGABA. The IC50 was 127 microM when cocaine was applied before the application of GABA. The concentration-response relations of cocaine in various GABA concentrations revealed that cocaine inhibited IGABA non-competitively. This effect of cocaine appeared to be independent of voltage. The present study suggests that the GABA receptor/channel complex is also a target for cocaine's action. The suppression of IGABA may contribute to cocaine-induced seizures.

Animals↗
PubMed1997

GABA(A) antagonist and nicotine-induced antinociception.

Rats, pretreated with saline or GABA(A) antagonist bicuculline (BIC) at the doses of 2, 4, 6, 10 and 20 mg/kg, were injected with nicotine (NIC, 1 mg/kg) 30 min later. Tail-flick (TF) latencies were measured before (baseline) and three times at 10 min interval after pretreated compounds, continued every 10 min up to 1 hr after NIC injection. In all groups, median TF latencies did not change from the baseline for the first 30 min after the pretreatment. Following NIC alone (control) and in the group pretreated with 2 mg/kg BIC, 60% rats reached ceiling TF latencies (20 sec) lasting for 10 min. In groups with higher BIC doses (4 to 10 mg/kg), median TF latencies were in the range of 5-7 sec with 30% rats reaching the ceiling TF latencies. Following 20 mg/kg BIC, one out of five rats reached 20 sec; the median was in the range of 4-5 sec. Significantly lower responses were observed following 4 mg BIC and higher doses with no difference among the groups. In conclusion, our novel data show that BIC alone, injected systemically, does not possess any effect on the thermal nociceptive transmission as measured by the tail flick test. However, pretreatment with BIC partially prevents NIC-induced antinociception, in a non dose related manner. This suggests that GABA(A) receptors may, at least in part, contribute to the complex mechanisms involved in NIC-induced antinociception.

Animals↗
PubMed1997

Ondansetron exhibits the properties of a local anesthetic.

UNLABELLED: The purpose of this study was to determine whether ondansetron (OND) has local anesthetic effects. Using a patch-clamp technique, we showed that OND concentration dependently blocked Na channel currents in freshly isolated neurons of rat brains with a 50% inhibition concentration of 12 microM. The blockade started immediately when OND was applied to the cell body using a fast perfusion system, reached a plateau within 15 s, and recovered to the control level within 30 s after washout of the OND-containing solution. Because this is a known property of local anesthetics, we used the tail-flick technique to verify this effect in vivo in Sprague-Dawley rats (n = 46). OND was injected subcutaneously into the tail at the doses of 0.08, 0.16, and 0.2 mg. The tail-flick latency increased 2 min after OND injection, reaching the plateau within 5 min. This effect was dose-related, lasting from 10 to 25 min. These preliminary data indicate that OND, a selective 5-HT3 receptor antagonist, might serve as a prototype molecule for development of a novel series of local anesthetics. IMPLICATIONS: Ondansetron is a drug used to prevent vomiting, especially in cancer patients after chemotherapy. We found that it also causes numbness when injected under the skin. This new action may contribute to its role in "calming the stomach." We studied the effect of ondansetron on the isolated brain cells of live rats.

Anesthetics, Local↗
PubMed1997

The effect of chronic nicotine and its withdrawal on ED50 inspired halothane requirement in rats.

BACKGROUND: Based on previously observed antinociceptive effect of chronic nicotine treatment in rats, the authors measured the ED50 inspired halothane, concentrations in rats having withdrawn from chronically infused nicotine, and in control rats. METHODS: Rats in nicotine group (n = 19) were chronically exposed to nicotine (6 mg/kg/day for 28 days) infusion via Alzet osmotic pumps. Those in the control group (n = 16) were subjected to a sham operation. In each group, half of the rats was used one month later to explore the effect of nicotine withdrawal. Halothane in oxygen was delivered at a rate of 2 L/min to a box measured 2,912 cm3. The ED50 halothane concentration, measured by mass spectrophotometry, was a midway gas tension at which 50% of rats responded to the tail pinching applied to the distal third of the tail for 30 s. RESULTS: In nicotine group, the results showed a lower concentration of ED50 inspired halothane on days 1 and 3 in the first week (p < 0.05). In the control group, repeated exposures to halothane gradually decreased the ED50, reaching lowest value on day 7 (p < 0.05 compared to day 1). Nicotine withdrawal did not alter the ED50 concentration of halothane in test rats compared with control rats. CONCLUSIONS: We conclude that chronic nicotine infusion could temporarily decrease the ED50 concentration of inspired halothane, and withdrawal of nicotine did not modify the ED50 concentration of halothane. In addition, the ED50 halothane concentration might be influenced by stress.

Anesthetics, Inhalation↗
PubMed1996

Tolerance-like phenomenon of nifedipine-induced antinociception.

We confirmed that repeated injection of nifedipine evokes an acute tolerance in rats. Nociceptive response was assessed by the tail-flick test. Rats, randomly divided into 3 groups, were injected once a week for 1 month with nifedipine intraperitoneally at the doses of: (A) 2 mg/kg; (B) 10 mg/kg; and (C) 10 mg/kg at the first injection and followed by dimethyl sulfoxide in the subsequent injections. After one month, group A and C were injected with 10 mg/kg and group B with 30 mg/kg nifedipine. In group A, 2 mg/kg of nifedipine did not change the TF latency but its repeated injections prevented the antinociceptive effect of 10 mg/kg nifedipine. In group B, only the first dose of 10 mg/kg and the last dose of 30 mg/kg produced a significant antinociception. In group C, the first but not the last dose of 10 mg/kg nifedipine, produced a significant antinociception. Our data suggest that a single dose of 10 mg/kg nifedipine or repeated doses of 2 mg/kg produced a tolerance-like phenomenon in nifedipine-induced antinociception.

Analgesics↗
PubMed1996

Multiple symmetrical lipomatosis (Madelung's disease): a case report.

Multiple symmetrical lipomatosis (Madelung's disease) is a rare disease of undetermined cause characterized by symmetrical deposits of non-encapsulated fat on the suboccipital area, cervical area, shoulders and trunk. The patients are usually middle-aged male alcoholics. The treatment is palliative surgical removal of excess fat from the neck and paracervical regions or any other lesion sites. Oriental report about multiple symmetrical lipomatosis (MSL) is very rare. Here a case of multiple symmetrical lipomatosis in a 43 year-old man is described. We describe his clinical course and review the literature.

Adult↗
PubMed1995

2,3-Butanedione monoxime protects mice against the convulsant effect of picrotoxin by facilitating GABA-activated currents.

While adult mice receiving picrotoxin (PTX) alone responded with clonic and tonic-clonic seizures, this response was greatly suppressed for mice simultaneously injected with 2,3-butanedione monoxime (BDM). For example, 60% and 10% of the mice convulsed when injected (i.p.) with 3.0 mg/kg PTX alone or PTX plus 205 mg/kg of BDM, respectively. In contrast, a non-oxime analogue of BDM, 2,3-butanedione (BTD), did not have this anticonvulsant effect. In order to explore the basis for the anticonvulsant effect of BDM, we recorded GABA-activated currents (IGABA) of frontal cortical as well as ventromedial hypothalamic neurons before, during and after exposure to this oxime. BDM had a biphasic effect on IGABA. That is, high concentrations (100 microM-40 mM) decreased and lower concentrations (0.01 microM-0.001 microM) potentiated IGABA; these effects of BDM reversed upon washout of the oxime. In contrast, BTD had no effect on IGABA. Finally, when 0.001 microM BDM, 10-30 microM PTX and GABA were co-applied the inhibitory effect of the toxin on IGABA was markedly suppressed. These data suggest that the anticonvulsant effect of oximes involves facilitation of the inhibitory action of GABA.

Animals↗
PubMed1994

Characterization of sua7 mutations defines a domain of TFIIB involved in transcription start site selection in yeast.

The SUA7 gene of Saccharomyces cerevisiae encodes the general transcription factor TFIIB. SUA7 was identified based on the ability of mutations at this locus to shift transcription start site selection at the cyc1 gene downstream of normal. Here, we report the nature of these mutations; the sua7-1 and sua7-2 alleles encode identical E62K replacements, and sua7-3 encodes an R78C replacement. Both Glu-62 and Arg-78 are phylogenetically invariant and occur within the most highly conserved region of TFIIB, immediately distal to a zinc finger motif. A double E62K,R78C mutant was constructed and exhibited the same phenotypes associated with the single mutants, including cold sensitivity and altered start site selection, suggesting that Glu-62 and Arg-78 are functionally related. This observation, and the opposite charge of the 2 residues, suggested that Glu-62 and Arg-78 might interact to form a salt bridge. This was tested by constructing reciprocal E62R and R78E replacements. The E62R mutant is phenotypically identical to the E62K mutant, whereas the R78E mutant is inviable. However, an E62R,R78E double mutant was not only viable but is phenotypically similar to the single mutants. These results define the highly conserved sequence adjacent to the zinc finger of TFIIB as a critical determinant of start site selection and suggest that an Glu-62-Arg-78 salt bridge is an important structural element of that domain.

Alleles↗
PubMed1994

A membrane-delimited pathway of G-protein regulation of the guard-cell inward K+ channel.

GTP-binding protein (G-protein) regulation of inward rectifying K+ channels in the plasma membrane of Vicia (Vicia faba L.) guard cells has previously been demonstrated at the whole-cell level. However, whether a cytosolic signal transduction chain is required for G-protein regulation of K+ channels in Vicia guard cells, or in any plant cell type, remains unknown. In the present study, we assayed effects of several G-protein regulators on inward K+ channels in isolated inside-out membrane patches from Vicia guard cell protoplasts. Guanosine 5'-[gamma-thio]triphosphate, a nonhydrolyzable GTP analog that locks G proteins into their activated state, decreased the open state probability (Po) of single inward K+ channels. This decrease in Po was accompanied by an increase in one of the closed time constants of the K+ channel. Guanosine 5'-[beta-thio]diphosphate, a GDP analog that locks G proteins into their inactivated state, slightly increased the Po of the inward K+ channel and shortened the closed time constants. Pertussis toxin and cholera toxin, which ADP-ribosylate G proteins at different sites, decreased the Po of the inward K+ channel. Our data indicate that G proteins can act via a membrane-delimited pathway to regulate inward K+ channels in the guard-cell plasma membrane.

Adenosine Triphosphate↗
PubMed1994

Inhibition of inward K+ channels and stomatal response by abscisic acid: an intracellular locus of phytohormone action.

Abscisic acid (ABA), a plant hormone whose production is stimulated by water stress, reduces the apertures of stomatal pores in the leaf surface, thereby lessening transpirational water loss. It has been thought that inhibition of stomatal opening and promotion of stomatal closure by ABA are initiated by the binding of extracellular ABA to a receptor located in the guard-cell plasma membrane. However, in the present research, we employ three distinct experimental approaches to demonstrate that ABA can act from within guard cells to regulate stomatal apertures. (i) The extent to which ABA inhibits stomatal opening and promotes stomatal closure in Commelina communis L. is proportional to the extent of ABA uptake, as assayed with [3H]ABA. (ii) Direct microinjection of ABA into the cytoplasm of Commelina guard cells precipitates stomatal closure. (iii) Application of ABA to the cytosol of Vicia faba L. guard-cell protoplasts via patch-clamp techniques inhibits inward K+ currents, an effect sufficient to inhibit stomatal opening. These results demonstrate an intracellular locus of phytohormone action and imply that the search for hormone receptor proteins should be extended to include intracellular compartments.

Abscisic Acid↗
PubMed1994

Effects of amperozide on schedule-induced polydipsia in rats.

Schedule-induced polydipsia occurs when food-deprived rats are exposed to a fixed-interval feeding schedule (FI = 60 s) for 1 h every day. Amperozide, a novel antipsychotic drug with a strong affinity for the 5-HT2 receptor, was injected i.p. after completion of the requisite training sessions. The experimental rationale is that although the intensity of licking behavior in schedule-induced polydipsia can be taken as an index for anxiety, the drug-induced motor dysfunction should be assessed. In experiment 1, we tested the effect of amperozide on schedule-induced polydipsia at doses of 2, 4, and 8 mg/kg. The data showed that each dose significantly diminished the amount of licking and water intake. The number of presses decreased only at the dose of 8 mg/kg. During five post-treatment daily sessions for 5 days, these three measures returned to normal levels except that the number of pellets earned during the sessions did not significantly change. In addition, the number of presses showed a rebound after the termination of amperozide administration. In experiment 2, in addition to the total water intake, number of licks, pellets earned and presses, we also analyzed the postpellet temporal variation in the number of licks and presses in each schedule-induced polydipsia session. The drug was stopped for one day after each dose of 0.2, 0.4, 0.8 and 1.6 mg/kg of amperozide. The data showed that doses from 0.2 to 0.8 mg/kg did not alter any measure in drug-treated sessions and that the dose of 1.6 mg/kg decreased the number of licks and water intake.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

A placebo-controlled evaluation of single, escalating doses of CL 284,846, a non-benzodiazepine hypnotic.

This report describes the first evaluation in humans of CL 284,846, a non-benzodiazepine compound with a preclinical profile indicative of sedative/hypnotic properties. Healthy, normal male volunteers were assigned randomly to receive single oral doses of 1, 5, 15, 30, or 60 mg of CL 284,846 or placebo on a double-blind basis. Observations were made over the subsequent 25 hours to determine the safety, pharmacokinetic profile, and psychometric effects of the test compound. CL 284,846 was well tolerated in the normal volunteers, causing no significant changes in vital signs, EEG, ECG, hematologic, or clinical chemistry laboratory parameters. Although few adverse events were noted at doses less than 60 mg, at the highest dose (60 mg), all volunteers reported transient neurologically related adverse events (e.g., impaired concentration, difficulty focusing, and impaired coordination), reflecting the central nervous system action of the compound. Although determination of hypnotic efficacy was not an objective in this Phase I study, daytime treatment with 60 mg of CL 284,846 was associated with greater reports of drowsiness and impaired performance on psychomotor tests. However, memory, as assessed by a word recall test, was not affected at any dose of the compound. Pharmacokinetic analyses revealed CL 284,846 to be absorbed and eliminated rapidly (Tmax = 0.9-1.5 hr, T 1/2 = 0.9-1.1 hr), with a dose-proportional AUC (area under cure). Plasma levels of CL 284,859, the primary desethylated metabolite of CL 284,846, were much lower in humans than in other species, indicating that the metabolism of CL 284,846 in humans may differ from that of rodents and dogs. Overall, CL 284,846 was well tolerated, and the authors recommend repeating dose safety and pharmacokinetic studies in healthy volunteers.

Acetamides↗