Search PubMed⌕ Search

Biomedical subjects

K M Johnson

Publications and source records attributed to K M Johnson.

At least 127 records · Page 7Linked to original sources
PubMed1992

Inhibition of the phospholipase C-linked metabotropic glutamate receptor by 2-amino-3-phosphonopropionate is dependent on extracellular calcium.

D,L-2-Amino-3-phosphonopropionate (AP-3), a proposed metabotropic receptor antagonist, produced a concentration-dependent increase in the formation of inositol 1,4,5-trisphosphate in rat hippocampal slices. The response was maximal at 1 mM and completely due to the L-isomer. D,L-AP-3 was half as efficacious as (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD), a selective agonist of this receptor. The response produced by maximally effective concentrations of L-AP-3 and 1S,3R-ACPD together for 5 min was not significantly different from that produced by 1S,3R-ACPD alone. However, pretreatment for 40 min with either 1 mM L-AP-3 or D,L-AP-3 completely inhibited the response to 1S,3R-ACPD. This inhibition was long-lasting (wash-resistant) and was reversed by reduction of the extracellular Ca2+ concentration. Also, pretreatment for 40 min with 1S,3R-ACPD reduced, but did not completely block, the response to readdition of 1S,3R-ACPD. L-AP-3 (1 mM) also produced a stereoselective 2.3-fold increase in the efflux of glutamate from the hippocampal slices. These data suggest that incubation of hippocampal slices with AP-3 induces a time-dependent desensitization of the metabotropic response by a mechanism that is dependent on extracellular Ca2+. The possible roles of receptor occupancy and inhibition of glutamate uptake by AP-3 are also discussed.

Alanine↗
PubMed1992

Arcaine and magnesium inhibition of the NMDA receptor ionophore complex: evidence for distinct voltage-dependent sites.

The inhibitory effects of the polyamine antagonist, arcaine, and magnesium on N-methyl-D-aspartate (NMDA) induced hippocampal [3H]norepinephrine release and [piperidyl-3,4-3H(N)]-[N-1-(2- thienyl)cyclohexyl]-3,4-piperidine (TCP) binding were studied. We report that the inhibitory effect of arcaine and magnesium on NMDA-induced [3H]norepinephrine release is diminished by increasing the extracellular K+ concentration, presumably reflecting a voltage-dependent block for both. However, unlike MK-801, the block by arcaine shows no evidence of use dependence. Further, the IC50 value for magnesium inhibition of [piperidyl-3,4-3H(N)]TCP binding varies with the state of activation of the channel, being the lowest when the channel is maximally activated and the highest when the channel is least activated. On the other hand, the apparent affinity of arcaine is not significantly affected by the activation of the channel by glutamate and glycine, but is decreased by the polyamine agonist, spermidine. These data suggest that the polyamine antagonist binding site is distinct from either the phencyclidine/MK-801 site or the voltage-dependent channel site for magnesium. Nonetheless, these data suggest that the site must be located in a region of the NMDA receptor ionophore complex capable of sensing transmembrane potential.

Animals↗
PubMed1992

Comparison of the role of local anesthetic properties with dopamine uptake blockade in the inhibition of striatal and nucleus accumbens [3H]acetylcholine release by cocaine.

The effects of cocaine on the electrically evoked release of tritium from brain slices previously loaded with [3H]choline were examined and used as an index of acetylcholine (ACh) release. In the striatum, cocaine dose-dependently inhibited ACh release, with an IC50 of 2.9 microM. At 10 microM cocaine, D2 receptor blockade by sulpiride resulted in only about a 45% reversal of the inhibition of ACh release, whereas inhibition due to either nomifensine or quinpirole was reversed by about 80%. 5-Hydroxytryptamine antagonists had no effect on the cocaine-induced inhibition of striatal ACh release, thus suggesting no involvement of this amine in cocaine's action. Antagonists against gamma-aminobutyric acidA, muscarinic, opioid and adenosine receptors were similarly ineffective at reversing cocaine's effect on ACh release. Comparison with the effect of procaine on striatal ACh release suggested that the inhibition of ACh release in the presence of sulpiride was due to the local anesthetic properties of cocaine. In the nucleus accumbens cocaine was about 5-fold less potent at inhibiting ACh release than in the striatum and sulpiride was much less effective at reversing the inhibitory effect of cocaine, suggesting that the local anesthetic effects of cocaine play a greater role in regulating ACh release in this area relative to dopamine uptake blockade. These data suggest that the local anesthetic effect of cocaine is prominent at concentrations found in the central nervous system after pharmacologically relevant systemic doses and depending on the degree of monoaminergic control of a particular brain area, may be even more important than the effects of cocaine arising from inhibition of reuptake.

Acetylcholine↗
PubMed1991

Effect of cocaine and 5-HT3 receptor antagonists on 5-HT-induced [3H]dopamine release from rat striatal synaptosomes.

The effect of serotonin (5-HT) on the release of tritium from striatal synaptosomes previously loaded with [3H]dopamine ([3H]DA) was studied. 5-HT stimulated both the spontaneous and Ca(2+)-evoked efflux of tritium in a concentration-dependent manner. This effect was not mimicked by the non-selective 5-HT agonist, d-lysergic acid diethylamide. Further, the stimulatory effects of 5 muM 5-HT were unaffected by the selective 5-HT3 receptor antagonists, MDL-72222 and GR-38032F. On the other hand, cocaine and the selective DA uptake inhibitor, nomifensine completely antagonized the effect of 5 muM 5-HT on spontaneous tritium efflux with IC50 values of 0.2 and 0.09 muM, respectively. The effect of 5-HT on Ca(2+)-evoked tritium efflux was also blocked by these DA uptake inhibitors, albeit at somewhat higher concentrations. These data support the hypothesis that 5-HT induces the release of DA from striatal nerve terminals via a mechanism involving the transport of 5-HT into the dopaminergic terminal, rather than by activating 5-HT3 receptors as has been proposed to account for the effect of 5-HT observed in striatal slices.

Animals↗
PubMed1991

Regulation of polyamine and magnesium inhibition of the N-methyl-D-aspartate (NMDA) receptor ionophore complex.

The inhibitory effects of spermidine, putrescine and magnesium on [3H]TCP binding in crude synaptosomes and well washed buffy coat membranes were studied. We report that the IC50 values for the drugs tested varied depending on the state of activation of the channel, being lowest when the channel is maximally activated and highest when the channel is least activated in the control buffy coat preparation. Comparison of the inhibitory characteristics of these 3 agents when activated by glutamate, glycine, and low concentrations of spermidine or magnesium strongly suggest that putrescine and magnesium share a common inhibitory mechanism, perhaps mediated by the voltage-dependent channel site for magnesium. Inhibition by spermidine, however, is clearly mediated by a distinct site, non-identical to the phencyclidine receptor. Glutamate appears to uncouple this inhibition in about one-half of the N-methyl-D-aspartate (NMDA) complexes, suggesting the possibility of distinct subpopulations of NMDA-operated ion channels. The potential physiological relevance of these findings is discussed.

Animals↗
PubMed1991

Pharmacological evidence for N-methyl-D-aspartate receptors on nigrostriatal dopaminergic nerve terminals.

The efflux of tritium from rat striatal synaptosomes labelled with [3H]dopamine was utilized as an index of dopamine (DA) release for the purpose of characterizing the receptors underlying the effects of L-glutamate. N-Methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA), and kainate each induced DA release in the absence of Mg2+, through NMDA was much more efficacious and only the NMDA response was inhibited by Mg2+. The response to L-glutamate was potentiated in a concentration-dependent manner by glycine. Further, it was completely inhibited by the competitive NMDA antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid and by the NMDA channel blocker phencyclidine. Finally, the response to L-glutamate was unaffected by either tetrodotoxin or the kainate-AMPA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. These data demonstrate the presence of NMDA receptors on dopaminergic nerve terminals that mediate the ability of L-glutamate to release DA and suggest an additional mechanism by which information from the nigrostriatal and corticostriatal pathways may be integrated.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1991

Growing up with a spinal cord injury.

Much of what we need to know to be independent adults is learned in the first five years of life. In the toddler, instead of reteaching learned skills, as we do with older spinal cord injury persons, we are teaching skills for the first time. It is therefore imperative to have a creative therapeutic team who can teach skills which were never acquired and encourage the child's cognitive growth as well as growth towards independence. This paper will include a case report of a 2 year-old C3-4 quadriplegic child rehabilitated through an interdisciplinary family-centered model of care. We will share some of the issues our team has encountered when "rehabilitating" very young children with spinal cord injuries based on the observations of the team members as well as the scant literature available. This will also include a parent's reflections of modification needed in family structure and roles.

Child Development↗
PubMed1990

Effects of acute and chronic administration of cocaine on striatal uptake, compartmentalization and release of [3H]dopamine.

The effects of acute and repetitive administration of cocaine were studied on several parameters associated with the uptake and release of [3H]dopamine ([3H]DA) in the striatum. It was found that repetitive administration of cocaine followed 7 days later by acute challenge with cocaine, produced an increase in the Vmax with no change in the affinity of the uptake carrier for either dopamine (DA) or cocaine. The intracellular compartmentalization of [3H]DA in synaptosomes was not altered by either acute or repeated treatment with cocaine. However, chronic administration of cocaine abolished the stimulatory effect that 1 microM amphetamine normally has on the efflux of [3H]DA from the fast pool in untreated synaptosomes. The K(+)-stimulated release of [3H]DA from slices of striatum was not affected by acute or chronically administered cocaine; however, chronically administered cocaine, plus acute challenge with cocaine potentiated the effect of amphetamine on the K(+)-induced release of [3H]DA. This was accompanied by a reduction of the effect of amphetamine on the spontaneous release of DA. In addition, chronically administered cocaine plus acute challenge with cocaine increased K(+)-stimulated release of [14C]acetylcholine [( 14C]ACh). These data suggest that repetitive administration of cocaine, in a regimen that elicits behavioral sensitization, alters the substrates through which amphetamine exerts its effects on the subcellular distribution and release of [3H]DA, and further, that challenge with cocaine of sensitized rats produces a compensatory increase in the uptake of [3H]DA that is correlated with increased depolarization-induced release of [14C]ACh.

Acetylcholine↗
PubMed1990

Chronic cocaine treatment impairs the regulation of synaptosomal 3H-DA release by D2 autoreceptors.

The effect of repeated administration of cocaine on presynaptic D2 autoreceptor sensitivity in synaptosomes was studied. In rats treated chronically with saline, the dopamine D2 agonist 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin (N-0437) caused a significant inhibition of the Ca2(+)-evoked 3H-DA release from synaptosomes prepared from the nucleus accumbens and from the striatum; this effect was blocked by the D2 antagonist sulpiride. However, chronic cocaine pretreatment abolished the effect of N-0437 in both areas, suggesting a subsensitivity of release-modulating terminal DA autoreceptors. Subsensitive DA autoreceptors would enhance stimulated DA release from mesolimbic and nigrostriatal terminals and may play a role in the behavioral sensitization observed in this paradigm.

Animals↗
PubMed1990

Noncompetitive excitatory amino acid receptor antagonists.

In the first article in this series, Watkins, Krogsgaard-Larsen and Honoré outlined the structure-activity requirements at the receptor sites for excitatory amino acids in the mammalian CNS. The postsynaptic depolarizing actions of glutamate are thought to be mediated by NMDA, AMPA and kainate receptors. Here David Lodge and Kenneth M. Johnson review some of the recent developments in the pharmacology of other means by which the function of these receptors may be modulated. Divalent cations, phencyclidine-like drugs, glycine analogues and polyamines all modulate NMDA receptors whereas barbiturates and some arthropod toxins reduce channel responses to non-NMDA receptor agonists. Modes of action and implications for physiology and pathophysiology are discussed.

Animals↗
PubMed1990

A multicenter clinical trial of oral ribavirin in HIV-infected people with lymphadenopathy: virologic observations. Ribavirin-LAS Collaborative Group.

A double-blind, randomized, placebo-controlled trial comparing two daily doses of oral ribavirin (600 and 800 mg) and a placebo was performed at four medical centers geographically distributed throughout the USA. One hundred and sixty-four HIV-infected adult men with lymphadenopathy were enrolled over a 2-month period and received active treatment for 24 weeks followed by a 4-week interval during which they did not receive the study drug. A marked interlaboratory variation in HIV isolation from peripheral blood mononuclear cells was observed, underscoring the critical role of quality assurance in similar multicenter trials. Nevertheless, the combined data indicate that ribavirin did not significantly suppress HIV activity (on measurement of reverse transcriptase activity) after week 6 or reduce serum p24 antigenemia.

AIDS-Related Complex↗
PubMed1990

A multicenter clinical trial of oral ribavirin in HIV-infected patients with lymphadenopathy. The Ribavirin-LAS Collaborative Group.

A double-blind, randomized, placebo-controlled trial comparing two daily doses of oral ribavirin and placebo was conducted at four medical centers. One hundred sixty-four adult men with lymphadenopathy were enrolled over a 2-month period and randomized to receive ribavirin 800 mg (53 subjects), ribavirin 600 mg (55 subjects), or placebo (56 subjects). Active treatment was administered for 24 weeks followed by a 4-week washout period. Nine subjects receiving placebo, four receiving ribavirin 600 mg, and none in the 800 mg group developed AIDS during the 24 weeks of active treatment. One patient randomized to the 800 mg group had Kaposi's sarcoma at study entry and was included in the intent-to-treat analysis. An overall significant difference in progression to AIDS was observed among the three treatment groups (p = 0.028) with patients randomized to receive 800 mg having a significantly longer time to AIDS than placebo patients (p = 0.012; relative risk, 9.0; 95% confidence interval, 1.1 to 70.8). There was no significant difference between the 600 mg and placebo groups (p = 0.15; relative risk, 2.3; 95% confidence interval, 0.7 to 7.6). Baseline CD4 cell count and hematocrit made independent contributions and formed a multivariate prognostic set for these progression data. The significant treatment superiority of 800 mg compared to placebo remained after adjustment for these factors (p = 0.019). After deletion of patients with major protocol violations at entry, the difference between the 800 mg and placebo treatment remained significant (p = 0.021).(ABSTRACT TRUNCATED AT 250 WORDS)

Acquired Immunodeficiency Syndrome↗
PubMed1990

Competitive inhibition of magnesium-induced [3H]N-(1-[thienyl] cyclohexyl)piperidine binding by arcaine: evidence for a shared spermidine-magnesium binding site.

The polyamine competitive antagonist arcaine (1,4-diguanidino-butane) produced complete inhibition of basal [3H]N-(1-[thienyl] cyclohexyl)piperidine ([3H]TCP) binding, with an IC50 value of 4.52 +/- 0.93 microM. Arcaine (5 and 10 microM) produced a decrease in the affinity without a significant change in the receptor density of [3H]TCP binding under equilibrium conditions. In addition, arcaine did not alter either N-methyl-D-aspartate-specific [3H] glutamate or strychnine-insensitive [3H]glycine binding. Furthermore, increasing concentrations of arcaine produced parallel rightward shifts in the concentration-response curves for both spermidine- and magnesium-induced [3H]TCP binding, suggesting that arcaine is a competitive inhibitor of both agonists. Similar rightward shifts were observed for barium- and strontium-induced [3H]TCP binding. In contrast, arcaine decreased the efficacy of glutamate- and glycine-induced [3H]TCP binding without changing their EC50 values, indicating a noncompetitive type of inhibition. These results imply that spermidine and certain divalent cations including magnesium share the same mechanism for enhancing [3H]TCP binding, whereas glutamate and glycine have different sites of action. This is further supported by the additive effect of spermidine when tested in the presence of maximal concentrations of glutamate and glycine. On the other hand, spermidine and magnesium were not additive and, in fact, magnesium was able to block the effects of spermidine under certain conditions. The possibility that magnesium is a partial agonist at the polyamine site is discussed.

Animals↗
PubMed1990

Spermidine reverses arcaine's inhibition of N-methyl-D-aspartate-induced hippocampal [3H]norepinephrine release.

The inhibition of N-methyl-D-aspartate (NMDA)-induced [3H]norepinephrine ([3HNE) release by a putrescine analog was studied. We report that arcaine, diguanidinobutane, a putative competitive polyamine antagonist, completely and noncompetitively antagonized NMDA-induced [3H]NE release from rat hippocampal minces with an IC50 value of 102 microM. Arcaine did not alter kainate- or potassium-induced [3H]NE release suggesting a specific effect on NMDA-mediated responses. Spermidine did not alter NMDA-induced [3H]NE release, nor did it reverse the effect of arcaine when introduced in a normal physiologic superfusion buffer. However, spermidine reversed the effect of arcaine when superfusing with buffer that contained 5% (v/v) of the organic solvent dimethylsulfoxide. This finding suggests that the polyamine site may be located at the intracellular surface of the cell membrane. Our results provide the first evidence for polyamine modulation of the NMDA receptor ionophore complex in a functional physiologic system.

Animals↗
PubMed1990

Characterization of the stimulatory and inhibitory effects of polyamines on [3H]N-(1-[thienyl]cyclohexyl) piperidine binding to the N-methyl-D-aspartate receptor ionophore complex.

Spermidine and spermine, as well as several other structurally related compounds, were tested in a [3H]N-(1-[thienyl]cyclohexyl) piperidine [( 3H]TCP) binding assay to determine the structural requirements of polyamines for activation of the N-methyl-D-aspartate-operated ion channel. Under nonequilibrium conditions, the polyamines enhanced [3H]TCP binding approximately 9-fold, with EC50 values ranging from 0.8 to 60 microM. The order of potency in enhancing [3H]TCP binding was N,N'-bis(3-aminopropyl)-1,3-propanediamine greater than N,N'-bis-(3-aminopropyl)-ethylenediamine greater than spermine greater than spermidine greater than N,N'-bis-(2-aminoethyl)-1,3-propanediamine. 1,3-Diaminopropane produced a partial agonistic effect, whereas putrescine, cadaverine, and 1,7-diaminoheptane were without effect at concentrations up to 1 mM. Eadie-Hofstee analysis of spermidine-induced [3H]TCP binding at equilibrium revealed a 3-fold increase in the affinity without a significant change in receptor density. This was further supported by kinetic data that showed that spermidine produced an increase in the association rate and a decrease in the dissociation rate of [3H]TCP binding to its site. Putrescine, cadaverine, and 1,3-diaminopropane antagonized the effects of spermidine by an apparently noncompetitive mechanism. Magnesium ions mimicked the effects of putrescine, suggesting the possibility that the inhibitory effects of Mg2+ and putrescine are mechanistically related.

Animals↗