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Biomedical subjects

M J Lewis

Publications and source records attributed to M J Lewis.

At least 127 records · Page 7Linked to original sources
PubMed1995

Effects of the benzodiazepine inverse agonist RO19-4603 on the maintenance of tolerance to a single dose of ethanol.

The time course of the novel benzodiazepine inverse agonist, RO19--4603 (0.075 or 0.150 mg/kg) in antagonizing the depressant effects of ethanol (EtOH) (0.50, 1.0 and 1.5 g/kg) and the development of tolerance on locomotor behaviors (e.g., ambulatory count, total distance and stereotypy count) were investigated in Sprague-Dawley rats given EtOH injections spaced at 24-hr intervals. A single dose of RO19--4603 prevented the development of tolerance to the 0.50- and 1.0-g/kg EtOH doses 24-hr post-RO19--4603 administration on most locomotor behaviors. On Day 1, the 0.150-mg/kg RO19--4603 dose prevented the reduction of motor behaviors after the 1.0- and 1.5-g/kg EtOH doses, whereas the 0.075-mg/kg RO19--4603 dose prevented the reduction of motor behaviors only after the 1.5-g/kg EtOH dose. The 0.075- and 0.150-mg/kg RO19--4603 doses also prevented the EtOH-induced reduction of motor behaviors after the 1.5-g/kg EtOH dose 24-hr post-RO19--4603 administration. RO19--4603 was without effect on activity when given alone. These data suggest that the motor impairing effects of EtOH and the development of tolerance to them may involve gamma-aminobutyric acidA-benzodiazepine receptor mechanisms that when occupied, even briefly by certain benzodiazepine inverse agonists, produce long-lasting effects on locomotion and tolerance.

Animals↗
PubMed1994

Ethanol self-administration in freely feeding and drinking rats: effects of Ro15-4513 alone, and in combination with Ro15-1788 (flumazenil).

Recent work in our laboratory demonstrated that Ro15-4513, a partial inverse benzodiazepine (BDZ) agonist, decreases ethanol (ETOH) self-administration in rodents under fluid deprivation conditions. The present study further examined the effects of Ro15-4513 (2.5 and 5.0 mg/kg) alone and in combination with Ro15-1788, (flumazenil) (8.0 and 16.0 mg/kg), a BDZ receptor antagonist on ETOH self-administration in freely feeding and drinking rats. Animals were trained to consume ETOH (11% v/v) using a limited access procedure. Measurements were taken at 10- and 60-min intervals. Ro15-4513 (2.5 and 5.0 mg/kg) markedly attenuated ETOH consumption at both intervals. The antagonistic actions of Ro15-4513 were completely blocked by the higher dose of flumazenil at both intervals; the lower dose failed to antagonize the Ro15-4513-induced reduction of ETOH intake. When flumazenil was given alone, both doses reduced ETOH self-administration at 60 min; although the magnitude of the antagonism was comparable to that of Ro15-4513 only with the highest does of flumazenil (16.0 mg/kg). Neither Ro15-4513 nor flumazenil alone or in combination significantly altered water intake at any of the tested doses. Rats pretreated with Ro15-4513 showed a substantial reduction in blood ethanol concentration (BEC) compared with the Tween-80 vehicle condition at the 10-min interval. However, the BEC of animals given Ro15-4513 in combination with flumazenil were similar to rats given Tween-80 vehicle. The present study extends our previous research by demonstrating that Ro15-4513 and flumazenil attenuate ETOH self-administration in non-food or water deprived rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Drinking↗
PubMed1994

Interactions of Ro15-4513, Ro15-1788 (flumazenil) and ethanol on measures of exploration and locomotion in rats.

The present study investigated the role of the GABAA-benzodiazepine (BDZ) receptor complex in mediating ethanol (ETOH)-induced increases in exploration (head-dipping) and locomotion of rats in a holeboard test. Male Sprague-Dawley rats were selected based on low basal exploratory rates to increase the likelihood that ETOH would increase these behaviors. The effects of the BDZ partial inverse agonist, Ro15-4513 (2.5 mg/kg), and the BDZ receptor antagonist, Ro15-1788 (flumazenil) (8.0 mg/kg), alone, and in combination with ETOH (0.25, 0.50 and 0.75 g/kg, IP) were investigated. The 0.25 and 0.50 g/kg doses of ETOH markedly increased both exploration and locomotion in low exploratory rats. The ETOH-induced increases were prevented by Ro15-4513 on both measures at a dose that produced no observable intrinsic action; however, this apparent lack of intrinsic activity on exploration may have been related to the low basal rates of responding in the subjects. The BDZ antagonist, flumazenil, completely reversed the antagonistic action produced by Ro15-4513 of the ETOH-induced stimulant effects on locomotion, however, flumazenil exerted only a marginal statistically significant effect on Ro15-4513's actions on head-dipping. When flumazenil was given alone, it increased head-dipping, but was without effect on locomotion. Flumazenil did not affect ETOH-induced increases in locomotion; however, ETOH and flumazenil appeared to show agonistic effects on exploration. The different effects exerted by flumazenil alone, and in combination with ETOH on head-dipping and locomotion suggest that the actions of flumazenil on these behaviors are mediated through separate mechanisms. The research further suggests that both the anxiolytic and locomotor activational effects of ETOH are mediated through the GABAA-BDZ receptor complex.

Animals↗
PubMed1994

Localization of Sed5, a putative vesicle targeting molecule, to the cis-Golgi network involves both its transmembrane and cytoplasmic domains.

The yeast Sed5 protein, which is required for vesicular transport between ER and Golgi complex, is a membrane protein of the syntaxin family. These proteins are thought to provide the specific targets that are recognized by transport vesicles. We have investigated the mechanism by which Sed5 protein is itself localized. Expression of epitope-tagged versions of the yeast, Drosophila and rat Sed5 homologues in COS cells results in a perinuclear distribution; immuno-EM reveals that the majority of the protein is in a tubulo-vesicular compartment on the cis side of the Golgi apparatus. A similar distribution was obtained with a chimeric molecule consisting of a plasma membrane syntaxin with the Drosophila Sed5 transmembrane domain. This indicates that the membrane-spanning domain contains targeting information, as is the case with resident Golgi enzymes. However, alterations to the transmembrane domain of Drosophila Sed5 itself did not result in its mistargeting, implying that an additional targeting mechanism exists which involves only the cytoplasmic part of the protein. This was confirmed by modifying the transmembrane domain of the yeast Sed5 protein: substitution with the corresponding region from the Sso1 protein (a plasma membrane syntaxin homologue) did not affect yeast Sed5 function in vivo.

Amino Acid Sequence↗
PubMed1994

Modulation of myocardial relaxation by basal release of endothelin from endocardial endothelium.

OBJECTIVE: The aim was to study the potential role of basal endothelin-1 release from endocardial endothelium in isolated ferret papillary muscle preparations. METHODS: The following interventions were studied: (1) no treatment (time control); (2) endothelin-1 (5 nM); (3) endothelin-1 (5 nM) in the presence of the specific ETA receptor antagonist, BQ123 (10 microM); (4) BQ123 (10 microM) in endocardium-intact muscles; and (5) BQ123 (10 microM) in endocardium-denuded muscles (n = 6 in each group). RESULTS: Untreated muscles remained stable throughout the experiment. BQ123 fully inhibited the positive inotropic effect of exogenous endothelin-1. In endocardium-intact preparations (n = 6), exposure to BQ123 induced a progressively earlier onset and time course of isometric twitch relaxation [time to peak tension -12.3(SEM 1.8)%, relaxation half time -13.3(1.1)%; both p < 0.01], but had no effect on peak tension or on rate of tension development. Selective denudation of endocardial endothelium induced similar relaxant effects, but also significantly reduced peak tension. In endocardial endothelium-denuded preparations (n = 6), addition of BQ123 did not result in further contractile changes. CONCLUSIONS: Endocardial endothelium in situ on papillary muscle preparations tonically releases endothelin, resulting in a significantly delayed onset of isometric twitch relaxation. There is no evidence for basal endothelin-1 release from microvascular endothelial cells in this superfused preparation. A similar release of endothelin-1 from endocardial endothelium in the intact heart could influence myocardial contractile behaviour independently of changes in coronary perfusion. Endothelin-1 may have a physiological role in modulating myocardial relaxation.

Animals↗
PubMed1994

Preliminary investigation of the efficacy of sublingual verapamil in the management of acute atrial fibrillation and flutter.

The antiarrhythmic properties of sublingual verapamil were investigated in seven patients with acute fast atrial flutter (n = 2) or fibrillation (n = 5). A rapid and significant (P < 0.05) reduction in the ventricular rate was achieved in all seven patients. The ventricular rate at peak plasma verapamil concentration (+/- s.d.) was significantly slower than on admission (101.6 +/- 11.3 and 159 +/- 5.3 beats min-1 respectively, P < 0.01). The ventricular rate remained controlled for over 4 h. Sublingual verapamil was rapidly absorbed with the maximum peak plasma concentration (153.3 +/- 15.5 ng ml-1) being achieved after 1.21 +/- 0.18 h. Side-effects of sublingual verapamil were limited to one report of a bitter taste. The sublingual administration of verapamil may provide an alternative method for the control of acute fast atrial fibrillation and flutter in selected patients.

Acute Disease↗
PubMed1994

The effect of two types of teacher training on implementation of Smart Choices: a tobacco prevention curriculum.

This study examined the implementation phase of a four-year research project to test the effectiveness of strategies to increase diffusion of Smart Choices, a school-based tobacco prevention program. The impact on curriculum implementation of two approaches to teacher training are compared. School districts were randomly assigned to a live workshop training or video training condition. The outcome of the evaluation was teachers' implementation of Smart Choices. Results show a lower proportion of video-trained teachers implemented the curriculum, but overall completeness and fidelity of implementation for those teachers who did teach the curriculum were comparable for the two groups. Video-trained teachers, however, were less likely to use brainstorming and student presentations/role plays, two of the methods prescribed by the curriculum. Implications of the results for teacher training are discussed.

Adolescent↗
PubMed1994

Myocardial relaxant effect of exogenous nitric oxide in isolated ejecting hearts.

In isolated myocytes and papillary muscles, both nitric oxide, acting through guanosine 3',5'-cyclic monophosphate (cGMP), and cGMP analogues exert a novel effect on myocardial contraction, influencing mainly the onset of relaxation. We studied the effect of the exogenous nitric oxide donor, sodium nitroprusside (0.1-10 microM), in isolated ejecting guinea pig hearts at constant filling pressure, afterload, and heart rate to identify its direct myocardial effects in the whole heart. Sodium nitroprusside induced concentration-dependent increases in coronary flow as well as premature and faster early left ventricular (LV) pressure decline, but did not change end-diastolic or peak LV pressure or peak rate of rise of LV pressure. There was no correlation between changes in coronary flow and LV pressure decline. Sodium nitroprusside effects were inhibited by hemoglobin, which inactivates nitric oxide. The cGMP-independent vasodilator nicardipine also increased coronary flow but did not influence early LV pressure fall. Thus exogenous nitric oxide exerts novel direct myocardial relaxant effects in the isolated ejecting heart, independent of its known vasodilator activity, and without compromising systolic function.

Analysis of Variance↗
PubMed1994

Modulation of left ventricular relaxation in isolated ejecting heart by endogenous nitric oxide.

Nitric oxide (NO) modulates myocardial contractile behavior in several isolated preparations, e.g., cardiac myocytes and papillary muscles, via elevation of intracellular guanosine 3',5'-cyclic monophosphate (cGMP). We have recently reported that the exogenous NO donor, sodium nitroprusside, selectively modulates left ventricular (LV) relaxation in the isolated ejecting guinea pig heart, independent of coronary flow. We now report the effects of endogenously released NO on LV performance in this preparation (constant heart rate and loading). Both bradykinin (1 nM, n = 6) and substance P (100 nM, n = 6) accelerated early LV relaxation (maximum change in time constant, tE, -10.5 +/- 1.6 and -13.4 +/- 2.1%, respectively; both P < 0.05), without significantly altering early systolic parameters (e.g., rate of LV pressure development). These effects were inhibited by hemoglobin (P < 0.05; n > or = 6), which inactivates NO. Bradykinin (100 nM, n = 10) had an additional negative inotropic effect, which was not inhibited by hemoglobin. Neither agonist altered relaxation in isolated papillary muscles. These data suggest that endogenous NO, probably released from coronary microvascular endothelial cells, modulates LV relaxation in the intact heart.

Animals↗
PubMed1994

Synergistic effects of ethanol and cocaine on brain stimulation reward.

The effects of two widely abused drugs, ethanol and cocaine, were examined alone and in combination on intracranial reward processes. In agreement with previous research, higher doses of both cocaine and ethanol alone produced facilitation of behavior maintained by brain stimulation reward. Low intraperitoneal doses of ethanol and cocaine, which alone did not affect performance, were found to reduce stimulation reward threshold and modestly increase response rate. The enhancement of brain stimulation reward by the combination of ethanol and cocaine suggests that both drugs may produce their rewarding effects through common neuronal substrates and that they may potentiate the abuse of each other.

Animals↗
PubMed1993

Plasma L-arginine levels in a rabbit model of hypercholesterolaemia.

A novel method for the quantitation of L-arginine in plasma samples has been developed, based on the technique of enantiomer labelling coupled to the capillary gas chromatographic separation of amino acids. Using this technique plasma L-arginine levels have been measured in rabbits fed a 1% cholesterol-containing diet and compared with rabbits fed a standard diet. Blood cholesterol levels were significantly elevated in the rabbits fed cholesterol but no significant difference was found in plasma L-arginine levels between the cholesterol-fed and control animals. No D-arginine was found in any of the plasma samples. It is concluded that the impairment in endothelium-dependent relaxation previously described in this animal model of hypercholesterolaemia is not due to deficiency of plasma L-arginine.

Animals↗
PubMed1993

pH-dependent binding of KDEL to its receptor in vitro.

The erd2 protein is the receptor responsible for recycling proteins bearing the carboxyl-terminal sequence KDEL (single-letter amino acid code) to the endoplasmic reticulum, following their loss from that organelle by the process of forward transport. To study the interaction of erd2p with the sequence KDEL we have reconstituted binding of erd2p to its ligand in vitro. Binding in vitro exhibits the same sequence specificity as retention of lumenal proteins in vivo and is strikingly sensitive to pH. Our results raise the possibility that erd2p-mediated sorting of lumenal endoplasmic reticulum proteins is facilitated by the pH differences between compartments of the secretory pathway.

Amino Acid Sequence↗
PubMed1993

Effects of ethanol on punished and nonpunished responding under conditions of equated reinforcement rates and similar response rates.

Lever pressing by pairs of rats was maintained under random-ratio (first subject) and yoked-interval (second subject) schedules of food presentation. The inter-reinforcement intervals generated under the ratio schedule comprised the interval values for the second (yoked) subject. This arrangement yielded nearly equivalent rates of food presentation for each subject pair. For the first rat of each pair a random-ratio schedule of shock presentation was added to the ratio schedule of food presentation. This manipulation resulted in similar rates of punished (first rat) and nonpunished (second rat) responding within subject pairs. Ethanol administration (0.25-1.5 g/kg) generally resulted in dose-related decreases in both punished and nonpunished responding. In general, punishment-specific effects were not obtained. These results suggest that ethanol may not be as effective as chlordiazepoxide or pentobarbital in increasing punished responding even when the effects of baseline response and reinforcement rates are controlled.

Animals↗
PubMed1993

Interleukin-1 beta modulates myocardial contraction via dexamethasone sensitive production of nitric oxide.

OBJECTIVE: Nitric oxide released by a calcium dependent constitutive NO synthase in endocardial endothelial cells exerts characteristic effects on myocardial contraction. Interleukin 1 beta (IL-1) induces the expression of a different calcium independent NO synthase in several tissues. Activity of the latter enzyme has recently been identified in cardiac myocytes but its functional effects are unknown. The aim of this study was to investigate the effects of IL-1 on contraction of isolated ferret papillary muscle preparations. METHODS: Electrically stimulated preparations were studied in the presence of acebutolol (1 microM), indomethacin (10 microM), and polymyxin (10 micrograms.ml-1). After a 3 h equilibration period, IL-1 (10 ng.ml-1) was added and contractile behaviour monitored over the next 3 h. The following groups were studied: (1) no IL-1; (2) IL-1 alone; (3) IL-1 in the presence of dexamethasone (3 microM); (4) IL-1 in the presence of NG-monomethyl-L-arginine (L-NMMA, 50 microM); (5) IL-1 in the presence of L-NMMA (50 microM) and L-arginine (500 microM). Cyclic GMP content was measured by radioimmunoassay in all preparations. RESULTS: No significant contractile changes were noted in group 1. In group 2, IL-1 raised myocardial cyclic GMP and induced a progressive abbreviation of isometric twitch, starting 30 min after addition, with a small decrease in peak isometric tension but no change in rate of tension development. These effects were similar to those previously documented for endocardial endothelial NO but were not inhibited by endocardial endothelial denudation. IL-1 effects were inhibited in groups 3 and 4, and partially restored in group 5. CONCLUSIONS: IL-1 activates a dexamethasone sensitive myocardial L-arginine-NO pathway which raises myocardial cyclic GMP and induces marked twitch abbreviation. These effects could potentially lead to cardiac depression by limiting systolic ejection, and may be relevant in conditions where IL-1 levels are increased.

Acebutolol↗
PubMed1993

Nitric oxide release from porcine mitral valves.

OBJECTIVE: The aim was to investigate the release of nitric oxide (NO) from porcine mitral valves. METHODS: The valves were sandwiched between gauze in a chamber constantly perfused by Holman solution. The presence of NO in the perfusate of the valves was detected by two methods: a bioassay cascade system using preconstricted rings of pig coronary artery as the detector tissue, and a chemiluminescent method, specific for NO. RESULTS: Porcine mitral valves release NO under basal conditions. Release can be increased by the agonists ADP, substance P, bradykinin, thrombin, and the calcium ionophore A23187. ADP was by far the most effective. NO release under basal conditions was inhibited by each of the three NO synthase inhibitors studied, but only NG-monomethyl-L-arginine (L-NMMA) reduced ADP stimulated release. A reversible inhibition of NO release occurred when valves were perfused with calcium-free Holman solution and NO release was inhibited by removal of the endocardial monolayer. CONCLUSIONS: The endocardial endothelium covering the mitral valves releases NO under basal conditions and following stimulation with several agonists. The NO synthase enzyme is calcium dependent. Different mechanisms may exist for the synthesis of basal and agonist dependent NO release in these cells.

Adenosine Diphosphate↗
PubMed1993

Three cases of the myelodysplastic syndrome with pericentric inversion of chromosome 16.

Inversion of chromosome 16, inv(16)(p13q22), is characteristic of acute myeloid leukaemia (AML) with eosinophilia and is rarely found in the myelodysplastic syndrome (MDS). We report three cases of MDS in which inv(16) was observed. They were classified to FAB subtypes RA, RARS and RAEBT; eosinophilia or abnormal eosinophils were not observed. The disease appeared to be stable in all three patients. MDS with inv(16) without eosinophilia may be a rare subgroup associated with a good prognosis.

Adolescent↗