Biomedical subjects

M S Dar

Publications and source records attributed to M S Dar.

At least 37 records · Page 2Linked to original sources

PubMed1992

Selective antagonism of acute ethanol-induced motor disturbances by centrally administered Ro 15-4513 in mice.

Results of the present investigation demonstrated that Ro 15-4513 when given ICV selectively antagonized ethanol-induced motor disturbances at doses that did not produce motor incoordination and lacked proconvulsant activity. Ro 15-4513 in 10-, 15-, and 22-ng doses antagonized, roughly in a dose-dependent manner, ethanol-induced motor incoordination. The 10-ng dose produced an optimal effect with nearly complete antagonism within 30 min postethanol. The higher, 15 and 22 ng, doses of Ro 15-4513 antagonized, as well as probably reversed, ethanol-induced motor incoordination. The stimulation and inhibition of spontaneous motor activity by 1 and 2 g/kg IP ethanol, respectively, were also selectively antagonized by Ro 15-4513. Neither an alteration in the latency and/or duration of pentylenetetrazol-induced convulsions nor an antagonism to sodium pentobarbital-induced motor incoordination and inhibition of spontaneous motor activity by Ro 15-4513 at dose levels that showed antiethanol effects were observed. Only the 150-ng dose of Ro 15-4513, which exhibited intrinsic activity as proconvulsant, attenuated sodium pentobarbital-induced motor incoordination. When given alone at doses higher than those used in motor coordination experiments, Ro 15-4513 markedly increased spontaneous motor activity dose dependently.

Animals↗

PubMed1992

Tolerance to adenosine's accentuation of ethanol-induced motor incoordination in ethanol-tolerant mice.

Our previously published reports have provided data that have supported a functional correlation between ethanol-induced changes in the characteristics of adenosine receptor, adenosine uptake and release in the brain, and ethanol-induced motor incoordination. The present data demonstrated a cross-tolerance between ethanol and adenosine further supporting the hypothesis that brain adenosine modulates the motor impairing effects of ethanol. Mice that received (-)-N6-cyclohexyladenosine (CHA) [0.25 mg/kg/day, intraperitoneally (ip)] for 10 days exhibited marked attenuation (cross-tolerance) to acute ethanol-induced motor incoordination compared with chronic saline (ip) controls. The attenuation of acute ethanol-induced motor incoordination was essentially same in animals that received CHA (25 ng/5 microliters/day for 10 days) by the intracerebroventricular (icv) route as opposed to the controls that chronically received artificial cerebral spinal fluid by the same route. Similarly, tolerance was exhibited to acute CHA (0.125 mg/kg ip and 12.5 ng/5 microliters icv) by animals fed liquid ethanol (19.5 g/kg/24 hr) for 10 days compared with none in the pair-fed sucrose controls. Scatchard plots using cerebellar tissue homogenates from animals given chronic CHA or chronic ethanol indicated no change in Bmax and/or Kd values for CHA binding when compared with CHA binding in tissues from their respective controls. However, a lack of any change in the binding characteristics cannot rule out the involvement of adenosine receptors in the observed cross-tolerance between ethanol and CHA. The results may suggest desensitization of adenosine A1 receptors due to chronic CHA and ethanol as an alternate possible explanation in the development of cross-tolerance between adenosine (CHA) and ethanol.

Adenosine↗

PubMed1991

In vitro autoradiographic evidence for adenosine modulation of ethanol-induced motor disturbances in rats.

It was previously shown that adenosine agonists and antagonists potentiate and decrease ethanol-induced motor disturbances, respectively. This interaction of adenosine and ethanol was functionally correlated with a significant increase in Bmax of cerebellar cortical high affinity adenosine A1 receptors after a single ethanol injection. Quantitative autoradiographic analysis of adenosine A1 and A2 binding sites in rat brain was carried out in animals treated acutely with saline or ethanol. Adenosine agonist binding at A1 receptors was increased in the molecular layer of cerebellum 15 min after ethanol injection. This increase returned to control values by 60 min. Adenosine antagonist binding at A1 receptors was not altered by ethanol treatment. Inclusion of a poorly hydrolyzable analogue of GTP in the incubation medium decreased binding throughout the brain for adenosine agonists but had less effect on agonist binding in the cerebellum and hippocampus of ethanol-treated rats 15 min after injection. The inhibitory effect of the GTP analogue was equal in saline- and ethanol-treated rats after 60 min. These findings suggest that acute ethanol treatment elicits a transitory increase in adenosine A1 receptor binding that is limited to the cerebellum and hippocampus and that this increased binding reflects an increased (or stabilized) coupling of the receptors to GTP-binding proteins. Acute ethanol treatment did not alter agonist binding at the high affinity A2a subtype of adenosine receptors in striatum.

Adenosine↗

PubMed1991

Cholecystectomy with and without drainage.

Thirty patients underwent cholecystectomy without drainage, and 16 matched controls cholecystectomy with drainage. The wound infection rate was lower, hospital stay shorter and overall complication rate less in undrained patients. This study suggests that surgical drainage after uncomplicated cholecystectomy is unnecessary and may be unwise.

Adolescent↗

PubMed1990

Functional correlation between subclasses of brain adenosine receptor affinities and ethanol-induced motor incoordination in mice.

To further investigate if the modulation of ethanol-induced motor incoordination is by brain adenosine A1 and/or A2 receptor, adenosine analogs with wide variability in their affinity for A1 and A2 subtypes were administered ICV and their effect on ethanol-induced (IP) motor incoordination was evaluated by rotorod. A dose-dependent marked accentuation of ethanol-induced motor incoordination by adenosine agonists (CHA, NECA, CPA, DCCA) tested, with nearly no effect on normal motor coordination in the absence of ethanol, was observed. There was a positive correlation between A2 affinity, A2/A1 affinity ratio but a negative correlation between A1 affinity and the potency (ED50) of adenosine agonists to accentuate ethanol-induced motor incoordination. However, with the high potency of CHA and NECA, both having significant affinity for A1 and A2 receptors, together with the well known membrane perturbation by ethanol, it seems difficult to rule out until more information becomes available the contribution of A1 receptor activation to adenosine modulation of ethanol-induced motor incoordination. The high density of high affinity A2 (A2a) in the striatum and of A1 in the cerebellum and several brain areas and the known importance of these two brain areas in the motor control, indirectly supports or at least provides a circumstantial evidence for a functional correlation between ethanol-induced motor incoordination and brain adenosine receptors.

Adenosine↗

PubMed1990

Central adenosinergic system involvement in ethanol-induced motor incoordination in mice.

To clarify if the behavioral interaction between ethanol and adenosine reported previously occur centrally or due to a peripheral hemodynamic change, the effect of i.c.v. adenosine agonists, N6-(R-phenylisopropyl)adenosine (R-PIA), N6-(S-phenylisopropyl)adenosine, 5'-(N-cyclopropyl)-carboxamidoadenosine, antagonists, theophylline and 8-p-(sulfophenyl)theophylline as well as enprofylline on ethanol-(i.p.)-induced motor incoordination was evaluated by rotorod. Adenosine agonists and antagonists dose dependently accentuated and attenuated, respectively, ethanol-induced motor incoordination, thereby suggesting a central mechanism of adenosine modulation of this effect of ethanol and confirmed our previous reports in which adenosine agonists and antagonists were given i.p. Enprofylline, a weak adenosine antagonist but potent inhibitor of cyclic AMP phosphodiesterase, did not alter ethanol's motor incoordination, further supporting involvement of brain adenosine receptor mechanism(s) in ethanol-adenosine interactions. Results from R-PIA and N6-(S-phenylisopropyl)adenosine experiments showed nearly a 40-fold greater potency of R-vs. S-diastereoisomer, suggesting predominance of adenosine A1 subtype. However, 5'-(N-cyclopropyl)-carboxamidoadenosine data indicate complexity of the mechanism(s) and point toward an additional involvement of a yet unknown subtype of adenosine A2. No effect of ethanol on blood or brain levels of [3H]R-PIA was noted and sufficient amount of the latter entered the brain to suggest adenosine receptor activation adequate to produce behavioral interaction with ethanol. There was no escape of i.c.v.-administered [3H]R-PIA from brain to the peripheral circulation ruling out a peripheral and supporting a central mechanism of ethanol-adenosine interaction.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗

PubMed1989

Central nervous system effects and behavioral interactions with ethanol of centrally administered dilazep and its metabolites in mice.

Dilazep (i.p.), a coronary vasodilator and an uptake inhibitor of adenosine, dose dependently potentiated acute ethanol-induced motor incoordination in mice. In view of peripheral cardiovascular depressive effects of dilazep, the effect of i.c.v. dilazep (25, 50 and 75 micrograms), and its metabolites, 1,4-bis(3-hydroxypropyl)perhydro-1,4-diazepine (BHPD) (15, 31 and 62 micrograms) and 1-[3-(3,4,5-trimethoxybenzoyloxy)propyl]perhydro-1,4-diazepine (TBPD) (62 and 125 micrograms) on ethanol-induced motor incoordination was studied. Dose-related potentiation of ethanol-induced motor incoordination was noted with dilazep and its metabolites. Whereas dilazep (i.p.) produced no apparent central nervous system (CNS) effects, by i.c.v. route, it caused CNS excitation including tonic-clonic seizures. Adenosine uptake inhibition, Ca2+ entry blockade or direct activation of adenosine receptors was ruled out as the possible mechanism of seizures because dipyridamole, verapamil or N6-(2-phenylisopropyl)-adenosine (R-PIA) administered i.c.v., while potentiating ethanol (i.p.)-induced motor incoordination did not produce seizures. The CNS excitation was minimal with BHPD and none with TBPD. Theophylline pretreatment partially blocked potentiation of ethanol-induced motor incoordination by dilazep and BHPD and not by TBPD. The data suggest dilazep-induced potentiation of ethanol-induced motor incoordination is partially due to central adenosine receptor mechanism and partly due to other yet unknown mechanism(s) and further supported our earlier reports about adenosine involvement in the CNS effects of ethanol. The data also suggest that dilazep (i.c.v.)-induced seizures are due to mechanism(s) other than adenosine uptake inhibition, Ca2+ entry blockade or direct adenosine receptor activation.

Animals↗

PubMed1989

Release of endogenous glutamate from rat cerebellar synaptosomes: interactions with adenosine and ethanol.

The effects of ethanol and adenosine receptor agonist R-PIA and antagonist theophylline on release of endogenous glutamate were tested in rat cerebellar synaptosomal preparation. Release was carried out for 5 to 60 sec after which time the released glutamate was separated from the synaptosomal membranes by rapid filtration. The amount of released glutamate in the filtrate was measured by an enzyme-linked fluorometric assay. Basal endogenous glutamate release was estimated as 3.7 +/- 0.3 nmol/mg protein/5 sec and was stimulated by high K+. Glutamate release consisted of an initial rapid phase for the first 10 sec that was followed by a relatively slower phase. Both Ca2+-dependent and Ca2+-independent glutamate release were observed which suggested the involvement of both neuronal and glial constituents of the synaptosomal preparation, respectively. Pharmacologically relevant concentrations of ethanol (25-100 mM) caused a trend toward a dose-dependent inhibition of glutamate release. R-PIA and theophylline inhibited and stimulated, respectively, basal release of glutamate and R-PIA-inhibited release was blocked by theophylline. Ethanol (25 mM) blocked the stimulatory effect of theophylline and the results of experiments following the inclusion of adenosine deaminase suggested the involvement of adenosine in this effect of ethanol. The results support our previous findings that suggest an involvement of cerebellar adenosine in the motor disturbing effects of acute ethanol and extend those findings by indicating that ethanol inhibits glutamate release from granule cells of the cerebellar cortex through an adenosine-sensitive mechanism.

Adenosine↗

PubMed1989

Effect of acute ethanol on release of endogenous adenosine from rat cerebellar synaptosomes.

The effects of pharmacologically relevant concentrations of ethanol on the release of endogenous adenosine from rat cerebellar synaptosomes were investigated. Release was conducted for 5, 10, 30, or 60 s after which time the incubation medium (containing the released adenosine) was rapidly separated from the synaptosomal membranes by vacuum filtration. The adenosine content of the filtrate was measured by HPLC-fluorescence detection. Both basal and KCl-stimulated adenosine release consisted of an initial rapid phase, for the first 10 s, that was followed by a relatively slower phase. Basal endogenous adenosine release was estimated as 199 +/- 14 pmol/mg protein/5 s. Potassium (chloride) increased adenosine release from the basal level to 433 +/- 83 pmol/mg protein/5 s. Ethanol caused a dose-dependent increase of adenosine release. The interaction between dilazep and ethanol indicates that ethanol-stimulated release does not involve the dilazep-sensitive transport system. The results support previous findings that indicate that cerebellar adenosine is involved in the mediation of ethanol-induced motor disturbances in the rat.

Adenosine↗

PubMed1989

Effect of acute ethanol on uptake of [3H]adenosine by rat cerebellar synaptosomes.

Many classes of CNS-acting drugs have been suggested to act at least partially via inhibition of adenosine uptake. Synaptosomal uptake of [3H]adenosine and the effect of acute ethanol on it were studied in a rat brain area known to be involved in the coordination and modulation of normal motor activity, the cerebellum. Uptake of [3H]adenosine was found to be linear with time (about 40 sec) and increasing concentrations (up to 1.5 microM) of adenosine. The uptake of [3H]adenosine was inhibited by dilazep (IC50 = 2.5 x 10(-7) M) in a dose-dependent manner. Pharmacologically and/or toxicologically relevant concentrations of ethanol (2.5 to 100 mM) significantly inhibited the uptake of [3H]adenosine between 12 and 15%. Lineweaver-Burk plots indicated that both in vitro (25 mM) and in vivo (1.5 g/kg i.p.; 30 mM blood level) ethanol lowered Km as well as Vmax values for adenosine uptake to nearly the same extent. In the case of in vivo ethanol, no ethanol was present during the assay since synaptosome preparation would wash out residual ethanol. The results of the present study indicate possible membranal alterations by in vivo ethanol. It is concluded that the uptake of [3H]adenosine is inhibited by intoxicating concentrations of ethanol in vitro and by acute ethanol (1.5 g/kg) in vivo. This may partially explain the modulatory role of endogenous adenosine in ethanol-induced motor disturbances.

Adenosine↗

PubMed1988

Mediation of acute ethanol-induced motor disturbances by cerebellar adenosine in rats.

The possible involvement of brain adenosine in acute ethanol-induced motor incoordination (MI) and inhibition of spontaneous motor activity (SMA) was investigated in male Sprague-Dawley rats. Pretreatment with theophylline or 7-(2-chloroethyl)-theophylline, adenosine antagonists, markedly reduced ethanol-induced MI and inhibition of SMA during a 60 min test period compared with saline + ethanol group. On the contrary, pretreatment with (-)-N6(R-phenylisopropyl)adenosine (R-PIA), an adenosine agonist, or dilazep, an adenosine uptake blocker, markedly potentiated the ethanol-induced MI as well as inhibition of SMA in a 60 min test period compared with saline + ethanol group. No effect on motor coordination was seen when the drug pretreatment was not followed by ethanol. However, the adenosine agonists and antagonists did alter SMA when the pretreatment with these drugs was not followed by ethanol. Ethanol clearance was not altered by the drug pretreatment as blood ethanol levels were similar in all groups except for lower ethanol levels in the R-PIA-treated group. Adenosine A1 binding studies, using 3H-R-PIA as the radioligand and crude membrane preparation from cerebellar cortex, revealed an increase in Bmax with no significant change in Kd in ethanol-treated animals vs. saline control. Theophylline pretreatment prevented the increase in Bmax elicited by ethanol. Collectively, the data suggest that endogenous cerebellar adenosine may be a participating factor in ethanol-induced motor dysfunctions.

Adenosine↗

PubMed1988

The effects of various methods of sacrifice and of ethanol on adenosine levels in selected areas of rat brain.

The effect of acute ethanol on adenosine content in four motor areas of the male Sprague-Dawley rat brain was investigated using HPLC-fluorescence detection. Since basal adenosine levels are difficult to assess due to extremely rapid turnover of adenosine, four different methods of sacrifice were also evaluated for adenosine measurement. The rank order for best results in measuring adenosine content with the various methods of sacrifice was: focused microwave irradiation greater than decapitation into liquid nitrogen greater than immersion into liquid nitrogen greater than decapitation. These differences probably reflect differences in degree of hypoxia and postmortem anoxia, factors well known to elevate adenosine, associated with the sacrifice method. Focused microwave irradiation of appropriate duration was found to be the best method of sacrifice and the results probably most closely reflect true basal adenosine levels. No significant alteration in adenosine content in any brain region examined was observed due to ethanol administration.

Adenosine↗

PubMed1988

The biphasic effects of centrally and peripherally administered caffeine on ethanol-induced motor incoordination in mice.

The possible biphasic effect of caffeine on acute ethanol-induced motor incoordination by rotorod evaluation was investigated in mice. Caffeine in various doses was administered intracerebroventricularly (i.c.v.) to mice implanted with permanent indwelling stainless steel guide cannulae and intraperitoneally (i.p.) to non-cannulated animals. A motor incoordinating test dose of ethanol, 2 g kg-1, was given i.p. in both cases. Caffeine less than 25 micrograms administered i.c.v., dose-dependently attenuated while 75 micrograms i.c.v. potentiated ethanol (i.p.)-induced motor incoordination. Similarly, caffeine less than 20 mg kg-1 given i.p., dose-dependently attenuated while 62.5 mg kg-1 potentiated ethanol (i.p.)-induced motor incoordination. The data obtained demonstrated that caffeine given either i.c.v. or i.p. exerted biphasic effects on ethanol-induced motor incoordination. The data also suggested that caffeine antagonized ethanol-induced motor micrograms i.c.v.; less than 20 mg kg-1 i.p.) caffeine is well known to display high affinity for adenosine binding sites. Therefore, the present investigation lends further support to our earlier suggestion that adenosine may be involved in the motor impairing effect of ethanol.

Animals↗

PubMed1987

Behavioral interactions of ethanol and methylxanthines.

The effect of the methylxanthines caffeine, theophylline and isobutylmethylxanthine (IBMX) on ethanol-induced ataxia and loss of righting reflex was investigated in three strains of mice. A significant potentiation of ethanol-induced ataxia was produced in all strains of mice at 20, 45 and 75 min after ethanol in mice pretreated with 62.5 mg/kg caffeine and 12.5 mg/kg IBMX. In mice pretreated with 40 mg/kg caffeine potentiation of ethanol-induced ataxia was observed only at 20 min after ethanol. Theophylline pretreatment produced no alteration in ethanol-induced ataxia. The results of methylxanthine pretreatment on ethanol-induced ataxia were similar, regardless of a shorter (10 min) or longer (75 min) pretreatment time. The methylxanthines produced no effect on motor coordination or behavior when administered separately. Although ethanol-induced loss of righting reflex was shortened by theophylline, neither caffeine nor IBMX altered the duration of loss of righting reflex. It is possible that inhibition of adenosine uptake, a known effect of the methylxanthines, may be a more likely explanation for the modulation of the behavioral effects of ethanol.

1-Methyl-3-isobutylxanthine↗

PubMed1986

Effect of chronically administered methylxanthines on ethanol-induced motor incoordination in mice.

The effect of chronic (10 days) administration of methylxanthines, caffeine, IBMX and theophylline on acute ethanol-induced motor incoordination has been investigated in the mice. In animals that received caffeine, 45 and 90 mg/kg/24 h, ethanol, 1.5 g/kg, produced motor incoordination significantly greater compared to that in the control groups. Significantly greater ethanol-induced motor incoordination was seen in animals fed IBMX, 30 and 60 mg/kg/24 h, compared to controls. Ethanol-induced increased motor incoordination in caffeine and IBMX-fed animals was also associated with significantly greater 3H-R-PIA binding in whole brains compared to tap water controls indicating an increase in brain adenosine binding sites. However neither motor incoordination nor 3H-R-PIA binding was altered in theophylline 75 and 150 mg/kg/24 h, fed animals. The increased motor incoordination associated with increased adenosine binding sites in the brains of caffeine and IBMX-fed animals suggests an involvement of central adenosine mechanisms in the motor incoordinating effect of ethanol and further supports our earlier suggestion for the role of adenosine in some of the central effects of ethanol.

1-Methyl-3-isobutylxanthine↗

PubMed1986

Protective effect of zinc against ethanol toxicity in mice.

Protection against the lethal effects of ethanol at 4.5 g/kg administered acutely was maximal when zinc was administered 60 min prior to ethanol. The timing of ethanol administration corresponded with elevated plasma levels of absorbed zinc. Protection was inversely related to the dose of zinc employed, as 0.5 mumol provided greater protection than 1.0 mumol, which provided greater protection than 2.0 mumol. Protection against ethanol lethality was greater if zinc was administered 60 min prior to each injection of ethanol. Acute zinc pretreatment did not alter the activity of liver alcohol dehydrogenase (ADH), nor did it alter the blood clearance of ethanol. Chronic zinc administration as ZnCl2, 100 micrograms/ml in the drinking water for 30 d, produced a 25% decrease in hepatic ADH activity, which was accompanied by a similar decrease in the intravascular clearance of ethanol.

Alcohol Dehydrogenase↗

PubMed1986

Estrogen modulation of uterine adrenergic-cholinergic interaction: effects on vasoactivity and adrenergic receptors in the guinea pig.

The regulation of uterine blood flow (UBF) in the guinea pig was investigated by determining the effects of steroid-catecholamine interaction on guinea pig UBF in cyclic (Day 0 = estrus) and ovariectomized (OVX)-steroid treated females. In cyclic guinea pigs, parallel elevations in uterine weight, UBF, beta and alpha receptor levels were observed during the estrus period, whereas uterine norepinephrine (NE) levels were low. In contrast, all parameters remained at low levels except NE levels during the luteal phase of the cycle which remained elevated in both normal and OVX-oil treated animals. Estrogen (E1)-treated females showed elevated uterine weights, UBF, beta, and alpha receptor levels but low uterine NE concentrations. Combined progesterone-estrogen (P2E1) treatment caused similar changes but maintained tissue NE at control levels. In the exposed uterine artery preparation, the sequential administration of acetylcholine followed by NE application induced a marked elevation in UBF in OVX, E-1-treated animals which was blocked by phentolamine (10(-6) M). This phenomena could not be demonstrated in either oil- or progesterone-treated OVX guinea pigs. In uterine membrane preparations from ovariectomized guinea pigs pretreated with either oil or progesterone, methacholine (cholinergic agonist; 10(-6) M) failed to alter the affinity of the alpha receptor for NE. However, in uterine preparations from OVX, estradiol-treated guinea pigs, methacholine significantly (P less than .05) increased the affinity of the alpha receptor for NE.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed1985

Decidua-associated changes in guinea pig uterine blood flow and volume: relation to uterine norepinephrine concentrations.

Changes in uterine blood flow (UBF) and uterine blood volume (UBV) during decidual tissue (DT) formation in the guinea pig were assessed at 2, 6, and 10 days postuterine trauma (PT). Uterine weight increased steadily between days 2 and 10 PT in DT-bearing animals as compared with the constant uterine weights observed in controls. Both UBF and UBV levels were elevated between days 2 and 10 PT in DT-bearing animals as compared with controls with the vascular changes being histologically related to the progressive stromal differentiation. Uterine norepnephrine (NE) levels were significantly (P less than or equal to 0.05-0.01) depressed in the hyperemic, DT-bearing uteri as compared with controls. These results indicate that the uterine hyperemia associated with DT formation in the guinea pig involves a sustained increase in uterine vascular volume as well as vascular perfusion rate under conditions of depressed uterine NE levels. These events are intimately associated with the support of stromal differentiation in the guinea pig.

Animals↗