Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

When acetylcholinesterase was inhibited by neostigmine, SK&F 96365 (1-(beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl)-1H-imidazole hydrochloride) at 10 microM caused no effect on the amplitude of single endplate potentials (e.p.p.s) but shortened the decay time in mouse phrenic nerve-diaphragm preparations. However, SK&F 96365 inhibited high-frequency stimulation-evoked long-lasting depolarization of the endplate region and accelerated the run-down of trains of e.p.p.s which were eliminated within 1 s. After a train of stimulation, SK&F 96365 produced a post-tetanic depression of single e.p.p.s. The post-tetanic effect gradually dissipated with full restoration in 10-15 s. During a train of stimulation, SK&F 96365 also depressed miniature endplate potentials (m.e.p.p.s), which were restored after termination of stimuli in parallel with the recovery of e.p.p. The decay times of miniature endplate currents during recovery phases changed slightly. In control preparations not treated with neostigmine, however, SK&F 96365 did not alter the amplitude and decay time of m.e.p.p.s or e.p.p.s but accelerated the decay of succinylcholine-induced endplate depolarizations. The results suggest that SK&F 96365 facilitates nicotinic receptor desensitization in addition to blocking receptor-operated Ca2+ channels.
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PMID:Facilitation of nicotinic receptor desensitization at mouse motor endplate by a receptor-operated Ca2+ channel blocker, SK&F 96365. 788 27

1. The negative inotropic effects of soman have been reported previously. It was suggested that the depression in atrial force of contraction was a consequence of continuous muscarinic receptor activation by excessive acetylcholine (ACh) accumulation and also possibly through direct interactions at the receptor-associated K+ channels by organophosphate (OP). 2. In this study, the protective effects of tacrine (THA), an antimuscarinic as well as a K+ channel blocker, against soman in guinea-pig atrium were investigated. 3. It was found that tacrine could antagonize the negative inotropic effects of soman. This antagonism occurred in a concentration dependent manner, with effective concentrations (ECs) for tacrine ranging from 1.7 to 12.1 microM when the atrium was equilibrated with 0.05-10 microM soman. 4. Inclusion of an oxime HI-6 (100 microM) in the regimen improved the efficacy of tacrine against soman (1 microM) by 16.1 fold. 5. Addition of a potent antimuscarinic, either atropine or glycopyrrolate with tacrine also improved tacrine's efficacy against soman significantly. 6. Atropine, at equivalent concentration, appeared to be the most effective of the three. At 0.1 microM concentration, atropine was 4.25 and 3.47 times more potent than HI-6 and glycopyrrolate respectively in enhancing THA efficacy. 7. Our results suggested that the immediate suppression of the muscarinic manifestations and the reactivation of the enzyme acetylcholinesterase for the removal of excess ACh are both critical in maintaining the mechanical functions of a heart during acute OP poisoning. The blockade of K+ channels by tacrine may also contribute to countering the depressant effects of soman.
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PMID:Protection by tacrine and some adjuncts against the depressant effects of soman in guinea-pig atrium. 811 29

The actions of the bispyridinium oxime HI-6 ([[[(4-aminocarbonyl)pyridino]-methoxy]methyl]-2- [(hydroxyimino)methyl]-pyridinium dichloride) were investigated in vitro on rat phrenic nerve-hemidiaphragm preparations. Isometric twitch and tetanic tensions were elicited at 37 degrees C with supramaximal nerve stimulation at frequencies of 20 and 50 Hz. To approximate normal respiration patterns, trials consisting of 30 successive 0.55 s trains were alternated with 1.25 s rest periods. Under control conditions, the above stimulation pattern generated tensions that were well maintained at both frequencies. In contrast, a marked depression of muscle tension was observed in diaphragms removed from rats administered 339 micrograms/kg soman (3 LD50) and tested in vitro. Addition of HI-6, 4 h after soman exposure, led to a nearly complete recovery of muscle tension at 20 Hz. At 50 Hz, muscle tensions still declined especially when trains were elicited at 1.25 and 3 s intervals. The recovery by HI-6 observed in this study appears to be mediated by mechanisms unrelated to acetylcholinesterase reactivation since no increase of enzymatic activity was detected and the effect was reversed by a brief washout in oxime-free physiological solution. The results suggest that the direct action of HI-6 may play a role in restoring soman-induced diaphragmatic failure but this effect would be significant primarily under low use conditions.
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PMID:Contribution of direct actions of the oxime HI-6 in reversing soman-induced muscle weakness in the rat diaphragm. 815 86

To study acute organophosphorus (OP) poisoning cases, 190 OP-intoxicated cases admitted to Civil Hospital, Ahmedabad, were investigated in depth. The group consisted of subjects ranging from 11 to 60 years of age, with the maximum number of cases in the age group 21-30 years and a male-to-female ratio of 2.1:1. Most of the subjects (71.61%) were partially educated, 24.2% of the cases were illiterate, and only 4.2% of the cases were highly educated. Socioeconomically, 21.1% of the subjects were of low economic status, 52.6% were low middle class, 16.8% were upper middle class, and only 9.5% were upper class. With regard to marital status of the subjects, 98 cases were married and 92 were unmarried. About 67.4% of the cases had the intention of committing suicide, 16.8% of the cases were the result of occupational exposure, and 15.8% of the cases were from accidental poisoning. Social and domestic problems (37.5%), marital friction (15.6%), financial stress (15.6%), love affairs (14.1%), job problems (10.9%), chronic illness (4.7%), and failure in examination (1.6%) were observed as the precipitating factors. Muscarinic manifestations such as vomiting (96.8%), nausea (82.1%), miosis (64.2%), excessive salivation (61.1%), and blurred vision (54.7%) and CNS manifestations such as giddiness (93.7%), headache (84.2%), disturbances of consciousness (44.2%), and typical pungent odor from mouth and clothes (77.9%) were the main presenting symptoms. Cardiac manifestations such as sinus tachycardia (25.3%), sinus bradycardia (6.3%), and depression of ST segments with T-wave inversion (6.3%) were observed electrocardiographically, with hypertension (10.5%) and muscular twitching in some (2.1%) cases. Biochemical changes such as albuminuria (12.6%) and azotemia (18.9%) with inhibition of acetylcholinesterase enzyme activity in blood were recorded in 78.9% of the cases. About 89.5% of the cases recovered completely, 4.2% of the cases absconded after partial recovery, and 6.3% of the cases died. The mortality rate (6.3%) depended on various factors such as the organophosphorus compound consumed, the amount ingested, the time interval for hospitalization, and the general health of the patient. Chances of recovery were higher when the patient was hospitalized at the earliest indication.
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PMID:A clinical, biochemical, neurobehavioral, and sociopsychological study of 190 patients admitted to hospital as a result of acute organophosphorus poisoning. 832 67

The presence and elimination rate of phosalone and its diethylphosphorus metabolites in blood serum and urine were studied in persons who had ingested a concentrated phosalone solution. Phosalone was detected only in serum samples. As it was rapidly hydrolysed and eliminated from the body, its diethylphosphorus metabolites were a more sensitive indicator of exposure. The concentration decrease of phosalone in serum and of total diethylphosphorus metabolites in serum and urine followed the kinetics of a biphasic reaction. The faster elimination half-times in serum, calculated for two persons, were 2.3 and 3.4 h for phosalone and 3.4 and 38.6 h for total diethylphosphorus metabolites. In the faster phase the average elimination half-time of total urinary metabolites in five persons was 25 +/- 17 h. The kinetic data for total urinary metabolites in a person occupationally exposed to phosalone indicated an early and very fast elimination phase (elimination half-time 1.3 h), which was overlooked in poisoned persons. The proportions of single metabolites in total urinary metabolites in poisoned persons depended on whether the total amount of diethylphosphorus metabolites was above 1000 or below 1000 nmol/mg creatinine. Diethylphosphorodithioate predominated at high and diethylphosphate at low concentrations of total metabolites. The correlation between the maximum concentrations of total metabolites, measured in urine of poisoned persons on the day of admission to hospital or a day later, and the initial depression of serum cholinesterase (EC 3.1.1.8) and erythrocyte acetylcholinesterase (EC 3.1.1.7) activities was poor (r = 0.6).
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PMID:Diethylphosphorus metabolites in serum and urine of persons poisoned by phosalone. 834 88

In rats lesioned by injecting the ibotenic acid (8 micrograms/site) into the unilateral nucleus basalis magnocellularis (NBM), the effect of treatment with bifemelane hydrochloride (BIF) or autotransplantation of the vagal nodosal ganglion was studied electrophysiologically by serial measurement of the event-related potential (ERP, P300) for 4 weeks. In addition, the effects on cholinergic markers were assessed by determining the specific binding of [3H]QNB (quinuclidinyl benzilate) to the muscarinic acetylcholine receptor (mAChR) as well as the activity of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE). The P300 latency was delayed and its amplitude remained low for 4 weeks in NBM-lesioned rats. In contrast, a return to normal occurred after 2-3 weeks in rats given daily intraperitoneal injections of BIF (15 mg/kg) and in autotransplanted rats. In lesioned rats, the cortical ChAT and AChE activities on the affected side did not recover, but the postsynaptic receptor response was transiently activated soon after lesioning. BIF increased specific mAChR binding (an early increase of affinity and a subsequent increase of receptor density) as well as presynaptic ChAT activity. Transplantation achieved the early activation of mAChR binding (increased receptor density) and continuously increased ChAT activity. Thus, the postsynaptic compensatory receptor mechanism of denervation supersensitivity acted as an early response to the depression of presynaptic cholinergic activity, but it could not improve the P300 response until the subsequent increase of cortical ChAT activity. Improvement of P300 combined with cortical cholinergic recovery after nodosal ganglion grafting or administration of BIF suggests that the neocortical ACh level may play an important role in regulating ERP.
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PMID:Effect of vagal autotransplantation and bifemelane hydrochloride on cholinergic markers and event-related potentials in rats with lesions of the nucleus basalis magnocellularis. 854 4

The dihydropyridine calcium channel blocker nifedipine did not affect spontaneous locomotor activity in mice when given alone but enhanced the depressant effects of the muscarinic receptor agonist oxotremorine and of the acetylcholinesterase inhibitor physostigmine. Such a behavioral depression might be due to neuronal changes induced by central calcium channel blockade combined with cholinergic activation. However, an involvement of hemodynamic factors, related to peripheral vasodilatation, cannot be excluded as locomotor depressant effects were also exerted by combinations of the two cholinomimetic agents with hydralazine, a non-calcium antagonist vasodilator.
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PMID:Enhancement by nifedipine of cholinergic-induced depression of locomotor activity in mice. 874 42

Laboratory and field studies were conducted to evaluate the effects of fenitrothion (O,O-dimethyl O-4-nitro-m-tolyl phosphorothioate) on the crayfish Procambarus clarkii. Acetyl- and butyryl-cholinesterase activities were measured in the muscle of P. clarkii exposed to different doses of fenitrothion (4, 20, and 100 microg/liter) for different times (up to 48 hr). A positive correlation was found between both cholinesterases, and acetylcholinesterase (AChE) was selected as a biomarker of exposure to this compound. Significant AChE depression (20%) was detected 2 hr after exposure to 20 microg/liter of fenitrothion, reaching a maximum at 48 hr (47%), followed by a slow recovery. Reactivation techniques using the nucleophilic reagent pyridine 2-aldoxime methiodide were assayed in fenitrothion-poisoned specimens, and the results suggested the utility of this method to diagnose exposure, particularly when control animals are not available. Finally, AChE inhibition was used to test a field population of P. clarkii potentially exposed to high concentrations of the organophosphorus pesticide fenitrothion, and a 55% inhibition was detected.
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PMID:Acetylcholinesterase inhibition in the crayfish Procambarus clarkii exposed to fenitrothion. 881 82

The effects of direct exposure to an organophosphate (OP) pesticide, dimethoate, were examined in free-living wood mice, Apodemus sylvaticus, in a wheat field. Male mice were radio-tagged at night and followed during 2-3-d periods, before and after an intraperitoneal injection of 50 mg/kg dimethoate which previous laboratory studies had demonstrated causes a maximum depression in brain acetylcholinesterase (AChE) activity of 75% relative to non-exposed mice. In subsequent weeks, survival was estimated by tracking and trapping data. Exposure to dimethoate significantly decreased locomotor activity in the first 6 h after administration resulting in a significant decrease in the area over which animals moved. These effects were limited to the night of treatment and disappeared 24 h later. The transient behavioral impairment of the dimethoate-treated animals appeared to have no effect on medium-term survival. Direct exposure to OPs sufficient to cause 75% depression of brain AChE is unlikely to be hazardous to wood mice if exposure is transient, as in the present study; it would be expected that sustained exposure sufficient to cause such behavioral effects would, however, be detrimental.
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PMID:Behavioral effects of acute sublethal exposure to dimethoate on wood mice, Apodemus sylvaticus: II--Field studies on radio-tagged mice in a cereal ecosystem. 897 27

Pontine cholinergic neurotransmission is known to play a key role in the regulation of rapid eye movement (REM) sleep and to contribute to state-dependent respiratory depression. Nitric oxide (NO) has been shown to alter the release of acetylcholine (ACh) in a number of brain regions, and previous studies indicate that NO may participate in the modulation of sleep/wake states. The present investigation tested the hypothesis that inhibition of NO synthase (NOS) within the medial pontine reticular formation (mPRF) of the unanesthetized cat would decrease ACh release, inhibit REM sleep, and prevent cholinergically mediated respiratory depression. Local NOS inhibition by microdialysis delivery of N(G)-nitro-L-arginine (NLA) significantly reduced ACh release in the cholinergic cell body region of the pedunculopontine tegmental nucleus and in the cholinoceptive mPRF. A second series of experiments demonstrated that mPRF microinjection of NLA significantly reduced the amount of REM sleep and the REM sleep-like state caused by mPRF injection of the acetylcholinesterase inhibitor neostigmine. Duration but not frequency of REM sleep epochs was significantly decreased by mPRF NLA administration. Injection of NLA into the mPRF before neostigmine injection also blocked the ability of neostigmine to decrease respiratory rate during the REM sleep-like state. Taken together, these findings suggest that mPRF NO contributes to the modulation of ACh release, REM sleep, and breathing.
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PMID:Pontine nitric oxide modulates acetylcholine release, rapid eye movement sleep generation, and respiratory rate. 898 99


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