Effect of Cholinergic and Cholinergic Blocking Drugs on Decamethonium Uptake by Slices of Mouse Kidney
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Abstract:
The accumulation of decamethonium by mouse kidney slices was investigated with particular reference to the possibility that this agent uses a choline transport system. Slices of mice kidneys were incubated (1 hour) in Krebs‐Ringer bicarbonate medium (37°, pH 7.4) containing 14 C‐decamethonium (2 × 10 ‐6 M) with or without the addition of other drugs. Choline and neostigmine stimulated decamethonium uptake at relatively low concentrations (10 ‐3 M and 3 × 10 ‐3 M choline, 5 × 10 ‐5 M and 10 ‐4 M neostigmine), whereas both agents at higher concentrations (3 × 10 ‐2 M choline, 10 ‐3 M and 10 ‐2 M neostigmine) depressed the uptake. Hemicholinium‐3 (10 ‐3 M), atropine (2 × 10 ‐5 M) and physostigmine (2 × 10 ‐4 M) inhibited decamethonium uptake, indicating that these agents in addition to choline and neostigmine share a common transport mechanism with decamethonium. The initial decamethonium influx (3 minutes incubation) could be stimulated by pre‐incubating the slices (1 hour) with 10 ‐3 M choline or 3 × 10 ‐4 M neostigmine (in the absence of decamethonium) before transfer to a final medium containing only decamethonium. Stimulation can thus be interpreted as an example of accelerative exchange diffusion, which should mean that efflux of choline or neostigmine accumulated by the slices accelerates decamethonium influx. It is concluded that decamethonium uses a specialized transport system, which seems to involve a choline carrier and to be in part at least identical with the system responsible for organic cation secretion by the intact kidney.Keywords:
Decamethonium
Physostigmine
Choline
Physostigmine
Cholinesterase
Avoidance response
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Physostigmine
Stereotypy
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During the past several years, several promising prophylactic treatments for nerve gas poisoning have been developed based on animal models, including pretreatment with the short acting cholinesterase inhibitors, physostigmine and pyridostigmine. In this study, we compared in man the effects of the centrally acting, reversible acetylcholinesterase inhibitor, physostigmine, with the effects of a similar non-centrally active agent, neostigmine. Physostigmine caused dramatically greater increases in behavioral inhibition, tachycardia, and hypertension, greater increases in serum prolactin, ACTH Cortisol, prolactin, and betaendorphin, and more nausea than did neostigmine.
Physostigmine
Cholinesterase
Acetylcholinesterase inhibitor
Pyridostigmine Bromide
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Physostigmine
Acetylcholinesterase inhibitor
Cholinesterase
Avoidance response
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Hemicholinium-3 (HC-3) was administered intraperitoneally to mice concurrently with the intraperitoneal administration of physostigmine or neostigmine. HC-3 increased the LD50 values for both physostigmine and neostigmine but did not alter the effect on brain ACh levels produced by these agents. Since HC-3 does not cross the blood brain barrier after intraperitoneal administration, the antidoting action of HC-3 is peripherally mediated and does not solely involve an inhibition of ACh synthesis. The increase in brain acetylcholine caused by neostigmine was related to a reduction in acetylcholinesterase activity, providing evidence that intraperitoneally administered neostigmine crosses the blood-brain barrier.
Physostigmine
Cholinesterase
Intraperitoneal injection
Acetylcholinesterase inhibitor
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Physostigmine
Parasympatholytics
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The purpose of this study was to determine the effects of two acetylcholinesterase (AChE) inhibitors, physostigmine and neostigmine, on self-stimulation behavior in the rat and to correlate their behavioral effects with total brain acetyicholine (ACh) and AChE. The effects of equimolar doses of physostigmine and neostigmine were compared after s.c. injection. Adult Holtzman male rats were implanted with chronic bipolar electrodes in the hypothalamus for optimal seIf-stimulation behavior. Physostigmine was much more effective than neostigmine in depressing self-stimulation. An increase in brain ACh and a decrease in AChE were obtained after physostigmine, which correlated with behavioral depressant effects. Similar findings were not observed with equimolar doses of neostigmine, indicating that the latter does not penetrate readily into the brain to affect this behavior. Even large doses of neostigmine which depressed self-stimulation did not cause an increase in brain ACh or a lowering of AChE, suggesting that this depression was due to a peripheral mechanism. It is concluded that in rats central cholinergic neuronal systems are involved in inhibiting the self-stimulation of the hypothalamus with an electrical current.
Physostigmine
Cholinesterase
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Abstract The antagonism of tubocurarine and diallylnortoxiferine by neostigmine, physostigmine, edrophonium and ambenonium, has been examined on the rat phrenic nerve diaphragm preparation. Ambenonium showed the greatest activity and physostigmine and edrophonium were the least potent and equally active. This order applied to both neuromuscular blocking agents, but all four antagonists show significantly greater activity against diallylnortoxiferine. The possibility that neostigmine and physostigmine have some qualitative differences in anticurare mechanism compared with edrophonium and ambenonium, on this preparation, is discussed.
Physostigmine
Edrophonium
Cholinesterase
Diaphragm (acoustics)
Phrenic nerve
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Abstract The actions of the anticholinesterase drugs, physostigmine, neostigmine and diisopropylfluorophosphate (DFP) on chick embryonic skeletal muscle in culture were studied. None of the anticholinesterases potentiated depolarization responses to acetylcholine. In high concentrations neostigmine and physostigmine produced depolarization. The neostigmine-induced, but not the physostigmine-induced, depolarization was antagonized by tubocurarine. DFP caused an increase in the rate of repolarization during the presence of a cholinomimetic. It is concluded that the cholinesterase present in cultured muscle fibres does not have a physiological role in hydrolysing acetylcholine and that physostigmine and DFP have an action at the ionic channels that are linked to the cholinoreceptor.
Physostigmine
Cholinesterase
Curare
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The ability of physostigmine alone and in combination with neostigmine to reverse d‐tubocurarine‐induced neuromuscular block was evaluated in surgical patients. The relaxation was maintained at a level of90 % twitch suppression during balanced anaesthesia, and antagonism was attempted with physostigmine 1.5 mgX3; neostigmine 0.5 mgX3; neostigmine 1.0 mgX3; or with a combination of physostigmine 0.75 mg and neostigmine 0.5 mg × 3. The measured parameters included the twitch force or EMG amplitude of the adductor pollicis brevis muscle after supramaximal 0.1 Hz stimulation and fading of these responses after repetitive 2 and 50 Hz stimuli. Although the restitution rate of twitch height and EMG amplitude were essentially the same with both antagonists, there was a considerable time‐lag in regeneration of the fades after repetitive stimuli with physostigmine as compared with the neostigmine group. The addition of physostigmine to a subeffective dose of neostigmine resulted in antagonism comparable to that seen in other groups. The clinical antagonism was satisfactory in all patients receiving physostigmine. The divergence of relaxation‐indicating parameters (twitch responses and fades) after physostigmine suggests dissimilar modes of action of the two antagonists at the neuromuscular junction.
Physostigmine
Neuromuscular transmission
Cholinesterase
Muscle relaxation
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