Influence of Skf‐525a Congeners, Strophanthidin and Tissue‐culture Media on Desensitization in Frog Skeletal Muscle

Terrar, D A

doi:10.1111/j.1476-5381.1974.tb09656.x

Cited by 32 publications

(16 citation statements)

References 20 publications

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“…He showed that in isolated cat muscles, ouabain, applied during the recovery phase after decamethonium-induced depolarization, slowed or prevented the normal recovery of the membrane potential. This effect may be species dependent as, in the frog under similar conditions, strophanthidin was ineffective (Terrar, 1974).…”

Section: Discussionmentioning

confidence: 99%

Labelled Decamethonium in Cat Muscle

Creese

Maclagan

1976

British J Pharmacology

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I Tritium-labelled decamethonium was infused intravenously in 12 cats at final rates of 1.3-4.2 nmol kg-' min-' to produce a steady plasma concentration which ranged between 0.21-1.3 gimol/l in different experiments. Muscle contractions were elicited by nerve stimulation and the potential at the end-plate regions of superficial fibres was recorded by extracellular electrodes. 2 Under these conditions, it was not possible to obtain a steady degree of neuromuscular block. The initial decrease in muscle contractions was followed by recovery towards the original value although the concentration of decamethonium in the plasma remained constant, or in some cases rose. The initial depolarization of the end-plate region also waned during the constant infusion of the drug. 3 Once the twitch tension had returned to control values during infusion of the drug, prolongation of the infusion for a total of four hours did not produce a secondary neuromuscular block. 4 Scintillation counting showed that during infusion oflabelled decamethonium the radioactivity ofthe muscles increased progressively with time. The uptake was less in the soleus muscle than in the fastcontracting flexor longus digitorum and extensor longus digitorum muscles. Muscles which had been denervated 12-13 days previously showed a greater uptake of labelled drug than control muscles from the contralateral limb. 5The labelled drug was localized by autoradiography of frozen sections of leg muscles following intra-arterial injection of decamethonium. Grain counts in individual fibres showed that small amounts of decamethonium had entered the muscle fibres along their entire length, and there was increased uptake of the drug into the cell in the region of the end-plate. 6 The mechanisms underlying the waning of the pharmacological response during constant application of depolarizing drugs are discussed.

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Section: Discussionmentioning

confidence: 99%

Labelled Decamethonium in Cat Muscle

Creese

Maclagan

1976

British J Pharmacology

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“…Either carbachol has a weak intrinsic blocking action which is greatly potentiated by quinacrine, or quinacrine has a depressant effect which is potentiated by agonist application. More specifically, quinacrine might potentiate desensitization (Rang & Ritter, 1970a;Magazanik & Vyskocil, 1973;Terrar, 1974) or it might be acting like barbiturates (Adams, 1976) and local anaesthetics (Adams, 1977;Neher & Steinbach, 1978;Ascher, Marty & Neild, 1978) BITS+ll/Tr = f*q+b*+a+fi,…”

Section: Resultsmentioning

confidence: 99%

“…Perhaps the best controlled of these studies was that of Terrar (1974), who found that several of the desensitization enhancing drugs tested by Magazanik (1971) greatly increased the rate of repolarization of frog end-plates perfused with low carbachol concentrations. Rather similar effects can be seen in Fig.…”

Section: Quinacrine and Desensitizationmentioning

confidence: 99%

“…Possibly this happens because the agonist concentration is changing in both space and time throughout the responses, which would invalidate the comparison between the sag and the relaxation. Relaxation time constants have not been determined yet for the compounds tested by Terrar (1974), but it is possible that they bind so tightly to the open channel that the time course of repolarization reflects the time course of channel block. Interestingly, the effect of agonist concentration on the repolarization time constant in Terrar's Fig.…”

Section: Quinacrine and Desensitizationmentioning

confidence: 99%

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Quinacrine (mepacrine) action at frog end‐plate.

Adams¹,

Feltz²

1980

The Journal of Physiology

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3. The depressant effect of quinacrine on ionophoretic responses to carbachol or acetylcholine is increased in acid solutions and decreased in alkaline solutions, suggesting that quinacrine is active as an acridinium ion.4. Quinacrine (2-10 /tM) causes a use-dependent block of end-plate channels which manifests as an inhibitory effect of an ionophoretic prepulse on the response to a test pulse. The inhibitory interaction decays exponentially with a time constant 8r that depends on the nature of the agonist used for the prepulse, on the quinacrine concentration, and on the membrane potential.5. Quinacrine (5-20 /tM) reduces the amplitude of e.p.c.s. and m.e.p.c.s. It also increases the rate of decay of the e.p.c. or m.e.p.c. tails, which remain exponential. The decay rate constant 1r/Tf increases linearly with quinacrine concentration both in the presence and absence of 3 /LM-neostigmine. The slope of this linear relation increases slightly with membrane hyperpolarization.6. These data suggest that quinacrine's main action is a slow, voltage dependent blockade of open end-plate channels, though there are probably additional effects on acetylcholinesterase and channel opening. In accordance with the open channel blocking model, 1/,r and l/r both increase linearly with quinacrine concentration. However the slopes of these lines lead to rather different estimates of the forward blocking rate constant (8 x 107 and 4 x 108 M-1 s-1 respectively).7. The unblocking rate constant is about 5 s-1 at --80 mV. It is much more voltage dependent than the forward rate constant.

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“…During prolonged application of ACh the end-plate current will often decrease over a period of seconds to minutes as the post-synaptic receptors enter a desensitized state and no longer respond to ACh (Fatt, 1950;Thesleff, 1955;Katz & Thesleff, 1957). If the agonist is removed the receptors then recover normal ACh sensitivity within seconds to minutes (Katz & Thesleff, 1957;Terrar, 1974;Scubon-Mulieri & Parsons, 1977).…”

Section: Introductionmentioning

confidence: 99%

A study of desensitization of acetylcholine receptors using nerve‐released transmitter in the frog

Magleby

Pallotta

1981

The Journal of Physiology

164

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SUMMARY1. Desensitization of acetylcholine (ACh) receptors was studied at the frog neuromuscular junction under voltage clamp.2. ACh was applied directly to junctional receptors by stimulating the motor nerve with trains of impulses. End-plate currents (e.p.c.s) were used to estimate the total number of channel openings by the junctional ACh receptors, and miniature end-plate currents (m.e.p.c.s) were used to measure changes in post-synaptic sensitivity. Under the conditions of these experiments the changes in m.e.p.c. amplitudes were shown to be post-synaptic in origin and thus provided a measure of desensitization.3. When the acetylcholinesterase was inhibited with diisopropylfluorophosphate, neostigmine, or collagenase treatment to prolong the duration of the nerve-released ACh in the synaptic cleft, desensitization developed during repetitive stimulation of 1000 impulses at 5-33 impulses/sec and then recovered after the conditioning trains, with a time constant of about 25 sec.4. When the acetylcholinesterase was active so that the duration of ACh in the synaptic cleft resulting from each nerve impulse was brief( < 300 gsec), desensitization developed in response to 300-500 pairs of nerve stimuli if the interval between the impulses of each pair was 25 msec or less. When the interval was 30 msec or greater, however, measurable desensitization did not occur, even if the total number of channel openings was many times greater than in the experiments with shorter intervals or inhibited esterase where desensitization readily occurred.5. The desensitization observed to pairs of impulses was enhanced by chlorpromazine and decreased when the post-synaptic membrane was depolarized, properties similar to those described previously for desensitization to bath and ionophoretic application of ACh.6. These results indicate that desensitization to nerve-released transmitter is not a simple consequence of receptor activation, is not due to blockade of the open receptor channels by ACh, and does not result from ACh binding directly to desensitized receptors with a resulting shift in the receptor population towards the desensitized state.7. We suggest that the desensitization observed to nerve-released transmitter is a two-step process with both steps initiated by ACh. In the first step ACh converts some receptors into a desensitizable state which has an apparent lifetime of less than 30 msec; in the second step ACh desensitizes the desensitizable state. pmY 316 K. L. MAGLEBY AND B. S. PALLOTTA

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Influence of Skf‐525a Congeners, Strophanthidin and Tissue‐culture Media on Desensitization in Frog Skeletal Muscle

Cited by 32 publications

References 20 publications

Labelled Decamethonium in Cat Muscle

Labelled Decamethonium in Cat Muscle

Quinacrine (mepacrine) action at frog end‐plate.

A study of desensitization of acetylcholine receptors using nerve‐released transmitter in the frog

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