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Biomedical subjects

G B Frank

Publications and source records attributed to G B Frank.

At least 37 records · Page 2Linked to original sources
PubMed1986

TMB-8 can block twitches without blocking high K+ or caffeine induced contractures in frog's skeletal muscle.

TMB-8 [8-(diethylamino)-octyl-3,4,5-trimethoxybenzoate] is known to inhibit calcium ion dependent processes in several tissues by stabilizing some intracellular stores of membrane-bound calcium. TMB-8 was used to study the excitation-contraction (E-C) coupling process in frog's skeletal muscle. TMB-8 (5 X 10(-5) - 10(-4) M) blocked electrically evoked twitches but not high K+ (123 mM)- or caffeine (2.36 mM)-induced contractures in isolated, curarized toe muscles. TMB-8 (10(-4) M) produced a small decrease (16%) in the action potential of frog's sartorius muscle fibres. However, reducing extracellular Na+ to 44.7 mM produced a similar reduction (17%) in action potential amplitude but did not suppress the twitch; i.e. it produced only a small increase (about 10%) in twitch amplitude. It is known that potassium contractures are produced by extracellular Ca++ ions which enter through calcium channels in the t-tubules and that caffeine produces contractures by sensitizing the sarcoplasmic reticulum to Ca++-induced Ca++ release. The present results suggest that TMB-8 blocks twitches by preventing the release of Ca++ ions bound to the intracellular surface of the t-tubular membrane which is often called the store of 'trigger-calcium' ions.

Action Potentials↗
PubMed1986

Mechanism for the opioid-induced twitch potentiations of frog's skeletal muscle.

The twitch-potentiating effects of opioids in the frog's skeletal muscle which are naloxone resistant and nonstereospecific were further studied. The rapid kinetics of the onset and of the offset (following washout) of the opioid effect indicates that the site for this action is the surface membrane of the muscle fibre. On the other hand, the lack of any twitch-potentiating effect by naloxone methylbromide, a quaternary derivative of naloxone, suggests that opioids which potentiate the twitch must enter the lipid phase of the membrane to act. Intracellular microelectrode experiments revealed no relation between the opioid effects on membrane electrical events and twitch potentiation. Blocking slow calcium channels with D-600 did not modify the opioid-induced twitch potentiation. The twitch potentiation was antagonized by increasing the extracellular calcium concentration, [Ca2+]o, to 8.64 mM. The effects of closely spaced multiple electrical pulses revealed that the opioids decreased the summated response relative to predrug controls. The results suggest that opioids facilitate the process of excitation-contraction coupling in the frog's skeletal muscle by the release of an additional amount of "trigger calcium" following a single electrical stimulus, thereby generating a potentiated twitch.

Animals↗
PubMed1986

A pharmacological explanation of the use-dependency of the verapamil (and D-600) block of slow calcium channels.

Contractures of the toe muscles of frogs produced by 123 mM K+ were reduced or blocked by verapamil (or D-600) when applied in concentrations of 10(-7) M or more. In concentrations between 10(-7) and 3 X 10(-5) M or less, little or no reduction was produced in the first test with high K+ after drug application. When tests were repeated at 10- to 15-min intervals, block was produced. This block decreased and eventually disappeared if the muscles were kept in the drug solution without testing for 25 min or more. In contrast, at 10(-4) M verapamil, the first contracture in response to high K+ was reduced or blocked. If exposure to 10(-4) M verapamil was limited to 0.5 hr, then recovery occurred in drug-free solution, but if the muscles were exposed to this concentration of verapamil for 2.5 hr or longer, the K+ contracture remained blocked, even in drug-free solution. These results provided an explanation for the frequency- and use-dependency effects of verapamil and D-600. Briefly, this explanation is that the drug receptor is inside the calcium channel which is closed to the extracellular fluid in the resting or in the inactivated state but open to the intracellular fluid at all times. The drug receptors will be effectively occupied and a block produced when lower drug concentrations are used if the calcium channels are opened, but verapamil will leave its receptor and diffuse into the intracellular fluid when the extracellular channel openings are closed. Further details of this mechanism are given in the paper.

Animals↗
PubMed1985

Stereospecific opioid drug receptors on excitable cell membranes.

In the past decade evidence has accumulated showing that there are stereospecific opioid drug receptors located on the surface membranes of neurones and skeletal muscle fibres which can block action potentials when opioid drugs are applied to the cells. The nature of this evidence and the difficulties involved in this area of investigation are discussed in detail. Two different mechanisms have been described for this depression of excitability; one, a direct blocking action on sodium channels (or the calcium channels in the case of cells with calcium action potentials) and the other, a stimulation of membrane potassium conductance which results in hyperpolarization and increased membrane conductance both of which decrease excitability. For the most part these different mechanisms seem to prevail in different cell types as will be discussed. Some other points discussed are as follows: first, in higher doses (or concentrations) opioids produce a local anestheticlike effect which cannot be antagonized by opioid antagonists; next, the opioid antagonists which are easily easily available and commonly employed change from antagonists to agonists as their concentration is increased; and finally, the evidence required for the demonstration of stereospecific opioid receptors is considered in some detail.

Action Potentials↗
PubMed1985

Displacement of the surface membrane bound calcium of the skeletal muscle fibers of the frog: effects of lanthanum and opioids.

Three opioids, viz. methadone, morphine and meperidine, were tested separately for their effects on the rate of 45Ca++ efflux from frog toe muscles. The experimental procedures were designed to provide reliable measurements of the displacement of 45Ca++ from surface binding sites using the thin and light toe muscle. La (2 mM) was used to test the ability of the experimental procedure to detect the displacement of calcium bound superficially to the muscle fiber membrane. La not only enhances the rate of efflux of 45Ca++ from surface membrane superficial stores but also inhibits the efflux of intracellular calcium. Of the opioids tested, only methadone (10(-4) or 10(-3) M) caused a slight but significant increase in the rate of 45Ca++ efflux from the surface bound (i.e., the La -displaceable) store of calcium of the muscle. The "calcium-displacement" effect of methadone was much weaker than that seen with La . Morphine (10(-4) or 10(-3) M) or meperidine (10(-4) or 10(-3) M) did not show any such effect on the bound 45Ca++ desaturation rate even under experimental conditions modified to enable the detection of the displacement of even small amounts of 45Ca++ from superficial binding sites on the muscles.

Animals↗
PubMed1984

Blockade of Ca2+ channels inhibits K+ contractures but not twitches in skeletal muscle.

The effects of the voltage-sensitive, calcium channel blocking agents, D-600 and verapamil, on twitches and K+-induced contractures were studied using frog's toe muscles. K+-contracture tension was reduced by concentrations as low as 10(-8) M and the contractures were blocked by 10(-6) M. There was no significant difference in the effects of the two drugs. Twitches were potentiated by 5 X 10(-5) M D-600 and blocked only at 3 X 10(-4) M. The latter concentration also produced contractures in the toe muscles. As shown by other workers, the higher concentration also blocks action potential production and this is probably the way in which it blocks the twitch. Raising the bathing solution Ca2+ concentration from 1.08 to 10 or 20 mM, produced only a small, inconsistent, noncompetitive antagonism of the D-600 block of K+ contractures.

Animals↗
PubMed1984

Naloxone-resistant effects of opioids on the twitch in frog skeletal muscle.

Morphine and several other opioid agonists including the enkephalins caused a dual action on the twitch in the isolated, curarized, and electrically stimulated frog toe muscle; a potentiating action at low drug concentrations and a potentiation followed by an inhibitory action at higher concentrations. The twitch potentiation was found to be nonstereospecific and resistant to antagonism by naloxone. The inhibitory action too was naloxone-resistant and is probably due to a nonspecific local anesthetic effect of the opioids on the electric properties of the frog skeletal muscle fibre membrane.

Animals↗
PubMed1983

Stereospecificity of an opiate action on the excitable membrane of frog skeletal muscle fibres.

Intracellular microelectrode studies were conducted to examine the actions of the optical isomers levorphanol and dextrorphan on the isolated frog sartorius muscle preparation. Both isomers, in bath concentrations which had minimal effect on action potential amplitude and gNa (3 X 10(-5) M), caused a large depression of gK. High bath concentrations (3 X 10(-4) M) of both drugs caused an initial depression of sodium and potassium conductance processes, gNa and gK, respectively, however only levorphanol, but not dextrorphan, could produce a specific, late-occurring depression of gNa that could be blocked by the opiate antagonists, nalorphine or naloxone. These findings indicate that the late-occurring depressant effect on gNa is stereospecific and reinforce previous findings which demonstrated that opiate drugs interact with opiate receptors associated with the sodium channels of the frog muscle fibre membranes.

Action Potentials↗
PubMed1983

Nalorphine: actions at an opiate receptor on frog skeletal muscle fibers.

Intracellular microelectrode studies were conducted to investigate the actions of the partial agonist-antagonist nalorphine at an opiate receptor on functional frog skeletal muscle fiber membranes. In high bath concentrations (greater than or equal to 10(-4) M), nalorphine alone produces agonist actions similar to the "full" opiate agonists. These actions were (i) to depress both the sodium and potassium (gNa and gK) conductance increases due to electrical stimulation by a nonspecific local anestheticlike mechanism and (ii) to depress gNa by a specific opiate receptor mediated mechanism. In a much lower bath concentration (1 X 10(-8) M) nalorphine acts to antagonize the specific opiate receptor mediated depression of gNa produced by the "full" agonist meperidine. Thus in this preparation nalorphine, "the partial antagonist," has the same actions as naloxone, which is often considered to be a full antagonist. The quantitative differences observed in the effects of these two opiate antagonists are discussed.

Action Potentials↗
PubMed1983

Calcium antagonism of an opiate drug effect on an excitable cell membrane.

When frog sartorius muscles are exposed to methadone (2-4 X 10(-4) M) the action potential recorded intracellularly is depressed and eliminated in 3 to 4 hr. This is due to a decrease in the sodium conductance as measured by the maximum rate of rise of the action potential. When the calcium concentration in frog Ringer's solution (normally 1.08 mM) was either lowered to 0.54 mM or raised to 2 mM, the effect of methadone on excitability was unchanged. However, increasing the extracellular calcium to 4 mM decreased the action of methadone. As this would also increase the intracellular calcium concentration, in other experiments the free intracellular Ca+ concentration was raised by adding 0.4 mM caffeine to the Ringer's solution. This also antagonized the depressant action of methadone. The antagonistic action of caffeine was not due to a direct effect of caffeine on sodium conductance because the administration of caffeine by itself caused a 10% depression of the action potential maximum rate of rise and caffeine did not antagonize the action of tetrodotoxin, which is a specific sodium channel blocking agent. Finally, it was shown that the calcium ionophore, A23187, in low concentrations antagonized the depressant actions of methadone and meperidine on action potential production. It was concluded that increasing the intracellular free calcium concentration antagonized the depressant effect on excitability produced by opiate drugs acting on an intracellularly oriented opiate drug receptor.

Action Potentials↗
PubMed1982

Ba2+ ions block K+-induced contractures by antagonizing K+-induced membrane depolarization in frog skeletal muscle fibres.

The effects of Ba2+ ions on twitches, K+-induced contractures, and on intracellularly recorded membrane potentials (Em) and depolarizations of frog skeletal muscle fibres were investigated. Exposure of toe muscles to choline--Ringer's solution with 10(-3) M Ba2+ with Ca2+ (1.08 mM) eliminated or very greatly reduced contractures produced by 60 mM K+. In contrast, not only did the same concentration of Ba2+ ions fail to depress the twitch tension of isolated semitendinosus fibres when added to Ringer's with Ca2+, but it even restored twitches that had been eliminated in a zero Ca2+ Ringer's solution. The resting Em of sartorius muscle fibres in choline--Ringer's solution was reduced about 20 mV by 10(-3) M Ba2+. This Ba2+ ion concentration also antagonized the K+-induced depolarization. Thus in the presence of 1 mM Ba2+, 20 mM K+ hyperpolarized rather than depolarized the fibres and 60 or 123 mM K+ produced only very slowly developing, small depolarizations. These results suggest that the loss of the K+-induced contracture in choline-Ringer's caused by Ba2+ ions is due to an inhibition of the K+-induced depolarization. The latter result is consistent with previous findings of other workers that Ba2+ ions block membrane K+ channels.

Action Potentials↗
PubMed1982

Roles of extracellular and "trigger" calcium ions in excitation--contraction coupling in skeletal muscle.

The experimental observations leading to the development of the "trigger" calcium hypothesis of excitation--contraction (E--C) coupling in skeletal muscle are discussed. Also considered in some detail are the experimental technique problems which interfere with the demonstration of this role for calcium. New findings reported are observations showing that in a zero Ca2+ solution after a delay of about 6--10 min, there is a stimulation of Ca2+ efflux. This is of sufficient size, even in very small toe muscles, to restore the twitch which previously had been reduced in size in the zero Ca2+. In studies with isolated fibre preparations it was demonstrated that depolarization contractures required extracellular Ca2+ ions for E--C coupling whereas twitches could use membrane-bound "trigger" calcium ions. Thus in zero Ca2+ the contractures were eliminated in a few seconds but twitch elimination took a few minutes. Finally, the roles in E--C coupling played by "trigger" and extracellular Ca2+ ions are summarized and discussed.

Animals↗
PubMed1982

The effects of reducing the extracellular calcium concentration on the twitch in isolated frog's skeletal muscle fibres.

When muscle fibres isolated from the frog's semitendinosus are placed in a calcium-free, bicarbonate buffered Ringer's solution the twitch declines in an irregular stepwise fashion and disappears usually within 1 to 9 min. There is often an initial period of twitch potentiation when the fibres are exposed to 0-Ca2+. Although considerably shorter than the time in 0-Ca2+ required to deplete intracellular calcium stores, the time required to eliminate the twitch is longer than estimates of the minimum time required to remove calcium from the fluid in the t-tubular network by free diffusion. When the calcium concentration was only partially reduced the twitch was potentiated at concentrations between 10 and 50% of the usual concentration in Ringer's. At lower calcium concentrations the potentiation is followed by a reduction, and in some fibres the twitch was eliminated without completely removing the calcium ions from the bathing solution. The results support the hypothesis that there is a store of calcium ions bound to the t-tubular membranes ("trigger calcium") which is required for excitation-contraction coupling during the twitch.

Animals↗
PubMed1982

Mg++ antagonism of a prejunctional opiate receptor mediated effect at the frog neuromuscular junction.

The effect of meperidine on the spontaneous release of acetylcholine (mepp amplitude and frequency) and on the release evoked by nerve stimulation (epp amplitude and quantal content) was investigated in frog sciatic nerve-sartorius muscle in vitro. Meperidine (8.5 X 10(-5) or 1.6 X 10(-4)M) had no effect on mepp frequency recorded intracellularly in the absence of neuromuscular blockers, but reduced mepp amplitude. This depression was not antagonized by 3 X 10(-8) M naloxone and was explained by a nonspecific depressant action of meperidine on the endplate. When mepps and epps were recorded intracellularly in the presence of high Mg++, the mean amplitudes of both potentials were reduced equally by meperidine (either 1.6 or 4.2 X 10(-4)M) i.e. there was no change in the quantal content, and 3 X 10(-8)M naloxone failed to antagonize these amplitude depressions. When epps were recorded in the presence of d-tubocurarine, the percentage depression of epp amplitude by meperidine was significantly greater than found in the presence of Mg++ and was partially antagonized by naloxone indicating an opiate receptor mediated effect of meperidine. Thus it was concluded that Mg++ prevents this prejunctional opiate receptor mediated depressant effect of meperidine on the evoked release of acetylcholine.

Acetylcholine↗
PubMed1981

Dual action of meperidine on the frog neuromuscular junction: a prejunctional, opiate receptor-mediated depression of transmitter release and a postjunctional, nonopiate receptor effect on the endplate.

The action of meperidine was investigated on the frog sciatic nerve-sartorius muscle in vitro. Meperidine (5 X 10(-5) M to 2 X 10(-4) M) depressed the twitch response to nerve stimulation but potentiated the response to direct muscle stimulation. When the nerve terminal action potential and the endplate potential (EPP) were recorded simultaneously, the EPP was depressed by meperidine but only a small and variable decrease in the nerve terminal action potential was observed which did not produce the EPP depression. The depression of the EPP was partly antagonized by naloxone (3 X 10(-8) M). Meperidine also depressed the EPP produced by iontophoresis of acetylcholine onto the endplate, but this depression was not antagonized by naloxone. It is concluded that there are two meperidine actions on junctional transmission in this preparation. One, a depression of the prejunctional transmitter release process. This depression is partly, if not completely, opiate receptor-mediated. The second is a depression of the response of the endplate to acetylcholine. The latter effect does not involve a naloxone-sensitive opiate receptor.

Acetylcholine↗
PubMed1980

Candidate mechanisms for inhibition of neurotransmitter release by narcotic analgesics and endorphins.

Some neurones are endowed with receptors for endorphins and narcotic analgesics. Activation of these receptors results in a depression of the release of transmitter per impulse. It is currently believed that narcotic analgesics and endorphins depress the stimulus-induced influx of calcium (Ca2+) into the terminal and thereby modify the amount of the ion which triggers the release of the transmitter from intracellular stores. The influx of Ca2+ is largely governed by the Ca2+ "channel", which opens during depolarization of the neuronal membrane either after an action potential (electrical stimulus) or in the presence of high extracellular potassium (K+) or nicotinic stimulants (chemical stimulus). The evoked influx of Ca2+ can be affected by a direct action on the Ca2+ "channel" or by primary actions on other membrane properties that subsequently regulate the Ca2+ "channel". In many tissues narcotic analgesics and endorphins fail to inhibit transmitter release. This may be accounted for by the possibility that either such neurones lack presynaptic opiate receptors or that the function of existing receptors remains latent under the experimental conditions employed. Currently, there is insufficient evidence for endorphins physiologically modulating transmitter release.

Analgesics, Opioid↗