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Biomedical subjects

G B Frank

Publications and source records attributed to G B Frank.

At least 19 recordsLinked to original sources
PubMed1994

The effects of verapamil on tetanic contractions of frog's skeletal muscle.

The effects of the organic calcium channel antagonist, verapamil, were tested on twitches and tetanic contractions (100 Hz, 2 sec) in frog toe muscles. At low concentrations (3 x 10(-6) M), verapamil had no effect on the maximum amplitudes of twitches, but significantly reduced the size of the tetanic responses. This depression was observed as an inability to maintain the maximum tetanic tension for more than 0.5 sec. With increasing concentrations up to 10(-4) M of verapamil, its depressant effect on tetanic responses gradually increased, and at very high concentrations (10(-4) M) of verapamil, twitches were also blocked. Intracellular microelectrode recordings showed that there was no block of the action potentials during the stimulus train at the concentration of 3 x 10(-6) M of verapamil. These results support the concept that during tetanic responses, the voltage sensitive Ca2+ channels in the t-tubules open and the Ca2+ ions entering via these channels are required to maintain the full strength of the contraction. At higher concentrations, verapamil blocked Na+ action potentials during the stimulus trains in a concentration and use-dependent manner.

Action Potentials↗
PubMed1994

Effect of the calcium channel agonist Bay K8644 on mechanical and electrical responses of frog skeletal muscle.

The effects of Bay K8644, a Ca2+ channel agonist, on the mechanical and electrical properties of frog skeletal muscle fibers were investigated. At relatively low concentrations, such as 10(-6) and 10(-5) M, Bay K8644 significantly potentiated the maximum amplitudes of twitch responses, and this effect was not reversed in the presence of the calcium channel antagonist nitrendipine. At higher concentrations, such as 10(-4) M, Bay K8644 depressed the amplitudes of twitch responses, and nitrendipine did not change this effect. At all concentrations, Bay K8644 greatly reduced the area under the tetanic force versus time curve, and this effect was not modified by the concomitant application of Bay K8644 and nitrendipine. Intracellular recordings revealed that the depressing effect of Bay K8644 on tetanic contractions was due to the blockade of sodium action potentials. In conclusion, the present results suggest that the modulation of twitch responses by calcium channel agonist and antagonists, at the concentration range used, is not related to the expected modulation of voltage-sensitive slow calcium channels in frog skeletal muscle fibers, and tetanic contractions are depressed by the calcium channel agonist Bay K8644 through its effect on sodium channels.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1991

Decrease in the size of tetanic responses produced by nitrendipine or by extracellular calcium ion removal without blocking twitches or action potentials in skeletal muscle.

The effects of removing extracellular Ca++ ions or of adding the organic calcium channel antagonist, nitrendipine, were tested on twitches and tetani (100 Hz for 2 sec) in frog toe muscles. Under conditions that did not reduce or that potentiated twitches, both procedures reduced the size of the tetanic responses. This depression was seen as an inability to maintain the maximum tetanic tension for more than 0.5 sec. Intracellular microelectrode recordings showed that the muscle fibers were depolarized (mean about 23 mV) during the stimulus train and the fiber only slowly repolarized after the train. The latter effect is the "late negative afterpotential" and it is produced by the accumulation of K+ ions in the t-tubules during the action potential train. Neither the depolarization nor the late negative afterpotentials were decreased in amplitude by nitrendipine. These results indicate that the voltage-sensitive, slow Ca++ channels are opened by the accumulation of K+ ions in the t-tubules during the tetanus and that the Ca++ ions entering via these channels are required to maintain the full strength of the tetanic contraction. It is suggested that this is a function of these Ca++ channels concentrated in the t-tubules of skeletal muscle fibers.

Action Potentials↗
PubMed1990

Dihydropyridine calcium channel antagonists block and agonists potentiate high potassium contractures but not twitches in frog skeletal muscle.

The effects of two dihydropyridine calcium channel antagonists (nitrendipine and nifedipine) and two agonists (Bay K8644 and CGP-28392) were tested on high K(+)-induced contractures of frog's toe muscles. All four drugs depressed or blocked maximum contractures induced by 123 mM K+. Agonist effects, i.e., an increase in contracture amplitude, were found with smaller contractures produced by lower high K+ concentrations (i.e., 10, 20, and 25 mM). Bay K8644 produced its maximum agonist effect at 10(-7) M and only depressed contractures with 10(-6) M. CGP-28392 had its greatest agonist effect with 10(-9) M and had only antagonist effects with 10(-7) M or more. Nitrendipine had no agonist effects but nifedipine produced agonist effects with all concentrations tested (10(-9) to 10(-4) M). These results support previous results indicating that these contractures are initiated by extracellular Ca2+ ions entering via the voltage-sensitive, slow calcium channels in the t-tubules. The results obtained in the present study also are consistent with the known pharmacological effects of these drugs on calcium channels.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1989

Blockade of K+ contractures in skeletal muscle by opioid drugs: a nonstereospecific effect.

The effect of several opioid drugs was tested on the K+ contractures in frog's skeletal muscle. These contractures are produced by the entrance of extracellular Ca2+ ions via the voltage-dependent, slow Ca2+ channels located in the T tubules. Morphine and other opioid agonists in concentrations ranging from 10(-10) to 10(-5) M inhibited K+ contractures. The stereoisomers, dextrorphan and levorphanol, were found to have identical potency in inhibiting high K+ contractures, suggesting that this was a nonstereospecific blockade of voltage-dependent calcium channels by the opioid drugs despite the low effective drug concentrations. In agreement with this conclusion it was found that the inhibition of K+ contractures by the opioids was not antagonized by naloxone. It also was observed using a sucrose gap apparatus that these opioid drugs in concentrations used to block the high K+ contractures did not reduce the K+-induced membrane depolarization. Raising the bathing solution Ca2+ concentration from 1.08 to 5 mM produced a reversal of the opioid-induced block of K+ contractures. Finally it was shown that while opioids completely blocked K+ contractures, they did not produce any effect on caffeine contractures showing that opioids do not deplete intracellular Ca2+ stores or inhibit the release of Ca2+ from intracellular sarcoplasmic reticulum stores. It was concluded that several opioid drugs in very low concentrations block K+ contractures in frog's skeletal muscle by a nonstereospecific block of voltage-dependent slow calcium channels.

Animals↗
PubMed1989

Opioid effects of racemic ketamine on the excitability of sciatic nerve and skeletal muscle fibers of the frog.

The effects of +/- ketamine were tested on the excitability of frog sciatic nerves using a sucrose gap apparatus and skeletal muscle fibers using intracellular microelectrodes. When applied extracellularly by perfusion, ketamine depressed the action potential of sciatic nerves in a dose-dependent manner. This depression was partially antagonized by the simultaneous treatment with a small concentration of naloxone. However, when the ketamine was applied intracellularly by placing it in a compartment with a cut end of the nerve, only very small and inconsistent decreases were produced. Ketamine also blocked excitability in skeletal muscle by depressing the sodium conductance (gNa). This also could be partly antagonized by the addition of a small concentration of naloxone to the solution bathing the muscle. These results support previous findings by other workers that ketamine has a stereospecific opioid agonist effect in addition to its other actions.

Action Potentials↗
PubMed1988

Nitrendipine blocks high potassium contractures but not twitches in rat skeletal muscle.

The effects of the organic calcium channel blocker nitrendipine was tested on electrically evoked twitches and on potassium depolarization-induced contractures of rat lumbricalis muscles. Nitrendipine (10(-7) to 5 X 10(-5) M) blocked only the potassium contractures. It was concluded that blocking calcium uptake through the slow voltage-sensitive calcium channels during potassium depolarization blocks the mechanical response of the muscle. Thus extracellular calcium ions are required for the excitation-contraction (E-C) coupling during depolarization contractures. On the other hand, electrically evoked twitches were not affected by nitrendipine; therefore, extracellular calcium ions entering via the slow voltage-sensitive channels are not required for E-C coupling during the twitch.

Animals↗
PubMed1987

Effects of enkephalin, applied intracellularly, on action potentials in vertebrate A and C nerve fibre axons.

The effects of leucine enkephalin and D-Ala2, Met5 enkephalinamide (DAMA) were tested on the excitability of sciatic nerves in the frog and guinea-pig and vagus nerves in the guinea pig and rabbit. Both enkephalins depressed the amplitude of the compound action potential of A and C fibres. This depression was blocked by small concentrations of naloxone. In the type of experiment carried out, the drugs were added to the cut end of the nerve and the drugs had to reach their site of action in the central bath by diffusion through the axoplasm. This method of application of drug was necessary because enkephalins had no effect on the action potential when applied extracellularly by perfusion. These results demonstrate the presence of stereospecific opioid receptors located on the inner surface of the cell membranes of peripheral vertebrate nerve axons, sensitive to block by some endogenous opioid peptides. A possible physiological role for these intracellular receptors is suggested.

Action Potentials↗
PubMed1987

Pharmacological studies of excitation-contraction coupling in skeletal muscle.

The use of drugs in the study of excitation-contraction (E-C) coupling in skeletal muscle during the 25-30 years and the role of these studies in the development of the "trigger-calcium" hypothesis was reviewed. In early studies, caffeine was used as a tool to test the function of the intracellular contraction apparatus when the twitch or depolarization contracture was eliminated by a procedure that was thought to block the coupling part of the E-C coupling process. Later it was shown that caffeine produced contractures by releasing Ca2+ ions from intracellular binding sites and then that caffeine produced this effect by sensitizing the sarcoplasmic reticulum to Ca2+-induced Ca2+ release. More recently, organic calcium channel blocking drugs (verapamil, D-600, and nitrendipine) were used to confirm earlier results showing that depolarization contractures but not twitches require the entrance into the cells via the slow Ca2+ channels of extracellular calcium ions for E-C coupling. Most recently, we have investigated the effects of TMB-8 (8-(diethylamino)-octyl-3,4,5-trimethoxybenzoate) on E-C coupling in frog skeletal muscle. This compound was shown by other workers to act in several tissues by stabilizing Ca2+ bound at intracellular sites. It was found that at the appropriate concentration TMB-8 blocked twitches but neither high K+ nor caffeine induced contractures. These results suggest that TMB-8 blocks twitches by preventing the release of Ca2+ ions bound to the intracellular surface of the t-tubular membrane, which is often called the store of "trigger-calcium" ions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
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↗