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Biomedical subjects

M J Su

Publications and source records attributed to M J Su.

At least 73 records · Page 4Linked to original sources
PubMed1986

A comparison of the antagonisms by neostigmine and diaminopyridine against the neuromuscular block caused by cobrotoxin and (+)-tubocurarine.

Cobrotoxin was about 11-fold more potent than (+)-tubocurarine on a weight basis in blocking neuromuscular transmission in mouse isolated phrenic nerve-diaphragm preparations. Neostigmine and diaminopyridine increased the concentrations of cobrotoxin for 70% inhibition of indirect contraction by 290 and 320%, and increased those of (+)-tubocurarine by 180 and 230%, respectively. More than additive increases were obtained when neostigmine and diaminopyridine were used simultaneously. Cobrotoxin, however, was only 6-fold more toxic than (+)-tubocurarine after intraperitoneal injection in mice. The lethal dose of (+)-tubocurarine was increased by 80% when both antidotes were used together, but only by 15-20% when used alone. In contrast, the lethality of cobrotoxin was not decreased by these drugs. Unexpectedly, the time to death after treatment with cobrotoxin was shortened when mice were pretreated with these antidotes.

4-Aminopyridine↗
PubMed1985

Acetylcholine hydrolysis during neuromuscular transmission in the synaptic cleft of skeletal muscle of mouse and chick.

Inhibition of acetylcholinesterase (AChE) by more than 80% by neostigmine or physostigmine resulted in a failure of tetanic contraction (100 Hz) in the isolated mouse nerve-diaphragm preparation. In the chick biventer cervicis muscle, however, the tetanic contraction was well maintained and even outlasted the period of nerve stimulation after inactivation of AChE. The concentration of (+)tubocurarine for 70% block of the indirect twitch response of the mouse diaphragm at 0.1 Hz was increased from 0.67 to 0.99 to 1.21-2.03 microM in the presence of neostigmine (0.15-1.5 microM) which inhibited AChE by 70% or more, while that to depress the tetanic contraction (50 Hz) was increased from 0.38 to 0.42 to 0.53-0.69 microM. In the chick muscle, physostigmine at 2.4 microM increased the concentration of (+)tubocurarine for 70% block of the twitch response from 1.68 to 4.14 microM, whereas that for block of the response to exogenous acetylcholine (ACh) was increased from 1.47 to 74.6 microM. On single stimulation, the relative peak concentrations of acetylcholine (ACh) at the postsynaptic receptor site of the mouse diaphragm and chick biventer cervicis were estimated to be increased by about 110 and 120% respectively, after complete inhibition of AChE. In the chick muscle, physostigmine increased the relative concentration of ACh by about 40-fold at the receptor site for exogenously applied ACh. It is concluded that the intrinsic ACh released from the nerve terminal is hydrolyzed by about 50% during the time of diffusion across the synaptic cleft whereas most of exogenous ACh is hydrolyzed before reaching the target.

Acetylcholine↗
PubMed1984

Presynaptic effects of snake venom toxins which have phospholipase A2 activity (beta-bungarotoxin, taipoxin, crotoxin).

The presynaptic effects of beta-bungarotoxin, crotoxin and taipoxin were studied in the mouse phrenic nerve-diaphragm preparation (27 degrees C). The phospholipase A2 activity, assayed by pH-stat titration, was reduced to 4-10% at 27 degrees C compared with that at 37 degrees C. The late neuromuscular blocking activity was also reduced by more than three fold for all toxins. In contrast, the early biphasic response to the toxins, i.e. immediate depression followed by facilitation, was not delayed. The evoked quantal release of acetylcholine was enhanced by all toxins at low Ca2+-concentrations during the phase of facilitation, without an increase of the maximal release. At the late phase of treatment with beta-bungarotoxin and taipoxin, the curve relating the quantal contents of endplate potentials with Ca2+-concentration was shifted parallel to the right at low Ca2+, but marked depression of the maximal release occurred at high Ca2+. When diaminopyridine was added at the time of the late phase block by beta-bungarotoxin, the quantal release could still be enhanced at low Ca2+-concentrations, even beyond control; however, the maximal release was not simultaneously restored. It is concluded that the late phase block, but not the early biphasic response, is due to an enzymatic action and the release mechanism is abolished when the hydrolysis of membrane phospholipids proceeds to a certain critical level.

Acetylcholine↗
PubMed1984

Potentiation between neostigmine and 3,4-diaminopyridine in antagonizing the neuromuscular block induced by D-tubocurarine.

The antagonisms to the d-tubocurarine-induced neuromuscular blockade by neostigmine and 3,4-diaminopyridine (DAP) were studied quantitatively in the isolated phrenic nerve-diaphragm preparation of mice in vitro and in lethality of mice in vivo by assaying concentrations of d-tubocurarine needed to produce 70% block of indirect muscle contraction and LD50, respectively. The "antagonist efficacies", defined as the ratio of d-tubocurarine concentration (dose) after pretreatment with antagonistic agents over that of control, were 1.87, 2.24 and 14.7, respectively, for neostigmine, DAP and both agents combined when the stimulus pulses were at 0.1 Hz. Under 50 Hz train stimulation, the antagonist efficacies were lower, being 1.85, 1.64 and 5.33, respectively. For the lethality to d-tubocurarine, the values were still lower, being only 1.21, 1.33 and 1.84, respectively. The synergism between neostigmine and DAP, as evident from the marked increase of antagonist efficacy in vitro, is more than expected from the possible interaction of the major pharmacological actions of these two agents.

4-Aminopyridine↗
PubMed1983

A study on the membrane depolarization of skeletal muscles caused by a scorpion toxin, sea anemone toxin II and crotamine and the interaction between toxins.

Quinquestriatus toxin (QTX) isolated from the venom of a scorpion (Leiurus quinquestriatus) and sea anemone (Anemonia sulcata) toxin II enhanced the twitch response of the rat and mouse diaphragms and like crotamine (isolated from the venom of Crotalus durissus terrificus) caused spontaneous fasciculation of the muscle. Trains of action potentials in muscles at 70-250 Hz, which could not be antagonized by (+)-tubocurarine, were triggered by single stimulation or occurred spontaneously after treatment with these toxins. QTX and toxin II prolonged the rat muscle action potential 3 to 4 fold whereas crotamine prolonged the action potential by only 30%. The membrane potential was depolarized from about -82 mV to -55 mV by crotamine 2 micrograms ml-1, -41 mV by toxin II 5 micrograms ml-1 and to -50 mV by QTX 1 microgram ml-1. The concentrations to induce 50% maximal depolarization (K0.5) were 0.07, 0.15 and greater than 0.4 microgram ml-1, respectively, for QTX, crotamine and toxin II, whereas the rates of depolarization were in the order toxin II greater than or equal to crotamine greater than QTX. The depolarizing effects of crotamine and QTX, but not of toxin II, were saturable. The depolarizing effects of all three toxins were irreversible whereas the membrane potential could be restored by tetrodotoxin non-competitively. Simultaneous treatment with crotamine and QTX or crotamine and toxin II at concentrations below K0.5 caused only additive effects on depolarization. When the muscle was depolarized by pretreating with a saturating concentration of crotamine, the onset of depolarization by QTX was greatly retarded whereas that by toxin II was unaffected. Action potentials were further prolonged in both cases. 8 It is inferred that all three peptide toxins act at sites on the sodium channel and the binding sites for QTX and crotamine overlap to a considerable extent. On the other hand, the site for toxin II appears not to overlap with that of crotamine but may overlap with that of QTX.

Animals↗
PubMed1982

Presynaptic toxicity of the histidine-modified, phospholipase A2-inactive, beta-bungarotoxin, crotoxin and notexin.

Beta-Bungarotoxin, crotoxin and notexin were treated extensively with p-bromophenacyl bromide in order to modify the histidine group of the active site and to greatly decrease the phospholipase A2(PLA) catalytic activity. They were studied for their residual presynaptic effects on the mouse isolated phrenic nerve-diaphragm and chick biventer cervicis muscle preparations. The modified toxins still had 1.7-5.2% PLA activity, which was inhibited by Sr2+, as is the enzyme activity of the native toxins. The neuromuscular blocking activity of these modified toxins, which was reduced 30-60 fold in the mouse diaphragm, was due to a presynaptic effect, as judged from the unchanged amplitude of m.e.p.p.s in the blocked preparations. In contrast to the native toxins, however, the presynaptic effect of modified beta-bungarotoxin and notexin was neither antagonized by Sr2+ nor accelerated by increasing the rate of nerve stimulation, indicating that the presynaptic effects of the modified beta-bungarotoxin and notexin are not likely to be due to their PLA enzyme activity. The modified toxins retained a much greater fraction of their early presynaptic effects in comparison to their enzymatic and neuromuscular blocking activities, although the time-course of the early effects was delayed. The results indicate that the modified neurotoxins per se have their own presynaptic effects, which are unrelated to the PLA enzyme activities.

Acetophenones↗
PubMed1981

A study on the interaction of crotapotin with crotoxin phospholipase A2, notexin and other presynaptic neurotoxins.

1 Crotapotin, the acidic subunit of crotoxin, greatly potentiated the presynaptic effect of isolated basic phospholipase A (PLA) of crotoxin in both mouse diaphragm and chick biventer cervicis muscles whereas the myotoxic effect was not affected significantly.2 In contrast to crotoxin PLA, the presynaptic effects of notexin and notechis-5, self-active single chain toxins, were antagonized by crotapotin while actions of beta-bungarotoxin were not affected.3 By assaying PLA activity, crotoxin PLA was found to be unstable in physiological salt solution, especially when in contact with muscle, due to massive non-specific binding to and destruction by the muscle.4 The decline of crotoxin PLA was greatly reduced by the presence of crotapotin but not by another acidic protein, volvatoxin A(2), or heparin.5 Notechis-5 was found to be stable even when in the presence of muscles.6 [(3)H]-acetylated crotoxin PLA, which retained about 40% of its original enzyme and presynaptic blocking activities, also bound rapidly to the mouse diaphragm on incubation and this binding was greatly hindered by the simultaneous addition of crotapotin.7 The prevention of binding of crotoxin PLA by crotapotin occurred mostly at those sites where the binding was easily dissociable on washing. No antagonism of binding occurred at the firmly binding site.8 The binding of [(3)H]-acetylated crotapotin was much less than that of crotoxin PLA, and interestingly, the binding was increased by the latter, suggesting that crotapotin may be first bound to the diaphragm together with crotoxin PLA.9 No specific binding at the endplate zone was found either for crotoxin PLA or for crotapotin.10 It is concluded that crotapotin potentiates the presynaptic effect of crotoxin PLA by curtailing its non-specific affinity with muscles, minimizing its dispersal and destruction en route to the nerve terminal, but not by acting as an affinity probe for the nerve terminal.

Animals↗
PubMed1977

Effects of Sr2+ and Mg2+ on the phospholipase A and the presynaptic neuromuscular blocking actions of beta-bungarotoxin, crotoxin and taipoxin.

1.beta-Bungarotoxin, crotoxin and taipoxin, presynaptic neurotoxins of snake venom origin, have about the same phospholipid-splitting activities as a much less toxic cobra phospholipase A2 in the presence of Ca2+ and deoxycholate. 2. Sr2+ was a much less effective activator of the enzymes than is Ca2+, the activation by Sr2+ being only 3-6% for beta-bungarotoxin and crotoxin and 12% for taipoxin. 3. Sr2+ also inhibited the Ca2+ -activated enzymes by 80% in the cases of beta-bungarotoxin and crotoxin, but only 16% in the case of taipoxin. 4. Mg2" had no significant effect on beta-bungarotoxin or crotoxin, but activated taipoxin in the presence or absence of Ca2". 5. In Sr2+ -Tyrode lacking Ca2+ all three toxins exhibited the same immediate depression followed by facilitation in the rat and mouse diaphragms, but the final blocking activity was only 3-10% with beta-bungarotoxin and crotoxin and was 30% with taipoxin. 6. In Sr2+ -Tyrode, increasing in the rate of nerve stimulation had less accelerating effect on the development of neuromuscular block than in Ca2+ -Tyrode for any of the toxins. 7. Removal of Mg2+ from Sr2+ -Tyrode did not diminish the potency of taipoxin in blocking neuromuscular transmission, suggesting that enzyme activity at the outer surface of the axolemma does not contribute to the neuromuscular blocking action. 8. All of the results indicate that there are close correlations between the presynaptic activities of these toxins and their phospholipid-splitting activities in the cationic environment prevailing in the axoplasm. Apparently the final blocking effect of these toxins is due to phospholipase A action within the nerve terminal.

Animals↗
PubMed1976

An analysis of the mode of action of carbachol on the chick biventer cervicis nerve--muscle preparation.

The mechanism of contracture evoked by carbachol in the isolated chick biventer cervicis nerve--muscle preparation was studied. At concentrations lower than 11 muM, carbachol progressively induced contracture at a rate much slower than did acetylcholine. A spontaneous increase of the response to carbachol, but not to acetylcholine, was observed 2-4 hr after isolation of the muscle. By contrast, no change of the response occurred in the denervated muscle. Anticholinesterase treatment shifted the dose-response curve for carbachol markedly to the left as far as the contracture attained after 4-6 min incubation was concerned. The shift was much less marked for the dose-response curve plotted against the initial rate of response defined as the contracture obtained after 1 min incubation. No enhancement of response was detected by inhibition of acetylcholinesterase in the denervated muscle. beta-Bungarotoxin which blocked neuromuscular transmission within 30 min, caused a transient enhancement of the response to carbachol. After 2-3 hr treatment, however, the spontaneous increase of response to carbachol was counteracted by the toxin. No potentiation of the response by anticholinesterase agents was observed after toxin treatment. When added in the presence of physostigmine or echothiophate, beta-bungarotoxin reduced the response to carbachol to the control level in 2 hr. The response to carbachol in the muscle treated with alpha-bungarotoxin and washed subsequently was also not potentiated by anticholinesterase treatment. Repetitive nerve stimulation in the presence of hemicholinium-3 caused a neuromuscular blockade but did not appreciably antagonize the response to carbachol more than that to acetylcholine either in the absence or presence of physotigmine. When calcium ion in the medium was decreased from 2.7 to 0.54 mM, ther response to nerve stimulation was nearly completely inhibited, but the response to carbachol was not affected and could still be potentiated by anticholinesterase. It is concluded that carbachol has both direct and indirect effects on the chick biventer cervicis muscle. At a low concentration, particularly in the presence of an anticholinesterase and if sufficient time of incubation is allowed, the indirect effect caused by release of acetylcholine may become more prominent than the direct action on the post-synaptic receptor. Both the mechanism and the store of acetylcholine for this indirect action appear to be different from those for the nerve impulse.

Acetylcholine↗
PubMedDate not supplied

Ionic mechanisms for the antiarrhythmic action of cinnamophilin in rat heart.

We investigated the electrophysiological effect and antiarrhythmic potential of cinnamophilin (Cinn), a thromboxane A(2) antagonist isolated from Cinnamomum philippinense, on rat cardiac tissues. Action potential and ionic currents in single rat ventricular cells were examined by current clamp or voltage clamp in a whole-cell configuration. In 9 episodes of ischemia-reperfusion arrhythmia, 10 microM Cinn converted 6 of them to normal sinus rhythm. Cinn suppressed the maximal rate of rise of the action potential upstroke (V(max)) and prolonged the action potential duration at 50% repolarization (APD(50)). Voltage clamp study showed that the suppression of V(max) by Cinn was associated with an inhibition of sodium inward current (I(Na), IC(50) = 10.0 +/- 0.4 microM). At 30 microM, V(1/2) for the steady-state inactivation curve of I(Na) was shifted from -84.1 +/- 0.2 to -93.0 +/- 0.5 mV. Cinn also reduced calcium inward current (I(Ca)) dose-dependently with an IC(50) value of 9.5 +/- 0.3 microM. Cinn (10 microM) reduced the I(Ca) with a negative shift of V(1/2) for the steady-state inactivation curve of I(Ca) from -32.2 +/- 0.3 to -50.7 +/- 0.4 mV. The prolongation of APD(50) was associated with an inhibition of the integral of potassium outward current with IC(50) values between 4.8 and 7.1 microM. At 10 microM, Cinn reduced I(Na) without a negative shift of its voltage-dependent steady-state inactivation curves. The inhibition of transient outward current (I(to)) by Cinn (3-30 microM) was associated with an acceleration of its time constant of inactivation and negative shift of its potential-dependent steady-state inactivation curves. The equilibrium dissociation constant (K(d)) of Cinn to inhibit open state I(to) channels, as calculated from the time constant of developing block, was 18.3 microM. The time constant of recovery of I(to) from inactivation state was unaffected by Cinn. The rate constant for the relief from the depolarization-dependent block of I(to) was calculated to be 23. 9 ms. As compared with its effect on I(to), Cinn exerted about half the potency to block I(Na) and I(Ca). These results indicate that the inhibition of I(Na), I(Ca) and I(to) may contribute to the antiarrhythmic activity of Cinn against ischemia-reperfusion arrhythmia.

Action Potentials↗
PubMedDate not supplied

Positive inotropic action of NMDA receptor antagonist (+)-MK801 in rat heart.

(+)-MK801, a noncompetitive NMDA receptor antagonist, was reported to exhibit anticonvulsive and neuroprotective activities during the postischemic period. Intravenous administration of (+)-MK801 produced tachycardia in rats, but bradycardia in pigs. We examined the mechanical and electrophysiological effects of (+)-MK801 on rat cardiac tissues. (+)-MK801 dose-dependently increased (3-100 microM) twitch tension in rat atria and ventricular strips. The spontaneous beating rate in rat right atria, however, was dose-dependently decreased by (+)-MK801. The inotropic effect of (+)-MK801 was affected neither by alpha(1)-antagonist (1 microM prazosin) nor by beta(1)-adrenoceptor antagonist (3 microM atenolol), but significantly by a transient outward K(+) channel blocker (3 mM 4-aminopyridine). (+)-MK801 did not cause any significant change of intracellular cAMP content. Electrophysiological study in rat ventricular cells revealed that (+)-MK801 concentration-dependently prolonged the action potential duration with a concomitant decrease in the maximum rate of the action potential upstroke (V(max)) and an increase in the recovery time constant of V(max). Voltage clamp study showed that (+)-MK801 (3 microM) reduced inward Na(+) current (I(Na)), along with a slowing of its recovery from inactivation and a slight negative shift of its voltage-dependent steady-state inactivation curves. At a much higher concentration (30 microM), (+)-MK801 slightly reduced the amplitude of L-type calcium inward current (I(Ca)), although the voltage dependence of its steady-state inactivation was unaffected. For the potassium currents in rat ventricular cells, 3 microM of (+)-MK801 reduced the peak transient outward current (I(to)), steady-state outward current (I(ss)) and inward current through K(1) channels. The inhibition of I(to) was associated with a prominent negative shift in the voltage dependence of its steady-state inactivation curve. The outward current through K(1) channels was unaffected. These results indicate that (+)-MK801 may be a strong I(Na) and I(to) blocker with some I(Ca) blocking activity. The inhibition of I(to) and other K(+) efflux would prolong action potential duration, produce positive inotropic action and contribute to the negative chronotropic effect of (+)-MK801.

Action Potentials↗