Assessment of neuromuscular blockade produced by atracurium in frog sartorius muscle

The neuromuscular effects of atracurium in frog sartorius muscle were studied and the results were compared with those obtained by tubocurarine in the same preparation. Single twitch (at 1 per 5 s) and tetanic stimulation (at 1-100 per s) of the motor nerve, stimulated with 5-10 V (maximum) and 0.2 ms pulse duration, were used to assess the neuromuscular blockade produced by atracurium and tubocurarine in the frog sartorius muscle. The results showed that atracurium was twice as potent as tubocurarine in reducing the amplitude of the indirectly-elicited twitch contractions in the frog sartorius muscle. The mean IC50 values (concentration to produce 50% inhibition of twitch tension) of atracurium and tubocurarine-induced depression of the indirectly-elicited twitch tension were 0.64 +/- 0.1 microM and 1.2 +/- 0.2 microM respectively (means +/- s.e., n = 6, P less than 0.001). Furthermore, atracurium had a shorter time of onset, time to 50% block and time to 95% recovery than tubocurarine.     

A pharmacological study of the effect of carbamazepine on neuromuscular transmission in the rat diaphragm

The effects of carbamazepine (0.042-0.42 mM) on neuromuscular transmission were studied on the isolated rat phrenic nerve diaphragm preparation using standard pharmacological and electrophysiological methods. Carbamazepine decreased (1) the antidromic activity of the phrenic nerve, (2) the amplitude of the endplate potential (EPP) and miniature endplate potential (MEPP), (3) the quantal content of the endplate potential, (4) the indirectly-elicited twitch tension, (5) the muscle contracture in chronically denervated muscle induced by acetylcholine (ACh) and (6) the amplitude of the compound phrenic nerve action potential, in a concentration-dependent manner. The antidromic activity of the phrenic nerve was the most affected, while the phrenic nerve compound action potential was least affected. However, the IC50 for carbamazepine (the concentration of carbamazepine that inhibited 50% of the response) was in the same order of concentration, i.e. 0.11-0.3 mM. Compared with the effect of carbamazepine on the indirectly-elicited twitch tension with its actions described above, it is concluded that carbamazepine interfered with the neuromuscular activity by inhibiting pre- and postsynaptic process and conduction in the phrenic nerve.     

Effects induced by bothropstoxin, a component from Bothrops jararacussu snake venom, on mouse and chick muscle preparations.

Bothropstoxin, a 13,700 mol. wt myotoxic phospholipase homologue isolated from the venom of Bothrops jararacussu and devoid of PLA2, proteolytic or hemolytic activities, inhibited muscle twitch tension, evoked either directly or indirectly through stimulation of the motor nerve in the mouse phrenic-diaphragm preparations. The compound action potential of the muscle was also abolished with a similar time course. In addition, the toxin (0.7 mM) evoked membrane depolarization which was inhibited in the presence of 10 mM Ca2+. In chick biventer cervicis muscle, the toxin (2 mM) induced a contracture that reached its maximum amplitude in 44.8 +/- 15.6 min (n = 6) and was not blocked by either d-tubocurarine or tetrodotoxin. The time to maximum amplitude was reduced to 5.5 +/- 1.0 min (n = 4) in nominally Ca(2+)-free Krebs solution and was completely abolished in Ca(2+)-free Krebs solution containing 1 mM EGTA.     

Glycopyrrolate intensifies neuromuscular blockade produced by atracurium in the rat diaphragm preparation

The effect of glycopyrrolate (Glycopyrronium, a muscarinic antagonist) (10 mumol.litre-1) and neostigmine (1 mumol.litre-1) on atracurium (0.1-100 mumol.litre-1) - induced neuromuscular blockade was studied in the rat isolated phrenic nerve-diaphragm preparation, to see if glycopyrrolate intensified the neuromuscular blockade produced by atracurium in this preparation. Atracurium had a rapid onset of blockade, reaching a complete block in 30-40 s. Glycopyrrolate had no significant effect on indirectly-elicited twitch (0.2 Hz) tension, whereas it significantly increased atracurium-induced depression of twitch tension and shortened the time needed to a complete block by 10 s. Combinations of glycopyrrolate+ neostigmine, only slightly reversed atracurium-induced blockade, if compared to the reversal by neostigmine alone. The mean concentrations to produce 50% depression of twitch tension were: 1.6 +/- 0.1 (atracurium), 0.3 +/- 0.1 (atracurium +glycopyrrolate), 4.8 +/- 0.2 (atracurium +neostigmine) and 2.7 +/- 0.1 mumol.litre-1 (atracurium +glycopyrrolate +neostigmine) (means +/- SEM, n = 6, P less than 0.001, with respect to control value of atracurium alone). It was concluded that glycopyrrolate enhanced atracurium-induced neuromuscular blockade in the rat diaphragm preparation, and that this effect should be noted when dosing glycopyrrolate in man.     

Action of Micrurus dumerilii carinicauda coral snake venom on the mammalian neuromuscular junction.

The venoms of coral snakes (mainly Micrurus species) have pre- and/or postsynaptic actions, but only a few of these have been studied in detail. We have investigated the effects of Micrurus dumerilii carinicauda coral snake venom on neurotransmission in rat isolated phrenic nerve-diaphragm muscle and chick biventer cervicis preparations stimulated directly or indirectly. M. d. carinicauda venom (5 or 10 microg/ml) produced neuromuscular blockade in rat (85-90% in 291.8+/-7.3 min and 108.3+/-13.8, respectively; n=5) and avian (95.0+/-2.0 min; 5 microg/ml, n=5) preparations. Neostigmine (5.8 microM) and 3,4-diaminopyridine (230 microM) partially reversed the venom-induced neuromuscular blockade in rat nerve-muscle preparations. In neither preparation did the venom depress the twitch response elicited by direct muscle stimulation. The contractures induced by acetylcholine in chick preparations were inhibited by the venom (95-100%; n=4; p<0.05). In rat preparations, the venom produced a progressive decrease in the amplitude of miniature end-plate potentials (m.e.p.ps control frequency=69.3+/-5.0/min and control amplitude=0.4+/-0.2 mV) until these were abolished. Neostigmine (5.8 microM) and 3,4-diaminopyridine (230 microM) partially antagonized this blockade of m.e.p.ps. The resting membrane potential was not altered with the venom (10 microg/ml). M. d. carinicauda venom produced dose-dependent morphological changes in indirectly stimulated mammal preparations. Twenty-five per cent of muscle fibers were affected by a venom concentration of 5 microg/ml, whilst 60.7% were damaged by 10 microg of venom/ml. In biventer cervicis preparations, the morphological changes were slower in onset and were generally characterized by undulating fibers and, to a lesser extent, by zones of disintegrating myofibrils. A venom concentration of 5 microg/ml damaged 52.2% of the fibers. These findings indicate that M. d. carinicauda venom has neurotoxic and myotoxic effects and that the neuromuscular blockade involves mainly a postsynaptic action.     

Mode of neuromuscular blocking action of a toxic phospholipase A2 from Pseudocerastes fieldi (Field's horned viper) snake venom

The effects of a toxic phospholipase A2 (Fr.Cb) isolated from the venom of Pseudocerastes fieldi were studied on the chick biventer cervicis muscle and the mouse phrenic nerve--diaphragm preparations. In the chick muscle, Fr.Cb (10 micrograms/ml) caused complete neuromuscular blockade without producing contracture or affecting the response of the muscle to acetylcholine. In the mouse diaphragm, Fr.Cb blocked the indirectly elicited contraction without affecting that evoked directly. In a low calcium medium (0.5 mM), Fr.Cb produced a triphasic change of the indirectly elicited contractions. The frequency of miniature endplate potentials (m.e.p.p.s) in the mouse diaphragm was first increased 3--4 fold 40 min after toxin (10 micrograms/ml) application, then gradually decreased, while the amplitude of m.e.p.p.s. was not decreased, even after the evoked release of transmitter had failed. Giant m.e.p.p.s were frequently observed. The quantal content first increased and then decreased gradually. The resting membrane potential and the compound phrenic nerve action potential were not significantly affected by the toxin at 10 micrograms/ml after 2 hr of incubation. The motor nerve terminals in the Fr.Cb intoxicated mouse diaphragm showed swelling and vacuolization of both synaptic vesicles and mitochondria. It is concluded that the toxin produces a neuromuscular blockade by acting selectively on the presynaptic site.     

Pharmacological evidence for a presynaptic action of venoms from Bothrops insularis (jararaca ilhoa) and Bothrops neuwiedi (jararaca pintada).

Whereas the presynaptic action of Crotalus durissus terrificus venom is well-established, Bothrops venoms have historically been considered to have only postsynaptic and muscular effects. However, some studies have also suggested a presynaptic action for these venoms. In this work, we used chick biventer cervicis preparations to compare the presynaptic actions of two Bothrops venoms (B. insularis and B. neuwiedi) with that of C. d. terrificus venom. At 10 microg/ml, all venoms produced irreversible blockade of the twitch tension responses, with no reduction in acetylcholine (ACh)-induced contractures and only a slight decrease in potassium induced-contractures. The times (in min) required to produce 50% neuromuscular blockade (C. d. terrificus: 16.3+/-0.7, n = 8; B. insularis: 30.0+/-1.9, n = 5; B. neuwiedi: 42.0+/-2.0, n = 8; mean +/- SEM) were significantly different among the venoms (p < 0.01). Lowering the temperature at which the experiments were done (from 37 to 24 degrees C) prevented neuromuscular blockade by the three venoms, indicating that enzyme activity may be involved in this response. At concentrations capable of causing complete neuromuscular blockade, creatine kinase release remained close to levels seen in control preparations incubated with Krebs solution alone (500-1200 IU/l). Commercial crotalic antivenom, but not bothropic antivenom, protected against the neuromuscular blockade caused by B. insularis and B. neuwiedi venoms. These observations indicate that bothropic venoms may contain components which act presynaptically in a manner similar to C. d. terrificus venom, and that at low venom concentrations a direct action on skeletal muscle does not contribute to this presynaptic neurotoxicity.     

Effects of 3,4-diaminopyridine on mechanical and electrical responses of frog single muscle fibres

The effects of 3,4-diaminopyridine (3,4-DAP) were studied on isolated muscle fibres of the frog in concentrations ranging between 0.025 and 5.0 mM. Isometric twitch and tetanus responses were recorded at temperatures between 2.5 and 3.9 degrees. 3,4-DAP caused a concentration-dependent increase in twitch amplitude, maximum effects being obtained at a concentration of 3 mM with a mean increase in tension of 70 +/- 12% of control (n = 7). 3,4-DAP in 3 mM concentration had only a slight increase in initial rate of rise of twitch tension (mean increase 8 +/- 4%) but increased the time to half peak tension by 59 +/- 9% and the time from peak tension to half relaxation by 78 +/- 10%. No significant effect of 3,4-DAP was observed on the initial rate of rise and total amplitude of the isometric tetanus. The twitch potentiating effect of 3,4-DAP developed gradually with the number of times the fibre was stimulated and reached a maximum level after 40-50 stimulations. A gradual increase in the duration of the action potential was also observed. It is suggested that 3,4-DAP, like 4-aminopyridine, potentiates the twitch by means of prolonging the duration of the action potential.     

Transfer of latamoxef into human burn blister fluid and its pharmacokinetic analysis

Latamoxef (LMOX) (50 mg/kg) was administrated intravenously to burned patients over 1 hour period. Burn blister fluid and serum were taken during 8 hours after injection, and concentrations of LMOX in burn blister fluid and serum were determined by bioassay using E. coli as a test organism. The serum concentrations of LMOX were 170.8 +/- 30.6 micrograms/ml at 30 minutes, 227.0 +/- 19.8 micrograms/ml at 1 hour, 90.3 +/- 21.4 micrograms/ml at 2 hours, 52.9 +/- 14.6 micrograms/ml at 3 hours, 38.7 +/- 13.3 micrograms/ml at 4 hours, 25.1 +/- 8.1 micrograms/ml at 5 hours, 20.5 +/- 8.1 micrograms/ml at 6 hours, 13.0 +/- 5.5 micrograms/ml (mean +/- S.D., n = 5) at 8 hours after the injection. The LMOX concentrations in burn blister fluid were 36.9 +/- 32.8 micrograms/ml at 30 minutes, 77.5 +/- 42.2 micrograms/ml at 1 hour, 85.4 +/- 19.6 micrograms/ml at 2 hours, 76.4 +/- 18.5 micrograms/ml at 3 hours, 63.5 +/- 17.8 micrograms/ml at 4 hours, 54.9 +/- 17.1 micrograms/ml at 5 hours, 34.8 +/- 10.3 micrograms/ml at 6 hours, 25.2 +/- 4.8 micrograms/ml (mean +/- S.D., n = 7) at 8 hours after the injection. The data obtained were analysed pharmacokinetically. The serum levels were analysed by two-compartment model, and the LMOX levels in burn blister fluid were analysed by the model, in which blister was considered as a small part of the peripheral compartment. In results, Tmax and Cmax of LMOX levels in burn blister fluid were calculated as 1.81 hours and 90.6 micrograms/ml, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

The presynaptic activity of bothropstoxin-I, a myotoxin from Bothrops jararacussu snake venom

Bothropstoxin-I from Bothrops jararacussu snake venom is a lysine-49 phospholipase A(2) with myotoxic and neurotoxic activities. In this study, we used mouse phrenic nerve-diaphragm preparations in the absence and presence of manganese (Mn(2+)), a presynaptic blocker, to investigate a possible presynaptic action of bothropstoxin-I. At concentrations of 0.9 mM and 1.8 mM, Mn(2+) produced 50% neuromuscular blockade in less than 4 min., which was spontaneously reversible at the lower concentration. Bothropstoxin-I (1.4 microM) irreversibly inhibited neuromuscular blockade by 50% in 31+/-4 min. (mean+/-S.E.M., n = 9). Pretreating preparations with 0.9 mM Mn(2+) prevented the blockade by bothropstoxin-I. When added after bothropstoxin-I, Mn(2+) produced its characteristic blockade and, after washing, the twitch tension returned to pre-Mn(2+) levels, indicating that bothropstoxin-I caused irreversible damage before the addition of Mn(2+). Electrophysiological measurements showed that a concentration of bothropstoxin-I (0.35 microM), which did not produce neuromuscular blockade, caused the appearance of giant miniature end-plate potentials with no change in the membrane resting potential but increased the quantal content. Preparations preincubated with Mn(2+) (0.9 mM, 30 min.) were protected against the depolarizing action of bothropstoxin-I (0.7 microM). These results show that, in addition to its well-known myotoxic effect, bothropstoxin-I also has a presynaptic action.     

Effect of lignocaine on chick biventer cervicis skeletal muscle

The effect of lignocaine (0.01-100 micrograms.ml-1) on amplitude of indirectly and directly-elicited twitch contractions and on contractures produced by acetylcholine (ACh) (0.1-10 mM) and tetraethylammonium (TEA) (1.2-12 mM) was studied in isolated biventer cervicis skeletal muscle of the chick. Lignocaine (0.01-0.9 microgram.ml-1) increased the amplitude of the indirectly-elicited twitch contractions. At high concentrations (10-100 micrograms.ml-1), lignocaine decreased or blocked the twitch tension and produced a contracture in the chick skeletal muscle. Lignocaine also reduced or blocked the directly-elicited twitch contractions in a dose-dependent manner. Lignocaine (10 micrograms.ml-1) reduced the ACh-induced contracture whereas it increased that produced by TEA. Physostigmine (2 micrograms.ml-1) increased the stimulating effect of lignocaine, at low concentrations. However, repeated exposures to lignocaine followed by physostigmine resulted in both increase and decrease in the indirectly-elicited twitch contractions. It was concluded that lignocaine had a dual action at the neuromuscular junction. In low concentrations, lignocaine increases the twitch tension, possibly by an anticholinesterase action, and in high concentrations it reduces or blocks the twitch tension, produces a contracture in the muscle, and reduces the ACh-induced contractures, whereas it increases the TEA-induced responses. Some of these effects of lignocaine may be interpreted in terms of effects on excitation-contraction coupling in muscle.     

The effect of 3,3-dipyridylmethyl-1-phenyl-2-indolinone on the neuromuscular transmission in the rodent skeletal muscles.

The effects of a cognition enhancer, 3,3-dipyridylmethyl-1-phenyl-2-indolinone (DPMPI) (21.5-645 microM), on neuromuscular transmission were studied electrophysiologically on diaphragms of mouse and rat and the soleus muscle of rat. The drug DPMPI (21.5-645 microM) increased both direct and indirect twitch tension of mouse diaphragm. It also increased (a) the frequency of miniature endplate potentials and (b) the quantal content of endplate potential. However, DPMPI (64.5 microM) affected neither the amplitude of the directly elicited action potential of soleus muscle in the rat nor the magnitude of the resting membrane potential of mouse diaphragm, although DPMPI (215 microM) decreased the amplitude of the compound action potential of phrenic nerve. Based on these results, it is concluded that DPMPI had several effects on neuromuscular transmission, i.e. it (a) facilitated the transmitter releasing process of the motor nerve terminal, (b) decreased the conduction in the phrenic nerve and (c) increased the directly elicited twitch tension.     

Verapamil intensifies neuromuscular blockade produced by gallamine and pancuronium at the chick neuromuscular junction

Experiments were performed to study the effect of verapamil on neuromuscular transmission and muscle contraction at a chick skeletal muscle-nerve preparation. In addition, the effects and interactions of verapamil with some muscle relaxants were studied in the same preparation. These effects were explored by studying the effects of verapamil on: directly-and indirectly-elicited twitch contractions, and neuromuscular blockade produced by gallamine and pancuronium. The results showed that verapamil (2-200 microM) had a differential effect on the twitch responses; more reductions occurred in the indirectly-elicited twitch tension, whereas the directly-elicited twitch response was reduced only by 20-30% of maximum indirectly-elicited twitch tension. Furthermore, in low concentrations (1-20 microM), verapamil significantly increased the neuromuscular blockade produced by gallamine (28-1280 nM) and pancuronium (18-573 nM). In high concentrations (greater than 200 microM), verapamil completely blocked the indirectly-elicited twitch response and produced a marked contracture in the chick skeletal muscle (1.0 +/- 0.1 g, n = 6). It was concluded that by reducing twitch tension and inhibiting neuromuscular transmission, verapamil increases (intensifies) neuromuscular blockade produced by muscle relaxants, e.g. gallamine and pancuronium.     

Laboratory and clinical studies of T-1982 (cefbuperazone in pediatric field

The authors have carried out the laboratory and clinical studies of T-1982 (cefbuperazone). The results were as follows: The sensitivity was estimated by the plate dilution method on 28 strains of S. aureus 26 strains of E. coli, 27 strains of K. pneumoniae, 25 strains of S. marcescens and 14 strains of Proteus sp. isolated from patients. The distribution of susceptibility of S. aureus was 1.25-25 micrograms/ml and the peak of distribution was 12.5 micrograms/ml. The strains of 84.6% of E. coli were inhibited at concentration of less than 0.39 micrograms/ml. The strains of 77.8% of K. pneumoniae were inhibited at concentration of less than 0.2 microgram/ml. The strains of 96% of S. marcescens was inhibited at concentration of less than 3.13 micrograms/ml. The distribution of susceptibility of Proteus sp. was 0.39-25 micrograms/ml. T-1982 was given to intravenous administration for 5 minutes and drip infusion for 30 minutes a single dose of 20 mg/kg of T-1982 to 2 and 2 children respectively. After intravenous administration of T-1982, the mean serum level was peak 88.4 +/- 8.7 micrograms/ml at 15 minutes, 52.5 +/- 2.7 micrograms/ml at 1 hour, 4.6 +/- 0.15 micrograms/ml at 6 hours respectively. Half-life was 89 minutes. And after drip infusion of T-1982, the mean serum level was 75.5 +/- 3.5 micrograms/ml at 30 minutes and 3.1 +/- 0.6 micrograms/ml at 6.5 hours respectively. Half-life was 82 minutes. The mean urinary excretion rate was 94.7%, 57.4 +/- 11.0% up to 6 hours after intravenous administration and drip infusion respectively. T-1982 was effective in 13 cases out of 13 cases with bacterial infections. No side effects were observed except for 1 case with elevation of serum GOT, 1 case with elevation of serum GPT and 2 cases with eosinophilia.     

Actions of the selective inhibitor of cholinesterase tetramonoisopropyl pyrophosphortetramide on the rat phrenic nerve-diaphragm preparation

1. Tetramonoisopropyl pyrophosphortetramide (iso-OMPA) added for 15 min to the rat isolated phrenic nerve-diaphragm in a concentration of 30 muM, produced a complete selective and stable inhibition of cholinesterase. A concentration of 3 muM produced near complete inhibition of cholinesterase, and a concentration of 300 muM also inhibited acetylcholinesterase marginally.2. Inhibition of cholinesterase was associated with a sustained increase in the neuromuscular blocking action of exogenous butyrylcholine but not of exogenous acetylcholine. Iso-OMPA, 300 muM, in addition caused transient increases in the sensitivity of the rat diaphragm to exogenous acetylcholine and butyrylcholine. In the same concentration, it had a curare-like action on the frog rectus abdominis muscle preparation.3. Iso-OMPA, 30 muM, caused reversible increases in the amplitude of the twitch response and tetanic responses, which were of a similar magnitude in the indirectly stimulated preparation and the directly stimulated curarized preparation. Caffeine had a similar effect on the twitch response and its effectiveness was increased by iso-OMPA, and vice-versa. Amongst anticholinesterases, octamethyl pyrophosphortetramide and tetraethylpyrophosphate also enhanced the amplitude of the tetanic response, but paraoxon, dyflos, and mipafox did not.4. It is concluded that iso-OMPA, in concentrations (3 and 30 muM) which in 15 min give near maximal or maximal selective inhibition of cholinesterase, has no effect on the transmission of nerve impulses at the neuromuscular junction, but enhances reversibly the amplitude of the contractile response to stimulation by a direct action upon the muscle fibre, which involves a mechanism related to but not identical with that by which caffeine potentiates twitch tension. In higher concentrations, iso-OMPA has a curare-like action at the neuromuscular junction.     

Cholera toxin and Gs protein modulation of synaptic transmission in guinea pig mesenteric artery.

Cholera toxin (CTX) was used to test whether the presynaptic beta-adrenoceptors of guinea-pig mesenteric artery are coupled via stimulatory GTP-binding proteins. The vascular smooth muscle cells were electrically quiescent unless stimulated and had a mean resting potential of -68.7 +/- 2.8 mV (n = 16) and input resistance of 12.1 +/- 0.5 M omega (n = 4). Perivascular nerve stimulation with brief square pulses evoked excitatory junction potentials (EJPs) in the muscle cells. Isoproterenol (0.1 microM) enhanced the EJP amplitude without modifying the passive membrane properties of the muscle cells. The beta-blocker, propranolol (0.5 microM), prevented the effects of isoproterenol on EJP amplitude. The permeant analogue of cyclic AMP, 8-bromocAMP, also potentiated EJP amplitude. EJP amplitude was markedly enhanced by treatment of the isolated blood vessels with CTX (10 micrograms/ml for 1 h). The muscle cells became hyperpolarized (-74.6 +/- 2.1 mV, n = 5), and their input resistances were significantly reduced (8.2 +/- 0.5 M omega, n = 4). These effects of CTX persisted after washout. Addition of GM1 ganglioside (5 micrograms/ml) prevented the CTX effects. The CTX enhancement of EJP amplitude was not prevented by application of depolarizing current (ca. 0.5 nA) the muscle cells (to counter the hyperpolarization). These results suggest that CTX increases the neurotransmitter release from the nerve terminals; the hyperpolarization may be due to an increase in K+ conductance. These effects of CTX may be mainly due to elevation of cAMP in the nerve terminal and in the muscle cell.     

Clinical study of diffusion of cefotiam into myocardial tissue

In 11 patients undergoing open-heart operation, 1 g of cefotiam (CTM) was administered intravenously by bolus technique at the start of operation. Samples of serum were obtained at 30, 60 and 90 minutes following administration. Samples of right atrial appendage tissue and serum were obtained simultaneously at the time of heart cannulation. Antibiotic concentrations of all samples were determined by agar well method using P. mirabilis ATCC21100 as the test organism. The results were as follows: Serum levels of CTM after 30, 60 and 90 minutes were 53.1 +/- 17.6 micrograms/ml (Mean +/- S.D., n = 10), 26.1 +/- 10.4 micrograms/ml (n = 11) and 13.5 +/- 5.5 micrograms/ml (n = 7) respectively. Myocardial tissue levels of CTM after 60 and 90 minutes were 9.4 +/- 4.7 micrograms/g (n = 4) and 4.8 +/- 2.7 micrograms/g (n = 7) respectively. The concentration ratios of the myocardial tissue to serum were 0.36 +/- 0.10 (n = 4) after 60 minutes and 0.35 +/- 0.09 (n = 7) after 90 minutes. CTM can transmigrate from blood to myocardial tissue easily as compared with other cephalosporins. Therefore, CTM, a new broad spectrum cephalosporin, can be considered as one of the highly useful antibiotics for the prevention and treatment of infections following cardiac operation.     

Blocking effects of hypaconitine and aconitine on nerve action potentials in phrenic nerve-diaphragm muscles of mice

The mechanisms of neuromuscular blockade by hypaconitine and aconitine were investigated electrophysiologically in isolated phrenic nerve-diaphragm muscles of mice. Hypaconitine (0.08-2 microM) and aconitine (0.3-2 microM) depressed the nerve-evoked twitch tension, without affecting the contraction evoked by stimulation of the muscle. At the concentrations of hypaconitine (up to 5 microM) and aconitine (up to 2 microM) that depressed the nerve-evoked twitch tension, the resting membrane potential of the muscle cells was unchanged. Hypaconitine (0.1-2 microM) and aconitine (2 microM) blocked the end-plate potential (epp), without affecting the amplitude of the miniature epp (mepp). The quantal content of end-plate potentials was decreased by these agents in parallel with the decrement in amplitude. The nerve compound action potential was inhibited by hypaconitine (5 microM) and aconitine (2-10 microM), as well as by 1 microM tetrodotoxin (TTX). When the nerve compound action potential was completely blocked by 2 microM aconitine, the muscle action potential was unaffected, although 1 microM TTX suppressed both potentials to the same degree. These results indicate the neuromuscular blockade produced by hypaconitine and aconitine were caused by reducing the evoked quantal release. The mechanism of this effect was attributed mainly to blocking of the nerve compound action potential.     

Effects of sodium selenite on neuromuscular junction of the mouse phrenic nerve-diaphragm preparation

The effects of sodium selenite on the neuromuscular junction of the phrenic nerve-diaphragm of the mouse were studied. Nerve-evoked twitches of the diaphragm of the mouse, the frequency of miniature endplate potentials, the quantal content of endplate potentials and the compound action potentials of the axon were measured. Sodium selenite induced a slight increase of the amplitude of the twitch, followed by twitch depression. The amplitude of the twitch, increased by selenite, became more prominent after the suppression of the twitch induced by cadmium ions, d-tubocurarine or magnesium ions. It appeared that the increased amplitude of twitch was due to the facilitation of transmitter release, since selenite significantly increased the frequency of miniature endplate potentials, and the amplitude and quantal content of endplate potentials; the amplitude and half decay time of miniature endplate potentials were unaffected. Twitch depression induced by selenite was enhanced by ammonium ions, high potassium and low magnesium and attenuated by high calcium. During the period of gradual depression of the twitch, selenite decreased the amplitude of compound action potentials of the phrenic nerve axon and caused the disappearance of endplate potentials. Ammonium ions enhanced the blockade of axonal conduction induced by selenite. Moreover, the depolarizing agents, ammonium and high potassium also induced an initial increase of twitch amplitude followed by depression of the twitch. These findings indicate that selenite probably alters the release of the transmitter by depolarizing the nerve membrane. The effects of selenite were antagonized by glutathione and cyanide, suggesting that the binding of selenite to sulfhydryl groups of the membrane was essential for inducing its pharmacological actions.