Assessment of neuromuscular blockade produced by atracurium in the rat diaphragm preparation. Measurements of tetanic fade, depression and recovery profile.

The effect of atracurium, a relatively new muscle relaxant, on neuromuscular transmission, in the rat diaphragm preparation, was studied, by analysing the characteristic features of tetanic fade and recovery pattern following a blocking concentration of atracurium (10 microns). Tetanic fade (TF) and peak tetanic tension (Tp) and its depression by atracurium, were analysed and the results were interpreted in terms of atracurium action at the neuromuscular junction. Atracurium reduced the sustained tetanic tension, elicited at 50 Hz for 0.5 s duration, and produced a marked tetanic fade in 38 s. Atracurium also reduced the peak tetanic tension by 40%, of the control value, in 38 s. Maximum tetanic tension was 5.7 g tension, and the time taken to completely block the tetanus was 4.75 +/- 0.15 min (means +/- SE, n = 8). Recovery from atracurium-induced blockade occurred in 30s (tetanic fade) and in 3-4 min (peak tetanic tension). It was concluded that atracurium produces a profound tetanic fade, at a time when the peak tetanic tension is reduced by only 40%. The data presented indicate that atracurium has a rapid onset of blockade, intermediate duration and a quick recovery profile at the rat neuromuscular junction.

Tetanic fade following atracurium-induced neuromuscular blockade in the rat diaphragm preparation.

1. The effect of atracurium on neuromuscular transmission was studied in the rat diaphragm preparation, by analysing the characteristics of tetanic fade and its recovery profile after using a blocking concentration of atracurium (10 mumol.litre-1). 2. Tetanic fade (TF), peak tetanic tension (Tp), and its depression, and end tetanic tension (Te), sustained tension, were analysed and compared to their respective control values before administration of atracurium. 3. The results showed that atracurium reduced the tetanic tension, i.e., the peak and end tetanic tensions, elicited at 50 Hz for 0.5 s duration, and produced a marked tetanic fade, which was developed fully in about 38 s. On the other hand, the peak tetanic tension (Tp) was only reduced by 40% (at 38 s) of its control value (5.7 g tension). The time taken to completely block Tp was about 5 min. 4. After washing out atracurium, recovery of the peak tetanic tension occurred within 3-4 min., while tetanic fade was reversed within 30 s. 5. It was concluded that atracurium produces a profound tetanic fade, at a time when the peak tetanic tension is only depressed by about 40% of the control value. The results indicated that atracurium had a powerful neuromuscular blocking action at the rat diaphragm preparation.

Effect of verapamil on the contractions produced by high potassium and by noradrenaline in human isolated saphenous vein.

The effect of a calcium channel blocker, e.g. verapamil, on the contractions produced by high potassium (K+) and noradrenalne (NA), was studied in the isolated saphenous vein in man. The aim of the present experiments was to see which of the two types of contractions was more sensitive to blockade by a calcium channel blocker, e.g. verapamil, and if verapamil had a differential effect on KCl and NA, whether this could be interpreted in terms of the presence of two calcium activation mechanisms in human saphenous vein. The results of the present investigation showed that KCl and NA contracted whereas verapamil relaxed the human saphenous vein. NA produced larger contraction (3.4 g tension) than did KCl (1.3 g tension). Lowering the calcium concentration in the external medium, from 2.5 mM to 1 mM, resulted in a reduced contraction in both NA and KCl responses, indicating dependence on influx of calcium. However, verapamil (1 microM) produced greater reduction in the KCl than NA-induced contraction, indicating that the NA contraction may involve additional mechanism, i.e. dependence on the release of calcium from intracellular Ca2+ stores. These results are in favour of the suggestion that the KCl-induced contraction was due to depolarization and voltage-dependent activation of calcium channels, whereas the NA-induced contraction was due to both depolarization and receptor-activation of the calcium channels, the latter being less sensitive to calcium channel blockers, e.g. verapamil. Thus, the KCl and NA-induced contractions in human saphenous vein may be due to two different calcium activation mechanisms; one is more sensitive (KCl) than the other (NA) to the presence of the calcium antagonist, verapamil.

Atropine sulphate enhances neuromuscular transmission in the rat.

The effect of atropine (0.001-10 mumol.l-1) on neuromuscular transmission in the rat hemidiaphragm preparation was investigated by analysing its effects on directly and indirectly-elicited twitch, tetanic, post-tetanic twitch responses and on the phenomenon of post-tetanic twitch potentiation. The effect of atropine on contractions produced by endogenous acetylcholine (ACh) or exogenous ACh (added directly into organ bath containing muscle) was studied in rat ileum. The results showed that atropine in low concentrations (1 mumol.l-1 or less), enhanced the indirectly-elicited twitch, tetanic and post-tetanic twitch responses in the rat diaphragm preparation. The mean EC50 value of atropine-induced increase in twitch tension was 0.08 +/- 0.01 mumol.l-1 (mean +/- s.e. mean, n = 6). Atropine had little effect on directly-elicited twitch tension, but in high concentrations (10 mumol.l-1 or more), it reduced the directly, and indirectly-elicited twitch contractions and produced a neuromuscular block in the rat diaphragm preparation. Atropine increased the contraction produced, in rat ileum, by endogenous ACh, i.e. ACh released from the phrenic nerve stimulated at 50 Hz for 20 s duration (control contraction: 1.3 +/- 0.1 g, contraction in atropine: 1.7 +/- 0.2 g). In contrast, atropine significantly reduced the contraction produced by exogenous ACh in the same preparation (control contraction: 3.0 +/- 0.5 g, atropine: 2.0 +/- 0.1 g), suggesting that a different mechanism may be involved in the latter effect of atropine. It was concluded that atropine, in low concentration, enhanced neuromuscular transmission, possibly via a presynaptic mechanism. In high concentration, atropine may reduce and then block transmission, possibly via pre- and postsynaptic mechanisms.

A pharmacologic study on the histamine releasing effect of atracurium and other muscle relaxants in rat isolated ileum.

In this study, the effects of histamine, antihistamines (terfenadine and mepyramine), 5-hydroxytryptamine, and muscle relaxants, atracurium, vecuronium and gallamine, on the tone and contractility of rat ileum were studied and compared in vitro. The aim of the present investigation was to measure, pharmacologically, the histamine releasing effect of muscle relaxants, e.g atracurium, vecuronium and gallamine, by comparing their contractile response in the absence and presence of antihistamines and comparing their mechanical responses with those produced by histamine and 5-hydroxytryptamine (5-HT). The results showed that the antihistamines, triludan(terfenadine) and mepyramine produced opposite effects in rat ileum. Terfenadine (0.1-20 microM) produced concentration-dependent contractions in the rat ileum, whereas mepyramine (0.1-10 microM) relaxed the muscle, e.g. by 1.2 g tension. Atracurium (0.5-500 microM), vecuronium (0.2-200 microM), and gallamine (0.1-7.0 microM) produced marked contractions (1.5-4.0 g tension) in rat ileum, and these contractions were markedly reduced by mepyramine (1.3 microM) or terfenadine (5 microM), implicating histamine release in the generation of these contractions. However, there was some residual contraction which was not blocked by mepyramine, but by 5-HT antagonist, methysergide (1 microM), indicating that a mechanism other than histamine release may be responsible for the residual contraction, i.e. release of other mediators such as 5-HT, prostaglandins, or calcium. 5-HT (0.5-500 microM) and histamine (0.5-500 microM) produced contractions in the rat ileum, but 5-HT was more effective than histamine in producing these contractions. Similarly, gall amine was more effective than atracurium and vecuronium in contracting the rat ileum.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of ethanol on spontaneous contractions and on the contraction produced by periarterial nerve stimulation and by acetylcholine in the rat isolated ileum.

1. The effect of ethanol (0.01-1000 mg.ml-1) on tone, contractility, and the contractions produced by periarterial nerve stimulation and by acetylcholine was studied in the rat isolated ileum. 2. In low concentrations, ethanol reduced the spontaneous contractions by 60 +/- 1.5% and in high concentrations, it produced a marked contraction in the muscle (3.2 +/- 0.3 g, mean +/- SE, n = 6). 3. In the presence of adrenergic, histaminergic, serotonin and prostaglandin antagonists, ethanol (1.8 mg.ml-1) reduced the contractions produced by periarterial nerve stimulation, at 1-100 Hz with 20 V and 0.2 msec pulse duration, by 80 +/- 3.4%. Ethanol also reduced the contractions produced by acetylcholine (0.001-1 microgram.ml-1), the mean EC50 values were 0.1 +/- 0.01 microgram.ml-1, control, and 0.96 +/- 0.1 microgram.ml-1, in ethanol, respectively. 4. Although the mechanism of action of ethanol at the gut smooth muscle is not clear, it is known that it may block conduction, depolarize the cell membrane and cause release of intracellular calcium, which is, in part, responsible for the contraction produced by ethanol in the rat ileum.

Local anaesthetics inhibit influx of calcium, sodium and potassium into rat ileum, diaphragm and human isolated saphenous vein.

The effects of 5 different local anaesthetics, lignocaine, prilocaine, etidocaine, mepivacaine, bupivacaine, on uptake of Ca2+, Na+ and K+ were studied, using a Kone Microlyte Analyzer, into 3 different types of muscle fibres, the rat ileum, rat diaphragm and human isolated saphenous vein. The aim of the present experiments was to see if local anaesthetics had a calcium antagonistic activity, like that produced by calcium antagonists, e.g. verapamil. The results showed that local anaesthetics in moderate and high concentrations (more than 100 microM) depressed uptake of Ca2+, as well as the Na+ and K+, although the depression of the uptake of Ca2+ was 7 and 2 times less than those of Na+ and K+. In low concentrations (1-10 microM), the local anaesthetics had no or little effect on Ca2+ uptake, although they still significantly reduced Na+ and K+ uptake. It was concluded that the effect of local anaesthetics on uptake of Ca2+, Na+ and K+ into rat ileum, diaphragm and human saphenous vein, is concentration-dependent, and that only at high concentrations do they have a calcium antagonistic activity in muscle. Furthermore, there was no clear evidence that the effect of local anaesthetics was species-dependent, since the uptake of Ca2+ was depressed by only about 17% more in smooth muscle than in skeletal muscle.

Design and preparation of a formulary--guide to the prescribing of medicines.

In recent years there has been a renewed interest in the use of local hospital 'formularies'. The development and preparation at The London Hospital (Whitechapel) of a guide of prescribing which embraces and extends the concept of a formulary is described. A method of involving staff in the preparation of text was developed to ensure the rapid production of a reasonably comprehensive guide which would command respect and a high degree of compliance. The use of word-processing techniques and graphic design expertise are described. The guide has been carefully introduced together with plans for monitoring compliance and its influence on drug expenditure. These are discussed in the light of one year's experience with the guide.