A comparative study of the effect of some centrally acting skeletal muscle relaxants in mice

The possibility of differentiating between sedative-hypnotics and centrally acting muscle relaxants has been investigated in mice. The ED50 values for loss of muscle tone and loss of righting reflex were determined for 2-(3î,6î-dioxaheptyl) aminomethyl-1,4-benzodioxane (ambenoxan), 2-(4î,7î-dioxaoctyl) aminomethyl-1,4-benzodioxane (WB 4123) and compared with mephenesin, meprobamate, methocarbamol and the sedative-hypnotic, sodium pentobarbitone. Comparison of the slopes of the regression lines for hypotonia and loss of the righting reflex for the compounds suggests that ambenoxan offers a greater separation between the two responses than clinically used muscle relaxants.     

Potency of nondepolarizing muscle relaxants on muscle-type acetylcholine receptors in denervated mouse skeletal muscle

Aim:

To investigate the changing resistance to nondepolarizing muscle relaxants (NDMRs) during the first month after denervation.

Methods:

The denervated and innervated skeletal muscle cells were examined on days 1, 4, 7, 14, 21, and 28 after denervation. Individual denervated and innervated cells were prepared from the flexor digitorum brevis of the surgically denervated and contralateral hind feet, respectively. Nicotinic acetylcholine receptors (nAChRs) in the cells were activated with 30 μmol/L acetylcholine, either alone or in combination with various concentrations of vecuronium. Currents were recorded using a whole-cell patch-clamp technique.

Results:

The concentrations of vecuronium resulting in half-maximal inhibitory responses (IC₅₀) increased 1.2- (P>0.05), 1.7-, 3.7-, 2.5-, 1.9-, and 1.8-fold (P<0.05) at Days 1, 4, 7, 14, 21, and 28 after denervation, respectively, compared to the innervated control. Resistance to vecuronium appeared at Day 4, peaked at Day 7, and declined at Day 14 after denervation. Nevertheless, IC₅₀ values at Day 28 remained significantly higher than those for the innervated control, suggesting that the resistance to vecuronium had not disappeared at Day 28.

Conclusion:

The NDMR doses required to achieve satisfactory clinical effects differ at different times after muscle denervation.     

The neuromuscular blocking effect of trimetaphan alone and in combination with different non-depolarizing muscle relaxants in the rat

The effect of trimetaphan alone and in combination with pancuronium, tubocurarine or metocurine (dimethyl tubocurarine) has been examined on the rat phrenic nerve diaphragm preparation. Trimetaphan alone produced neuromuscular blockade in an all-or-none fashion once a concentration of between 2.39 X 10(-4) and 3.00 X 10(-4) M had been exceeded. Concentrations of trimetaphan below this threshold produced a dose-dependent potentiation of all three non-depolarizing relaxants studied. This potentiation was equal for tubocurarine and metocurine, but less for pancuronium.     

The effect of methylmercury on skeletal muscle in the rat: a histopathological study

Methylmercury (MeHg)-induced neurotoxicity includes skeletal muscle symptoms (extremity weakness and wasting, muscle cramp) in addition to ataxia and disturbances of sensory and visual function. The underlying mechanisms responsible for the skeletal muscle symptoms are still poorly understood. In this study the effects of MeHg exposure on skeletal muscle were investigated in rats receiving orally administered MeHgCl at 5 mg/kg/day for 12 days. MeHg-treated rats gradually lost body weight and showed muscle weakness and wasting. Seven days after the last MeHg dose, MeHg levels in the skeletal muscle were as high as those in liver, kidney, or cerebrum. The obvious histopathological finding in skeletal muscle was a decrease in mitochondrial enzyme activity. These changes were more prominent in mitochondria-rich soleus muscle than in extensor digitorum longus muscle. Our findings confirm that MeHg exposure disturbs mitochondrial energy metabolism in skeletal muscle.     

Different magnitude of resistance to nondepolarizing muscle relaxants in the denervated mouse skeletal muscle

Aim:

To test the hypothesis that different magnitude of resistance of denervated skeletal muscle to nondepolarizing muscle relaxants (NDMRs) is related to their varying potencies at ɛ-AChR and γ-AChR.

Methods:

Both innervated and denervated mouse muscle cells, and human embryonic kidney 293 (HEK293) cells expressing ɛ-AChR or γ-AChR were used. The effects of NDMRs on nAChR were explored using whole-cell patch clamp technique.

Results:

NDMRs vecuronium (VEC), atracurium (ATR) and rocuronium (ROC) produced reversible, dose-dependent inhibition on the currents induced by 30 μmol/L acetylcholine both in innervated and denervated skeletal muscle cells. Compared to those obtained in innervated skeletal muscle cells, denervation shifted the concentration-response curves rightward and significantly increased the 50% inhibitory concentration (IC₅₀) values (VEC: from 11.2 to 39.2 nmol/L, P<0.01; ATR: from 24.4 to 129.0 nmol/L, P<0.01; ROC: from 37.9 to 101.4 nmol/L, P<0.01). In HEK293 cell expression system, ATR was less potent at γ-AChR than ɛ-AChR (IC₅₀ values: 35.9 vs 22.3 nmol/L, P<0.01), VEC was equipotent at both receptor subtypes (IC₅₀ values: 9.9 vs 10.2 nmol/L, P>0.05), while ROC was more potent at γ-AChR than ɛ-AChR (IC₅₀ values: 22.3 vs 33.5 nmol/L, P<0.05).

Conclusion:

Magnitude differences of resistance to different NDMRs caused by denervation are associated with distinct potencies of NDMRs at nAChR subtypes.     

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 substance P on the mechanical and electrical responses of frog, chick and rat skeletal muscle

The effect of substance P (SP) on the electrical and contractile responses of skeletal muscles of frog, chick and rat were studied using electrophysiological techniques. In low concentrations, SP increased the amplitude of twitch and tetanic contractions in response to motor nerve stimulation of frog, chick and rat preparations, increased the amplitude and duration of frog sciatic nerve compound action potential and reduced the contracture responses produced by acetylcholine (ACh) or tetraethylammonium (TEA) in the chick skeletal muscle. In all these actions, the effect of SP was calcium-dependent. The results provide evidence that SP had a dual action; a prejunctional facilitatory effect by causing a further release of ACh and/or Ca2+ entry or release, and postjunctional effect by reducing the sensitivity of the postjunctional membrane to depolarizing drugs.     

The effect of the analgesic flupirtine on automobile driving

The purpose of the present study was to investigate the effects on driving ability of the new analgesic ethyl-N-(2-amino-6-(4-fluor-phenylmethylamino) pyridin-3-yl) carbamate (flupirtine, D 9998) in comparison with pentazocine and placebo. Flupirtine was tested in a double blind cross-over experiment in 12 healthy volunteers using 7 different tests which are known to correspond to the most important aspects of driving ability. Subjects were given 3 consecutive doses of flupirtine of 100 mg each and tested following the first and third administration. The comparison drug pentazocine and placebo were administered in the same dosage regimen (a single dose of pentazocine amounting to 50 mg). Significant differences between flupirtine and placebo could not be detected. Following single dosage of pentazocine subjects more often reported a general feeling of discomfort, including nausea, dizziness and motion sickness, than was the case after administration of flupirtine. While single administration of pentazocine did not produce any significant differences from placebo, multiple administration resulted in both objective and subjective fatigue symptoms. It was concluded that flupirtine, in contrast to pentazocine, did not produce any impairment in driving ability in healthy volunteers.     

The effect of ondansetron on gastric emptying in the conscious rat

The 5-HT3 receptor antagonist ondansetron (GR38032F) enhanced the action of a protein-rich solution in delaying gastric emptying in the conscious gastric fistula rat, but had no effect on the emptying of isotonic or hypertonic saline, acid or FOY-305 which delays emptying by release of cholecystokinin (CCK). The specific CCK-A antagonist (L-364,718) increased gastric emptying of protein-rich meals. L364,718 also increased emptying in the presence of ondansetron. They indicate that protein-rich meals release both CCK and 5-hydroxytryptamine which act in different ways to control gastric motility.     

Microcomputer use in measuring onset,duration, and recovery from nondepolarizing skeletal muscle relaxants in rabbits

This report describes a method which has been developed to use an Apple II Plus microcomputer in studies of the time course and dose response of potential skeletal muscle relaxant drugs. Rabbits are anesthetized with pentobarbital, tracheotomized, and the right common carotid artery is cannulated for direct measurement of blood pressure and heart rate. The ulnar nerve is stimulated at the elbow. Twitch, “train-of-four” (T₄), tetanus, and posttetanic potentiation (PTP) are monitored by a force displacement transducer. These analog physiological signals are led from a polygraph through an lsaac Cyborg analog-to-digital converter attached to the microcomputer where they are stored in digital form. Each animal receives the test drug twice. Spontaneous recovery is allowed following the first administration while the second dose is reversed with neostigmine. The rate of onset, time and magnitude of maximal effect, time and rate of recovery, and time and magnitude of cardiovascular changes are all automatically calculated for both the control and the neostigmine reversal experimental phases. The effect of the test dose on each parameter is rated to provide a composite score for each dose of the test compound as the dose-response series is completed. All parameters are plotted using a dot-matrix printer and data are stored to disk. When doses, in 0.1-log intervals, from the dose which produces no measurable effect to those doses producing unacceptably long durations, have been administrated, the computer uses the composite scores to report an optimal dose. Using regression analysis, the dose required to provide a 90% depression of twitch is calculated. This calculated dose is compared to equiefficacious doses of other test compounds. A tabular, graphic, and narrative report of the drug's effects is generated by the computer with comparison to other compounds of pctential interest. These programs and methods provide efficient data collection and data analysis. They provide for standard report generation. Finally, they allow for comparisons to be made among many pharmacologic parameters of many test compounds, thus providing understanding of the mechanisms of action of the test compounds.     

The effect of dantrolene sodium on rat skeletal muscle in relation to the plasma concentration.

Dantrolene sodium is a muscle relaxant used in the treatment of spasticity. It has been shown to interfere with calcium release from the sarcoplasmic reticulum and thus to inhibit excitation--contraction coupling. The effect of dantrolene sodium on the twitch tension of the tibialis anterior muscle of the rat was measured after 2 mg/kg i.v. or 25 mg/kg orally. Plasma concentrations were estimated at maximum twitch depression and during recovery from the block. In a separate series of experiments the half-life of labelled dantrolene sodium was measured in blood plasma, skeletal muscle and heart muscle of rats. Dantrolene sodium 2 mg/kg i.v. gave a maximal block of approximately 47%, the mean dantrolene sodium concentration was then 5.8 microgram/ml. A half-life for distribution of 1.1 min and an elimination half-life of 31 min after intravenous administration were observed, elimination rate constants in skeletal and heart muscle were comparable. Recovery from the block went much slower, the half-time of the process being approximately 80 min. Dantrolene sodium 25 mg/kg orally gave a maximal block of approximately 38% at a mean plasma concentration of 3.6 microgram/ml after 14 min. The recovery was again very slow. These experiments demonstrated that dantrolene sodium acts according to a two-compartment pharmacokinetic model. There was a discrepancy between duration of effect and plasma concentration of dantrolene sodium in the rat. This suggests that the receptor for dantrolene sodium is not located in the central compartment.     

Evaluation of oral skeletal muscle relaxants in the morphine-induced straub tail test in mice

Morphine is known to produce a characteristic and reproducible elevation of the tail in mice (Straub tail response). The morphine-induced Straub tail response in mice has been used to evaluate skeletal muscle relaxant (SMR) activity of compounds administered intraperitoneally (i.p.). This model was used to evaluate the oral (p.o.) efficacy of a number of SMRs and other pharmacological agents. Male mice (n ≥ 5) were given test drugs p.o. followed by morphine sulfate [15 mg/kg subcutaneously (s.c.)] 15 min later. The mice were scored all or none for a Straub tail reaction 45 min later. Graded doses of active compounds were further evaluated for ED₅₀ estimation by probit analysis. ED₅₀ values (mg/kg) were estimated for the following compounds: baclofen (6.4), chlorpromazine HCl (3.8), cyclobenzaprine HCl (24.6), dantrolene Na (14.4), diazepam (8.3), haloperidol (6.2), naloxone HCl (8.7), phenoxybenzamine HCl (47.6), phentolamine HCl (265), and trifluoperazine HCl (25.4). These ED₅₀ values appeared to correlate with initial adult human daily oral doses for muscle relaxation. The following compounds inhibited the Straub tail response in ≤ 40% of the mice tested at the doses indicated (mg/kg): carisoprodol (300), lidocaine (100), mephenesin (300), phenytoin (100), procainamide HCl (100), procaine HCl (100), propranolol HCl (100), quinidine sulfate (100); and all selected calcium-channel blockers (30), antidepressants (30), and neuromuscular blocking agents (> 10 times the literature i.p. ED₅₀ values with the exception of gallamine triethiodide at 30 mg/kg) that were tested. Pentobarbital Na was active only at doses that impaired the righting reflex. This animal model was thus determined to be useful for evaluating SMR efficacy and in predicting.     

家兔不同形态肌肉的肌梭分布情况

目的探究家兔不同形态肌肉的肌梭分布。方法肌构筑法和HE染色法。结果家兔胸大肌为一扇形的阔肌,肌重11．21g,肌梭密度为12．98个／g,但各部位的肌梭密度不同,横行纤维中部最高(21．68个／g),斜行纤维以远端为高;跖肌是一羽肌,肌重3．94g,肌梭密度为16．94个／g,内侧部近端最高(47．71个／g),外侧部以中部密度最高(19．77个／g);趾长伸肌为长肌,肌重2．20g,肌梭密度26．24个／g,其肌腹中部密度最高(44．76个／g)。结论不同形态肌的肌肉的梭分布与肌纤维排列有关;不同形态的肌肉或同一块肌肉,肌梭分布不均匀;小肌较大肌、伸肌较屈肌有更高的肌梭密度。     

Adenosine modulation of resting vascular tone in rabbit skeletal muscle

Summary The effects of adenosine and adenosine antagonists on arteriolar vessel diameters were studied in the rabbit tenuissimus muscle in situ by means of intravital microscopy. Topically applied adenosine dose-dependently dilated transverse and terminal arterioles, an effect which was competitively antagonized by alkylxanthines. Topically applied alkylxanthines per se evoked dose-dependent vasoconstriction with the same potency order as for their adenosine antagonism. Furthermore, the concentrations of alkylxanthines eliciting vasoconstriction correlated with the observed pA₂ values for their adenosine antagonism. The data indicate a physiological role of adenosine, or other purines, as regulator of resting vascular tone in mammalian skeletal muscle. Send offprint requests to Lars Gustafsson at the above address