Long-term effects of botulinum toxin on neuromuscular function

BACKGROUND: Recent reports indicate increased incidence of Clostridium botulinum infections, particularly among drug abusers and tissue allograft recipients. Botulinum toxin also has potential application in biochemical warfare. The neurotoxin-induced paralysis often requires mechanical ventilation with and without muscle relaxants. The authors investigated the long-term effects of botulinum toxin on muscle function, expression of nicotinic acetylcholine receptors (nAChRs), and their interaction with muscle relaxant, atracurium. METHODS: Rats (n=30) were injected with varying doses (0.625, 2.5, and 10 U) of botulinum toxin into the tibialis muscle. Control animals (n=9) received an equivalent volume of saline. At 128 days after injection, neuromuscular function, pharmacodynamics of atracurium, and nAChRs were evaluated. RESULTS: Nerve-evoked tensions, including tetanic tension and muscle mass, were decreased on the toxin-injected side in a dose-dependent manner relative to saline-injected controls as well as the contralateral side. Specific muscle tension and specific tetanic muscle tension (tensions/muscle mass) were not reduced. The ED10 of atracurium was reduced, the ED50 was unchanged, and the ED90 was increased in the highest (10-U) dose of toxin group. The atracurium plasma concentration to maintain a steady state 50% paralysis was significantly reduced in the 10-U toxin group. The nAChR concentrations in the tibialis muscle were significantly increased in a dose-dependent manner in all experimental groups. CONCLUSION: Botulinum toxin causes dose-dependent long-term neuromuscular changes. The loss of tension generating capacity is almost exclusively related to muscle atrophy, because the specific tension did not change. The decreased ED10, unaltered ED50, and increased ED90 to atracurium suggest its interactions with different isoforms of receptors having varying sensitivity to atracurium. The absence of fade, despite the persistent botulinum toxin-induced denervation (increased nAChRs), suggests that the up-regulated nAChRs may have compensated for the prejunctional effects of botulinum toxin.     

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.     

Prednisolone-induced muscle dysfunction is caused more by atrophy than by altered acetylcholine receptor expression

Large doses of glucocorticoids can alter muscle physiology and susceptibility to neuromuscular blocking drugs by mechanisms not clearly understood. We investigated the effects of moderate and large doses of prednisolone on muscle function and pharmacology, and their relationship to changes in muscle size and acetylcholine receptor (AChR) expression. With institutional approval, 35 Sprague-Dawley rats were randomly allocated to receive daily subcutaneous doses of 10 mg/kg prednisolone (P10 group), 100 mg/kg prednisolone (P100 group), or an equal volume of saline (S group) for 7 days. A fourth group of rats was pair fed (food restricted) with the P100 rats for 7 days (FR group). On Day 8, the nerve-evoked peak twitch tensions, tetanic tensions, and fatigability, and the dose-response curves of d-tubocurarine in the tibialis cranialis muscle were measured in vivo and related to muscle mass or expression of AChRs. Rate of body weight gain was depressed in the P100, FR, and P10 groups compared with the S group. Tibialis muscle mass was smaller in the P100 group than in the P10 or S groups. The evoked peak twitch and tetanic tensions were less in the P100 group than in the P10 or S groups, however, tension per milligram of muscle mass was greater in the P100 group than in the S group. The 50% effective dose of d-tubocurarine (microg/kg) in the tibialis muscle was smaller in the P10 (33.6 +/- 5.4) than in the S (61.9 +/- 5.0) or the P100 (71.3 +/- 9.6) groups. AChR expression was less in the P10 group than in the S group. The evoked tensions correlated with muscle mass (r(2) = 0.32, P < 0.001), however, not with expression of AChR. The 50% effective dose of d-tubocurarine did not correlate with muscle mass or AChR expression. Our results suggest that the neuromuscular dysfunction after prednisolone is dose-dependent, and derives primarily from muscle atrophy and derives less so from changes in AChR expression. Implications: The mechanisms by which chronic glucocorticoid therapy alters neuromuscular physiology and pharmacology are unclear. We suggest that the observed effects are dose-dependent and derive primarily from muscle atrophy and derive less from changes in acetylcholine receptor expression.     

Tetanic fade during neuromuscular blockade produced by atracurium in the rat diaphragm preparation

In the present investigation, we studied and measured the phenomenon of tetanic fade and peak tetanic tension depression in the rat diaphragm preparation in the presence of a blocking concentration of atracurium (e.g., 10 μmol.l^-1). Atracurium (10 μmol.l^-1) produced a pronounced tetanic fade (i.e., 47–69% reduction of total sustained tetanic tension) at a time (15 s) when it reduced the peak tetanic tension by only 25%. The time course for total tetanic fade was 30–35 s, whereas the time taken for complete peak tetanic tension depression was 3-3.5 min, suggesting that the two effects were produced via different mechanisms, involving presynaptic and postsynaptic mechanism. It was concluded that atracurium produces a profound tetanic fade, with respect to its effect on twitch or tetanic tension, suggesting that the drug is a potent neuromuscular blocker, with rapid onset of blockade.     

Effects of botulinum toxin A on functional outcome during distraction osteogenesis.

Distraction osteogenesis is useful for correcting limb length inequality, deformities, or short stature. Despite success with bone formation, soft tissue maladaptations including muscle and joint contracture may lead to undesirable results. Botulinum toxin A has been useful in treating spasticity in cerebral palsy, and has been used clinically in select cases to allay contracture in distraction osteogenesis. This study examines the toxin's efficacy in preventing distraction-induced loss of muscle strength and range of motion. The left tibias of 15 New Zealand White rabbits were distracted 1.5 mm/day until approximately a 20% gain was achieved. Each treatment group was divided into animals injected with saline or botulinum toxin in either the gastrocnemius or tibialis anterior muscles. A control group of two additional animals underwent no surgical procedure. Strength and range of motion were assessed prior to, and following, the experiment. At the study's end, animals were euthanized and muscles were harvested, when lengths and weights were recorded. All muscles injected with botulinum toxin showed decreased wet weight and persistent weakness upon completion of the study. Range of motion decreased in all distracted animals. When the gastrocnemius was injected, its strength was reduced but the tibialis anterior strength was preserved, and the limb achieved 22% greater dorsiflexion than saline controls (p = 0.016). When the tibialis anterior received the toxin, plantarflexion was increased by 23% (p = 0.049). Botulinum toxin injection prior to limb distraction increases the "post-lengthened" excursion of the injected muscle and this increased length may have a protective effect on its antagonist. In toxin-injected gastrocnemius muscles, the level of equinus contracture is reduced due to length gains in the Achilles tendon while the anterior tibialis maintains its ability to generate torque. Injection of botulinum toxin in the gastrocnemius may minimize equinus contracture and protect the anterior tibialis from damage during human tibial lengthening. Longer follow-up studies are needed to ensure that toxin-induced muscle weakness resolves with time.     

Effect of atracurium on twitch, tetanic and post-tetanic twitch responses at the rat neuromuscular junction

The effect of atracurium on the phenomenon of post-tetanic potentiation, which is believed to be of a presynaptic origin, i.e. due to endogenous transmitter release, was investigated to see if atracurium had a presynaptic inhibitory mechanism at the rat neuromuscular junction. The results showed that atracurium (0.8-80 microM) reduced the indirectly elicited twitch, tetanic and post-tetanic twitch tensions, in a dose-dependent manner. Atracurium (1 microM) produced a tetanic fade in the preparations stimulated at 20 Hz and above. The acetylcholine (ACh) released at high frequencies of nerve stimulation was collected, in the presence of physostigmine (0.77 microM), added to a rat ileum preparation, in which it produced a small contraction which was blocked by atracurium (1 microM), which in turn blocked the contracture produced by ACh (1 microM) added directly to the organ bath. It was concluded that, in addition to its well-known competitive blockade of postsynaptic ACh receptors, atracurium may also have a presynaptic inhibitory effect at the neuromuscular junction.     

Atracurium and vecuronium: repeated bolus injection versus infusion.

The purpose of this study was to compare the characteristics of recovery from neuromuscular blockade after either atracurium or vecuronium given by intravenous infusion or by repeated injection. Four groups of 10 patients each were studied during nitrous oxide narcotic anesthesia. An initial intravenous dose of 2 x ED95 of either muscle relaxant was followed by an intravenous infusion started at 5% recovery of control twitch tension and adjusted for 95% block or by repeated injection of 0.6 x ED95 administered whenever twitch tension had returned to 25% of control. There were no significant differences between the maintenance doses required based on method of administration: atracurium repeated injection, 1.6 +/- 0.3 x ED95 h-1; atracurium infusion, 1.7 +/- 0.3 x ED95 h-1; vecuronium repeated injection, 1.8 +/- 0.5 x ED95 h-1; and vecuronium infusion, 1.6 +/- 0.4 x ED95 h-1. Nevertheless, differences of up to 20 min were noted in the recovery indices in the following order: atracurium repeated injection = atracurium infusion less than vecuronium repeated injection less than vecuronium infusion. A single dose of neostigmine (7 micrograms/kg) significantly reduced the recovery indices, thereby eliminating their differences.     

The Effects of botulinum toxin A on muscle histology during distraction osteogenesis

Distraction osteogenesis is a highly successful method of bone formation, yet muscle fibrosis and contractures can result in significant morbidity. In the current study, we investigate the efficacy of botulinum toxin A in preventing fibrosis and potentially increasing muscle development in distracted muscles. Fifteen New Zealand White rabbits underwent tibial distraction at 1.5 mm/day until a 20% gain was achieved. Treatment groups were divided by drug (saline or botulinum toxin) and target muscle (gastrocnemius or tibialis anterior). Two additional control animals received no treatment. Bromeodeoxyuridine was delivered continuously throughout the 8‐week experiment, and following muscle harvest. Tissues were stained for BrdU, Pax‐7, vimentin, and haematoxylin and eosin staining. Mitotic activity increased in all distracted animals; however, in the animals receiving botulinum toxin A injections into the gastrocnemius, the antagonist tibialis anterior suffered up to 9% less fibrosis than distraction alone (p = 0.024). Use of botulinum A toxin did not appear to promote or improve neogenesis of muscle fibers, nor did it decrease fibrosis in the injected muscles. It appears from this study, and a previously published study on the effects of this toxin on muscle function, that botulinum A toxin maybe of some benefit in decreasing morbidity in the antagonist muscle but not the muscle injected with the toxin. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27:310–317, 2009     

Decreased muscle speed, strength and fatigability following two hours of tourniquet-induced ischaemia.

Contractile and morphological properties of the rabbit tibialis anterior muscle were measured 48 hours following a two-hour ischaemic episode. Ischaemia was induced using a specially-designed pneumatic tourniquet placed on the rabbit thigh. Maximum tetanic tension of muscle subjected to ischaemia (381 +/- 77 g) was only about 30% of the tension generated by control muscles (1,212 +/- 67 g). The rate of rise of tetanic tension of muscles subjected to ischaemia (15.9 +/- 3 g/ms) was only 33% of control values (44.5 +/- 5.9 g/ms). Muscle fatigue index increased significantly from 0.22 +/- 0.7 in control muscles to 0.55 +/- 0.09 in ischaemic muscles suggesting that muscles subjected to ischaemia had a greater endurance capacity than control muscles. Morphologically, focal necrotic regions and inflammatory cells were observed in ischaemic muscle fibers. Taken together, these data are consistent with selective damage to the fast glycolytic muscle fibers within the ischaemic tibialis anterior muscles. Thus, ischaemia results in overall decreased muscle speed, strength and fatigability.     

Interactıon of Botulınum Toxın Type A wıth Local Anesthetıc Agents: An Experımental Study with Rabbıts

Injection of botulinum toxin is a painful procedure, limiting the number of patients treated. This study was designed to establish whether infiltration of local anesthetics plays a role in the effectiveness of botulinum toxin. For the study, 24 New Zealand white rabbits were divided into three groups. In all three groups, local anesthetics (prilocaine, lidocaine, lidocaine, and epinephrine) were injected into the right anterior auricular muscle before a 2.5-U injection of botox A. The contralateral anterior auricular muscle of all the rabbits was injected with the same dose of the toxin to serve as a control. Photographic documentation was recorded; electromyographic study was performed; and results were statistically analyzed. The results show that local anesthetics do not play a role in the efficacy of botulinum toxin. Thus, the use of infiltrative local anesthetics before botulinum toxin injection is a safe method for achieving a less painful procedure for the patient.     

GDNF overexpression fails to provoke muscle recovery from botulinum toxin poisoning: a preliminary study

Glial cell line-derived neurotrophic factor (GDNF) has potent axonal growth and survival effects on motoneurons. This study used transgenic Myo-GDNF mice to assess the effects of targeted GDNF overexpression on functional recovery after botulinum toxin type A (BTxA) chemodenervation. BTxA (0.1 U) was injected into the tibialis anterior (TA) muscle of wild-type CF1 and transgenic Myo-GDNF mice. On days 1, 7, 14, and 21 after injection, evoked muscle force production and muscle mass were measured (n = 6, for each group at each time point). Greater maximal tetanic force and calculated specific force were evoked in Myo-GDNF animals when compared with control CF1 animals at days 1, 7, and 21. However, the differences were not statistically significant. Similarly, modest reductions in muscle atrophy in the Myo-GDNF group at all time points were not statistically significant. Targeted overexpression of GDNF in the muscles of Myo-GDNF mice did not improve motor recovery in the first 21 days after BTxA chemodenervation.     

Effects of botulinum toxin‐induced paralysis on postnatal development of the supraspinatus muscle

The mechanical environment plays an important role in musculoskeletal tissue development. The present study characterized changes in supraspinatus muscle due to removal of mechanical cues during postnatal development. An intramuscular injection of botulinum toxin type A (BTX) was used to induce and maintain paralysis in the left shoulders of mice since birth while the right shoulders received saline and served as contralateral controls. A separate group of animals was allowed to develop normally without any injections. Muscles were examined postnatally at various time points. The maximum isometric tetanic force generated by the muscle was significantly reduced in the BTX group compared to saline and normal groups. The paralyzed muscles were smaller and showed significant muscle atrophy and fat accumulation on histologic evaluation. Myogenic genes myogenin, myoD1, myf5, myf6, and fast type II myosin heavy chain (MHC) isoform were significantly upregulated while slow type I MHC isoform was significantly downregulated in the BTX group. Adipogenic genes C/EBPα, PPARγ2, leptin, and lipoprotein lipase were significantly upregulated in the BTX group. Results indicate that reduced muscle loading secondary to BTX‐induced paralysis leads to fat accumulation and muscle degeneration in the developing muscle. Understanding the molecular and compositional changes in developing supraspinatus muscles may be useful for identifying and addressing the pathological changes that occur in shoulder injuries such as neonatal brachial plexus palsy. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29:281–288, 2011     

Effects of neuromuscular-blocking drugs in rats in vivo: direct measurements in the diaphragm and tibialis anterior muscle

BACKGROUND: Effects of neuromuscular-blocking drugs are often investigated in rodents using both the diaphragm in vitro and the tibialis anterior muscle in vivo. Differences in the properties of these muscles cannot be neglected. We evaluated the neuromuscular effects of drugs on the rat diaphragm in vivo in comparison with the tibialis anterior muscle, directly measuring twitch tension with a force transducer. METHODS: Respectively using sternotomy and an approach via the gluteal space, transducers were attached to the diaphragm and the tibialis anterior muscle. Phrenic and sciatic nerves were stimulated supramaximally by single square pulses to record isometric contraction of muscles. Pancuronium, vecuronium, or rocuronium was infused continuously at a rate adjusted repeatedly until stable tension was obtained. Effective doses for 50% (ED 50) and 90% (ED 90) depression of tension were calculated, using a cumulative infusion dosing method. RESULTS: Isometric contraction of the diaphragm could be recorded despite movements of the heart and lungs. For all three drugs, both mean ED 50 and ED 90 were more than twice as large for the diaphragm as for the tibialis anterior (P<0.05). In addition, slopes of dose-response curves for the diaphragm were significantly less steep than those of the tibialis anterior for the three drugs. CONCLUSION: Neuromuscular-blocking effects on the diaphragm can be recorded in vivo. According to direct contractile force measurement, the diaphragm is more resistant to non-depolarizing neuromuscular-blocking drugs than the tibialis anterior muscle.     

Experimental study on the influence of tension, immobilisation and denervation on muscle transplantation

To observe the effects of tension and immobilisation on denervated muscle, rats' denervated soleus muscles were transplanted orthotopically at different tensions: high, neutral, moderate and low tension with immobilisation. Results were evaluated by measuring muscle mass, twitch and tetanic tension, and histologically by HE staining. The results showed better preservation of muscle weight in the high tension group. Atrophy and loss of function were rapid during the first 4 weeks and were greatest in the low tension group. Rate of atrophy was slowed and relatively stabilised at the eighth postoperative week. We conclude that increased tension with immobilisation produced slower initial atrophy and loss of function in denervated muscle flaps. Although slower, the atrophy continued during the prolonged immobilisation and there was no significant difference compared with neutral tension at a later period. Moreover, immobilisation produced atrophy and affected function regardless of the amount of tension. Increased tension decelerates and decreased tension accelerates denervation atrophy of muscle. Thus denervation, immobilisation and reduced tension are all detrimental in muscle transplantation.     

Stiffness and muscle function with age and reduced muscle use.

Changes in passive muscle stiffness with age and disuse were assessed in male Fischer-344 and Brown Norway rats. Three groups of rats were studied: young (approximately 7 months old), old (approximately 33 months old), and old that had undergone 2 weeks of hindlimb unweighting, a model of reduced muscle use. Four hindlimb muscles were examined: the soleus (postural), plantaris (locomotor), extensor digitorum longus (nonpostural), and peroneus longus (nonpostural). Supramaximal stimuli elicited peak tetanic tensions throughout the available range of motion (amount of muscle elongation before the maximal attainable contractile or tetanic tension is obtained) for each muscle, permitting the creation of length-tension curves. Passive tension (amount encountered at each millimeter of change in muscle length) was also recorded throughout the available range of motion and was unchanged with aging and unchanged or reduced with hindlimb unweighting; muscle stiffness remained unchanged under both conditions. Passive tension, however, accounted for a greater proportion of total tension with age and particularly with hindlimb unweighting. A significant loss in muscle range of motion, resulting in a leftward shift in the length-tension curve, occurred with aging in only the plantaris. Hindlimb unweighting resulted in a marked loss in muscle range for all four muscles studied, suggesting that the remaining muscle force was constrained to a very small arc. Significant declines in muscle mass and peak contractile tension, associated with age and hindlimb unweighting, were observed for all four muscles.     

Bupivacaine-induced myotoxicity and its effect on botulinum toxin paresis

PURPOSE: To determine the effect of the coinjection of bupivacaine with botulinum toxin type A on the degree of muscular paralysis. Enhancement of paralysis could allow a decreased dose of neurotoxin treatment, thus reducing the risk for neutralizing antibody formation. METHODS: Prospective, randomized, double-blind study. Sixteen consecutive patients undergoing treatment of glabellar furrows received botulinum toxin A reconstituted with bupivacaine 0.75% to one corrugator muscle and botulinum toxin A reconstituted with nonpreserved normal saline to the contralateral muscle. Patients were evaluated on days 0 (injection day), 3, 7, 30, 60, and 90. Patients also completed a questionnaire each visit regarding their assessment of paralysis, asymmetry, and adverse effects. RESULTS: At 1 week after botulinum toxin A injection, 68.8% of the patients showed greater weakness on the bupivacaine-reconstituted side as opposed to 25.0% of patients showing greater weakness on the saline-reconstituted side. At 1 and 3 months, there was no statistical difference in weakness between the saline and the bupivacaine sides. The survey revealed that 56% of the patients had greater pain on the saline side, 31% on the bupivacaine side, and equal pain in 13%. CONCLUSIONS: Reconstituting botulinum toxin A with bupivacaine is safe, does not limit efficacy, and does not reduce the degree or relative duration of muscular paralysis. Reconstituting botulinum toxin A with bupivacaine results in faster onset of paresis, possibly due to a synergistic effect of bupivacaine induced myotoxicity. Utilizing bupivacaine may result in less pain for patients.     

Intravenous ranitidine antagonizes intense atracurium-induced neuromuscular blockade in rats

The neuromuscular action of ranitidine, an H2-receptor antagonist, was investigated by determining its effect on atracurium-induced neuromuscular blockade in urethane-anesthetized and mechanically ventilated male Sprague-Dawley rats. An intravenous bolus and an infusion of atracurium were administered to produce a stable 93 +/- 5% (n = 11) neuromuscular blockade as judged by tibialis anterior muscle twitch response. Ranitidine administered as a 1, 5, or 10 mg/kg normal body weight IV bolus during continuous atracurium infusion produced marked antagonism of neuromuscular paralysis. The percentage of antagonism (25 +/- 9%; n = 4; 53 +/- 19%, n = 4; and 79 +/- 9%, n = 3, respectively) was linearly related to the dose of ranitidine (r = 0.86, P less than 0.05). These results suggest that IV ranitidine has a significant anticholinesterase action against atracurium-induced neuromuscular blockade.     

Evaluation of a device for the measurement of the evoked tensions of the rectus abdominis muscle

A device was developed to measure the evoked tensions of the rectus abdominis muscle which consisted of a fluid-filled reservoir wedged between the rectus abdominis muscle and a self-retaining retractor. The evoked contractions of the rectus muscle were compared with that of the tibialis anterior muscle in twelve dogs anaesthetised with pentobarbitone. Significantly greater amounts of tubocurarine were required to depress the response to train-of-four stimuli and the twitch tensions of the rectus muscle than the tibialis. The tibialis recovered faster, spontaneously or after neostigmine, than the rectus in eight of the animals; the opposite occurred in the other four. The present device can be useful during surgery for the evaluation of abdominal muscle tension.     

Cisatracurium am M. orbicularis oculi Vergleich der neuromuskulären Wirkung von Cisatracurium und Atracurium am M. orbicularis oculi und M. adductor pollicis

OBJECTIVES: Muscle relaxants have different pharmacodynamic profiles in various muscles. Therefore, results obtained for one muscle cannot be extrapolated to other muscles. In the adductor pollicis muscle cisatracurium exerts a pharmacodynamic profile comparable to atracurium, despite the known difference in onset time. However, studies evaluating the neuromuscular effect of cisatracurium in different muscles are lacking. Accordingly, this study compares the pharmacodynamic profile of cisatracurium and atracurium in the orbicularis oculi muscle (OO) - which shows a neuromuscular course similar to the diaphragm and the laryngeal muscles - and the adductor pollicis muscle (AP). METHODS: Forty-five patients (ASA I-II), scheduled for elective spinal surgery were anaesthetized with propofol and fentanyl. Endotracheal intubation was performed without using a muscle relaxant. Neuromuscular transmission was monitored using acceleromyography in both muscles. Patients received 0.1 mg/kg (2x ED(95)) or 0.15 mg/kg (3x ED(95)) cisatracurium, or 0.5 mg/kg atracurium (2x ED(95)) at random. Onset and recovery times were measured according to the recommendation of the Copenhagen Consensus Conference. RESULTS: Onset time was significantly shorter in the OO than in the AP following 0.15 mg/kg cisatracurium and 0.5 mg/kg atracurium (P<0.05). No differences in onset time between the two muscles were found after 0.1 mg/kg cisatracurium. The recovery of T(1) to 10% of its control was completed sooner in the OO than in the AP in all three groups (P<0.05). CONCLUSIONS: Cisatracurium shows a dose-dependent shorter onset time in the OO than in the AP. This is consistent with the current view that the onset of non-depolarizing neuromuscular blockers is more rapid in the OO than in the AP. However, at least a dose of 3x ED(95) of cisatracurium was necessary to show a difference in onset time between both muscles. In contrast, atracurium is reported to lead to a significantly shorter onset of neuromuscular block in the OO following 2x the ED(95). The more rapid recovery of T(1) to 10% of its control in all three groups in the OO is due to the relative resistance of this muscle to muscle relaxants.     

Skeletal muscle adaptations following spinal cord contusion injury in rat and the relationship to locomotor function: a time course study.

Experimental spinal cord injury (SCI) via contusion of moderate severity results in residual locomotor deficits, including a lack of coordination and trunk stability. Given that muscle contractile properties and fiber composition adapt to reduced neural input and/or weight bearing, contusion-induced locomotor deficits may reflect changes in hindlimb skeletal muscle. Therefore, we examined muscle adaptations during early (1 week), intermediate (3 week), and late (10 week) stages of motor recovery after moderate SCI. Forty-two Sprague Dawley rats underwent SCI via 1.1mm cord displacement with the OSU impact device or served as age and weight-matched or laminectomy controls. Subsets of rats had soleus (SOL) in vitro physiological testing or SOL and extensor digitorum longus (EDL) myosin heavy chain (MHC) fiber type analysis. At 1 week post-SCI during paralysis/paresis, a significant decrease in wet weight occurred in the plantaris, medial/lateral gastrocnemius (MG/LG), tibialis anterior, and SOL. Changes in contractile properties of the SOL did not accompany muscle wet weight changes. By 3 weeks, the loss of weight-bearing activity early after SCI induced significant decreases in SOL peak twitch and peak tetanic tension as well as significantly greater IIx MHC expression in the EDL. By 10 weeks post-SCI, after several weeks of weight supported stepping, muscle wet weight, contractile properties and MHC composition returned to baseline levels except for MG/LG atrophy. Thus, muscle plasticity appears to be extremely sensitive to locomotor deficits and their resolution after moderate spinal cord contusion.