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PubMed2000

cGMP-mediated phosphorylation of heat shock protein 20 may cause smooth muscle relaxation without myosin light chain dephosphorylation in swine carotid artery.

Nitrovasodilators such as nitroglycerine, via production of nitric oxide and an increase in [cGMP], can induce arterial smooth muscle relaxation without proportional reduction in myosin light chain (MLC) phosphorylation or myoplasmic [Ca2+]. These findings suggest that regulatory systems, other than MLC phosphorylation and Ca2+, partially mediate nitroglycerine-induced relaxation. In swine carotid artery, we found that a membrane-permeant cGMP analogue induced relaxation without MLC dephosphorylation, suggesting that cGMP mediated the relaxation. Nitroglycerine-induced relaxation was associated with a reduction in O2 consumption, suggesting that the interaction between phosphorylated myosin and the thin filament was inhibited. Nitroglycerine-induced relaxation was associated with a 10-fold increase in the phosphorylation of a protein on Ser16. We identified this protein as heat shock protein 20 (HSP20), a member of a family of proteins known to bind to thin filaments. When homogenates of nitroglycerine-relaxed tissues were centrifuged at 6000 g, phosphorylated HSP20 preferentially sedimented in the pellet, suggesting that phosphorylation of HSP20 may increase its affinity for the thin filament. We noted that a domain of HSP20 is partially homologous to the 'minimum inhibitory sequence' of skeletal troponin I. The peptide HSP20110-121, which contains this domain, bound to actin-containing filaments only in the presence of tropomyosin, a characteristic of troponin I. High concentrations of HSP20110-121 abolished Ca2+-activated force in skinned swine carotid artery. HSP20110-121 also partially decreased actin-activated myosin S1 ATPase activity. These data suggest that cGMP-mediated phosphorylation of HSP20 on Ser16 may have a role in smooth muscle relaxation without MLC dephosphorylation. HSP20 contains an actin-binding sequence at amino acid residues 110-121 that inhibited force production in skinned carotid artery. We hypothesize that phosphorylation of HSP20 regulates force independent of MLC phosphorylation via binding of HSP20 to thin filaments and inhibition of cross-bridge cycling.

Actins↗
PubMed2004

Is the degree of sensitivity to nondepolarizing muscle relaxants related to requirements for postoperative ventilation in patients with myasthenia gravis?

The purpose of this study was to examine whether the degree of sensitivity to nondepolarizing muscle relaxants is related to the requirement for postoperative ventilatory support in patients with myasthenia gravis. Thirty-six patients with myasthenia gravis undergoing trans-sternal thymectomy were monitored by electromyography in order to assess the neuromuscular response to vecuronium. After calibration to 100% of baseline electromyographic response values using an EMG monitor, incremental doses of 5, 10 and 20 microg/kg of vecuronium were administrated to produce 95% neuromuscular blockade and to obtain a cumulative dose-response curve for each patient. A univariable logistic regression with odds ratio was used to examine the predictive variables of prolonged postoperative ventilation. Depending on their postoperative ventilatory needs, patients were divided into an early extubation group and a prolonged ventilatory group. There were no significant differences between the two groups in terms of vecuronium ED95 (prolonged ventilation group: 23.2 +/- 18 microg/kg; early extubation group: 23.2 +/- 18 microg/kg P=0.129) and vecuronium requirement to maintain less than 25% neuromuscular blockade (prolonged ventilation group: 24 +/- 1.7 mg/kg; early extubation group: 3.8 +/- 4.5 mg/kg P=0.249). There were, however, significant differences in the incidence of a history of previous respiratory crises and the presence of bulbar palsy between the early extubation and prolonged ventilation groups. History of previous respiratory crisis (odds ratio (OR), 3.5; 95% confidence interval (CI), 1.0-13; P=0.03) and presence of bulbar palsy (OR, 3.7; 95%CI, 0.9-15; P=0.049) were associated with the need for prolonged postoperative ventilation. However, we failed to demonstrate that the degree of sensitivity to nondepolarizing muscle relaxants was related to an increased requirement for postoperative ventilation in patients with myasthenia gravis.

Dose-Response Relationship, Drug↗
PubMed1988

Effect of biliary obstruction on muscle relaxation with vecuronium.

Vecuronium bromide was used as a muscle relaxant in 30 patients undergoing biliary surgery. Ten patients had biliary obstruction, 10 patients without biliary obstruction were elderly (78 +/- 1.2 yrs; mean +/- SEM) and 10 patients without biliary obstruction were young or middle-aged (35 +/- 3.0 yrs). The muscle response to ulnar nerve stimulation was measured electromyographically. The results indicate that the neuromuscular blocking effect of vecuronium is significantly prolonged in patients with biliary obstruction. The mean total dose of vecuronium was lower in the patients with biliary obstruction (1.2 +/- 0.1 micrograms kg-1 min-1) than in the elderly patients (1.7 +/- 0.2 micrograms kg-1 min-1) and young patients (2.0 +/- 0.2 micrograms kg-1 min-1; P less than 0.05). There were no statistically significant differences in the distribution half-lives or in the distribution volumes of vecuronium between the groups.

Adult↗
PubMed1982

Several methods for the evaluation of muscle relaxants in gamma motor activity.

(1) The active tension-extension diagram of slowly (2 mm/sec) stretched triceps surae muscle of the decerebrate cat has been shown to be a sensitive indicator of spinal motor activity. For example, diazepam at doses larger than 0.01 mg/kg shifted the diagram parallel to the right. (2) The effects of central muscle relaxants on the gamma system can be observed in functionally isolated group Ia fibres but also in the "integrated" afferent discharges of the whole (or a part of) S1 dorsal root in response to stretching of the triceps surae muscle. The latter has statistically more value than the former recording. The effect of diazepam could block the gamma fibres selectively. Diazepam at doses larger than 0.1 mg/kg could block the gamma activity totally. (3) More than 3 months after degeneration with dry ice, the reinnervated muscle shows a fully recovered twitch tension but fails to show gamma activity (alpha muscle). Diazepam has no effect on the discharge from the muscle spindles in the alpha muscle.

Animals↗
PubMedDate not supplied

Mesolimbic dopamine turnover effects of benzodiazepines do not correlate with sedative and muscle-relaxant potencies.

Benzodiazepines are known to decrease the dopamine turnover in the mesolimbic dopaminergic system in stimulated rather than in basal conditions. Stimulation of dopamine turnover can be achieved by administration of the dopamine antagonist haloperidol. In the present paper, we tested the hypothesis that the effect of the benzodiazepines on the mesolimbic dopamine turnover is mediated by the benzodiazepine receptor, comparing the minimal potency of inhibition of the stimulated dopamine turnover with the ED50 values for the sedative and muscle-relaxant actions of the compounds. Five compounds were studied: desmethyldiazepam, lorazepam, flunitrazepam, triazolam and brotizolam. In contrast to the other compounds, lorazepam appeared to have no effect on the haloperidol-induced increase in DOPAC concentration. The relative potency of the benzodiazepines for this effect on the haloperidol-induced DOPAC increase is very different from that on sedation and muscle relaxation, suggesting that the effect on the mesolimbic dopamine turnover is not mediated by the classical benzodiazepine receptor. Since the background of this study was the relation between the dopaminergic effects and the development of psychotic symptoms during benzodiazepine withdrawal, this different pattern of the benzodiazepines is suggested to be an indication that benzodiazepines may differ qualitatively in the development of withdrawal symptoms after long-term treatment.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2005

Structural basis for Ca2+-regulated muscle relaxation at interaction sites of troponin with actin and tropomyosin.

Troponin and tropomyosin on actin filaments constitute a Ca2+-sensitive switch that regulates the contraction of vertebrate striated muscle through a series of conformational changes within the actin-based thin filament. Troponin consists of three subunits: an inhibitory subunit (TnI), a Ca2+-binding subunit (TnC), and a tropomyosin-binding subunit (TnT). Ca2+-binding to TnC is believed to weaken interactions between troponin and actin, and triggers a large conformational change of the troponin complex. However, the atomic details of the actin-binding sites of troponin have not been determined. Ternary troponin complexes have been reconstituted from recombinant chicken skeletal TnI, TnC, and TnT2 (the C-terminal region of TnT), among which only TnI was uniformly labelled with 15N and/or 13C. By applying NMR spectroscopy, the solution structures of a "mobile" actin-binding domain (approximately 6.1 kDa) in the troponin ternary complex (approximately 52 kDa) were determined. The mobile domain appears to tumble independently of the core domain of troponin. Ca2+-induced changes in the chemical shift and line shape suggested that its tumbling was more restricted at high Ca2+ concentrations. The atomic details of interactions between actin and the mobile domain of troponin were defined by docking the mobile domain into the cryo-electron microscopy (cryo-EM) density map of thin filament at low [Ca2+]. This allowed the determination of the 3D position of residue 133 of TnI, which has been an important landmark to incorporate the available information. This enabled unique docking of the entire globular head region of troponin into the thin filament cryo-EM map at a low Ca2+ concentration. The resultant atomic model suggests that troponin interacted electrostatically with actin and caused the shift of tropomyosin to achieve muscle relaxation. An important feature is that the coiled-coil region of troponin pushed tropomyosin at a low Ca2+ concentration. Moreover, the relationship between myosin and the mobile domain on actin filaments suggests that the latter works as a fail-safe latch.

Actins↗
PubMedDate not supplied

Muscle relaxant choices for rapid sequence induction.

Rapid sequence induction (RSI) for intubation using neuromuscular blockade (NMB) is the most common method of achieving emergent tracheal intubation.(1) The ideal muscle relaxant for RSI would have four characteristics: a rapid onset to minimize the risk of aspiration and hypoxia, a rapid recovery to facilitate the return of ventilation if intubation proves difficult, minimal hemodynamic effects, and minimal systemic effects.(2) However, the ideal drug has yet to be found or created, so succinylcholine has been widely used for more than 40 years as a muscle relaxant in patients with full stomachs or who require emergent intubation.(3,4) Recently, rocuronium has received consideration as an alternative.(1,4) This article discusses both agents.

Androstanols↗
PubMed1977

[Electroencephalographic effects of chlorphenesin carbamate, a new central muscle relaxant, in rabbits (author's transl)].

Electroencephalographic (EEG) effects of chlorphenesin carbamate were investigated in rabbits with chronic electrode implants, and compared with those of chlormezanone and methocarbamol. Chlorphenesin carbamate (50 mg/kg i.v., 100 mg/kg i.d.) induced a drowsy pattern of spontaneous EEG consisting of high voltage slow waves in the cortex and amygdala, and desynchronization of hippocampal theta waves. Chlormezanone also elicited similar EEG changes but such were much more potent than chlorphenesin carbamate. Methocarbamol showed no effect on spontaneous EEG. Chlorphenesin carbamate caused sedation in this period and muscle relaxation was more potent than that of chlormezanone. The EEG arousal response to auditory stimulation and to electric stimulation of the posterior hypothalamus, centromedian thalamus and mesencephalic reticular formation was slightly depressed by chlorphenesin carbamate. Chlorphenesin carbamate, as with chlormezanone, markedly depressed the limbic afterdischarges elicited by hippocampal stimulation. These EEG effects of chlorphenesin carbamate were qualitatively similar to but much weaker than those of chlormezanone, whereas the muscle relaxant effect of chlorphenesin carbamate was more potent than that of chlormezanone.

Acoustic Stimulation↗
PubMed1984

CGS 8216, Ro 15-1788 and methyl-beta-carboline-3-carboxylate, but not EMD 41717 antagonize the muscle relaxant effect of diazepam in genetically spastic rats.

Diazepam (0.4-4 mg/kg i.p.) reduced the spontaneous tonic activity in the electromyogram (EMG) recorded from the gastrocnemius-soleus muscle of spastic mutant Han-Wistar rats in a dose-dependent manner. The muscle relaxant effect of diazepam was antagonized by the benzodiazepine antagonists Ro 15-1788 (5 mg/kg i.p.), beta-CCM (2 mg/kg i.p.) and CGS 8216 (5 mg/kg i.p.), but not by EMD 41717 (50 mg/kg i.p.). These results add further support to the hypothesis that Ro 15-1788, CGS 8216 and beta-CCM do antagonize all pharmacological effects of benzodiazepines while EMD 41717 displays more selectivity in antagonizing the different actions of benzodiazepines.

Animals↗
PubMed1997

Force decline during muscle relaxation promotes calcium release to the cytosol.

During relaxation of skeletal muscle, an initial rapid decline of intracellular Ca2+ concentration ([Ca2+]i) (phase 1), is followed by a brief phase in which the decline of [Ca2+]i is markedly slowed or even reversed (phase 2). Phase 2 appears as a prominent "bump" on records of the time course of declining [Ca2+]i during relaxation. The goal of this study was to test the hypothesis that phase 2 represents a release of Ca2+ to the cytosol that occurs with net cross-bridge detachment during relaxation. The experimental approach was to measure [Ca2+]i with indo 1 in stimulated bullfrog semitendinosus muscles and to determine if phase 2 was diminished during relaxation of contractions in which cross-bridge interactions had been reduced by two different methods: 1) stretching muscles to reduce the overlap between actin and myosin filaments or 2) decreasing stimulus duration. The results showed that, when either method was used to reduce cross-bridge interactions during contraction, then the size of phase 2 during relaxation was also decreased. Phase 2 was eliminated during relaxation of contractions in which cross-bridge interactions had been reduced to a lower contraction force approximately 30% of maximum. These findings are consistent with the hypothesis that the phase 2 of [Ca2+]i decline represents a release of Ca2+ to the cytosol that occurs with net cross-bridge detachment during relaxation. This conclusion is consistent with previous studies that suggest that cross-bridge detachment lowers the affinity of troponin for Ca2+.

Actins↗
PubMed1982

Changes in ambulatory activities and muscle relaxation in rats after repeated doses of diazepam.

Changes in rat ambulatory activity and muscle tone after diazepam treatments (2.5, 5, 10, and 20 mg/kg orally) were compared under single and repeated (for 2, 4, 7, and 14 days) administration schedules. Ambulatory activity in the open field test was enhanced by a single dose of 2.5 mg/kg and reduced by 20 mg/kg. However, after all repeated treatment schedules, diazepam resulted in dose-dependent elevations of activity. Even with a treatment period of only 2 days, 20 mg/kg diazepam produced a marked increase in ambulation, which became more conspicuous with increases in the treatment periods. Acutely administered diazepam produced a dose-dependent reduction in muscle tone, but tolerance was noted to this effect during repeated administrations. Thus, time- and dose-dependent increases in ambulation during repeated treatments with diazepam can be partially explained by time-dependent tolerance development to its muscle relaxant effects. The enhancement in ambulation after short-term repetitive dosings of benzodiazepines can be used as a simple indicator for detecting their disinhibitory potentials.

Animals↗
PubMed2003

Anticonvulsant, sedative and muscle relaxant effects of carbenoxolone in mice.

BACKGROUND: Carbenoxolone, as an antiulcer medicine, has some pharmacological properties such as: the inhibition of gap junctional (GJ) intercellular communication. In vitro studies have shown, carbenoxolone to abolish the generation of full or partial ectopic spike generation, by 4-aminopyridine, as well as spontaneous epileptiform activity in CA3 or CA1 regions of the rat hippocampal slices via closing GJ channels. Thus, we considered the possible anticonvulsant effects of carbenoxolone in animal seizure models. RESULTS: ED50 values of diazepam and carbenoxolone in the pentylenetetrazole model were 1.13 mg/kg and 283.3 mg/kg, respectively. In this model, carbenoxolone in doses of 200 and 300 mg/kg prolonged the onset time of seizure and decreased the duration of seizures. In the maximal electroshock model, carbenoxolone in a dose of 400 mg/kg decreased the duration of seizure producing protection against seizure but failing to protect against mortality in comparison with diazepam. In the potentiation of pentobarbitone sleep test, carbenoxolone significantly increased sleeping time and decreased latency in doses of 100, 200 and 300 mg/kg in mice dose dependently. In the traction test, carbenoxolone (400 mg/kg) showed muscle relaxant activity and in the accelerated rotarod test, carbenoxolone in doses of 200 and 300 mg/kg showed a decline in motor coordination. CONCLUSION: It can be concluded that carbenoxolone possesses anticonvulsant, muscle relaxant and hypnotic effects, which could contribute to the control of petit mal and grand mal seizures.

Animals↗
PubMed1999

Differential mechanisms of urethral smooth muscle relaxation by several NO donors and nitric oxide.

We have examined the mechanisms of action of a broad spectrum of nitric oxide (NO) donors, including several S-nitrosothiols, sodium nitroprusside (SNP) and nitroglycerine (GTN), in relation to their relaxant activity of urethral smooth muscle. For all the compounds examined, NO release (in solution and in the presence of urethral tissue), relaxation responses, elevations in cGMP levels and the effect of thiol modulators were evaluated and compared with the effect of NO itself. Whilst all NO donors, except GTN, released NO in solution due to photolysis or chemical catalysis, this release was not correlated with their relaxant activity in sheep urethral preparations, which were furthermore not affected by the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (cPTIO; 0.3 mM). A substantial NO-generating activity was found for S-nitroso-L-cysteine (CysNO) and S-nitroso-N-acetyl-D,L-penicillamine (SNAP) in the presence of urethral cytosolic fractions, suggesting metabolic activation to NO in the cytosol of the target tissue. In contrast, NO generation from S-nitroso-N-acetyl-L-cysteine (N-ac-CysNO), S-nitrosoglutathione (GSNO) and SNP were reduced by the presence of urethral homogenate and/or subcellular fractions, suggesting direct NO transfer to tissue constituents. NO donors and NO gas induced dissimilar degrees of cGMP accumulation in urethral tissue, while they were essentially equipotent as urethral relaxants. Furthermore, 1H-[1,2,4] -oxadiazole-[4,3-a]-quinoxalin-1-one (ODQ; 10 microM) inhibited both relaxation and cGMP accumulations, but with different potency for the different compounds. Oxidation of sarcolemmal thiol groups with 5-5'-dithio-bis[2-nitrobenzoic acid] (DTNB; 0.5 mM) enhanced relaxations to GSNO, an effect that was reversed by dithiotreitol (DTT; 1 mM), suggesting a direct effect through nitrosylation/oxidation reactions at the cell membrane, while relaxations to NO and to all the other compounds were not affected by these treatments. Finally, photodegradation of SNP induced the formation of a stable intermediate that still evoked NO-cGMP-mediated relaxations. This indicates that the assumption that SNP is fully depleted of NO by exposure to light should be revised. It can be concluded that important differences exist in the mechanisms by which distinct NO donors relax urethral smooth muscle and they cannot be regarded simply as NO-releasing prodrugs.

Alkylation↗