Regulation Of Muscle Tone Research Articles

Cataplexy-related neurons in the amygdala of the narcoleptic dog

The amygdala plays an important role in the interpretation of emotionally significant stimuli and has strong projections to brainstem regions regulating muscle tone and sleep. Cataplexy, a symptom of narcolepsy, is a loss of muscle tone usually triggered by sudden, strong emotions. Extracellular single-unit recordings were carried out in the amygdala of narcoleptic dogs to test the hypothesis that abnormal activity of a subpopulation of amygdala neurons is linked to cataplexy. Of the 218 cells recorded, 31 were sleep active, 78 were active in both waking and rapid-eye-movement sleep, 88 were maximally active during waking, and 21 were state independent. Two populations of cells showed a significant change in activity with cataplexy. A population of sleep active cells localized to central and basal nucleus increased discharges prior to and during cataplexy. A population of wake active cells localized to the cortical nucleus decreased activity prior to and during cataplexy. We hypothesize that these cell populations have a role in mediation or modulation of cataplexy through interactions with meso-pontine regions controlling atonia. The anticholinesterase physostigmine, at doses which increased cataplexy, did not alter the activity of the cataplexy-related cells or of other amygdala cells, suggesting that its effect on cataplexy is mediated ‘downstream’ of the amygdala. The α-1 blocker prazosin, at doses which increased cataplexy, increased discharge in a subgroup of the cataplexy active cells and in a number of other amygdala cells, indicating that prazosin may modulate cataplexy by its action on amygdala cells or their afferents.

Trypsin induces activation and inflammatory mediator release from human eosinophils through protease-activated receptor-2.

Protease-activated receptors (PARs) are a unique class of G protein-coupled receptors, which are activated by proteolytic cleavage of the amino terminus of the receptor itself. PARs are most likely involved in various biological responses, such as hemostasis and regulation of muscle tone; however, the roles of PARs in the functions of inflammatory and immune cells are poorly understood. Because eosinophils are most likely involved in allergic inflammation and are exposed to a variety of proteases derived from allergens and other inflammatory cells, we investigated whether PARs regulate effector functions of eosinophils. Human eosinophils constitutively transcribe mRNA for PAR2 and PAR3, but not those for PAR1 and PAR4. The expression of PAR2 protein was confirmed by flow cytometry. When trypsin, an agonist for PAR2, was incubated with eosinophils, it potently induced superoxide anion production and degranulation; 5 nM trypsin induced responses that were 50-70% of those induced by 100 nM platelet-activating factor, a positive control. In contrast, thrombin, an activator for PAR1, PAR3, and PAR4, showed minimal effects. The stimulatory effect of trypsin was dependent on its serine protease activity and was blocked 59% by anti-PAR2 Ab. Furthermore, a specific tethered peptide ligand for PAR2 potently induced superoxide production and degranulation; the effects of peptide ligands for PAR1, PAR3, and PAR4 were negligible. These findings suggest that human eosinophils express functional PAR2, and serine proteases at the inflammation site may play important roles in regulating effector functions of human eosinophils. The expression and functional relevance of other PARs still need to be determined.

Dopamine receptors in the subthalamic nucleus are involved in the regulation of muscle tone in the rat

The effects of injecting an irreversible dopamine receptor antagonist, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) bilaterally into the subthalamic nucleus (STN) on changes in muscle tone and behaviour were investigated. Increased muscle tone (i.e. rigidity) was assessed quantitatively as increases in tonic electromyographic (EMG) activity in the hindlimb muscles of conscious, unrestrained rats. Significant, sustained increases in EMG activity were observed for 3–5 h post-injection in the tibialis and gastrocnemius muscles following injection of EEDQ into the STN. This effect was associated with 73% dopamine D1 and 66% dopamine D2 receptor occupancy in the STN, while dopamine receptors in surrounding regions were minimally occupied. These results provide new evidence that dopamine receptors located in the STN play an important role in the regulation of normal muscle tone.

Changes in Muscle Tone Are Regulated by D1 and D2 Dopamine Receptors in the Ventral Striatum and D1 Receptors in the Substantia Nigra

Muscle rigidity associated with antipsychotic drug treatment is believed to result from reduced striatal dopamine neurotransmission. In the current study the regulatory roles of dopamine D1 and D2 receptor subfamilies in the dorsal (DSTR) and ventral striatum (VSTR) and substantia nigra (SN) were investigated on muscle tone, assessed as increases in tonic electromyographic (EMG) activity. Rats were injected with the irreversible D1/D2 antagonist N-ethoxycarbonyl-2-ethoxy, -1,2-dihydroquinoline (EEDQ), the reversible D1 antagonist SCH23390, or D2 antagonist sulpiride. Increased EMG activity was observed following injection of EEDQ and SCH23390 into the SN or VSTR, and sulpiride into the VSTR. Mapping, using quantitative autoradiographic analysis of dopamine receptor occupancy after striatal injections, showed D1 and D2 receptors in discrete ventral sites were associated with EMG increases. Overall the results support roles for dopamine D1and D2 receptors in the ventral striatum, and D1 receptors in the substantia nigra, in the regulation of muscle tone.

Phosphodiesterase isoenzymes as pharmacological targets in the treatment of male erectile dysfunction

Based on the increasing knowledge of intracellular signal propagation in cavernous smooth muscle tone regulation, which is of major importance to the understanding of both the physiology of erection and the pathophysiology of erectile dysfunction, selective phosphodiesterase (PDE) inhibitors have recently been introduced in the treatment of erectile dysfunction. The first promising clinical data on the use of the orally active PDE5 inhibitor Sildenafil in the treatment of erectile dysfunction were accompanied by boosting research activities on cavernous intracellular signal transduction and phosphodiesterase characterization with the aid of molecular biology and protein chemistry. The presence of mRNA transcripts specific for 14 different human phosphodiesterase isoenzymes and isoforms in human cavernous tissue was shown by RT-PCR: Three isogenes of PDEI, PDE2A and 10A, which hydrolyse cAMP as well as cGMP, the cAMP-specific PDE3A, four isogenes of PDE4, PDE7A and PDE8A, as well as cGMP-specific PDEs PDE5A and PDE9A. Using anion exchange chromatography, the activities of PDE isoenzymes 2, 3, 4, and 5 were detected in cytosolic supernatants of human cavernous smooth muscle. To date, the efficacy and safety of several next generation PDE5 inhibitors for use in the treatment of male erectile dysfunction are under evaluation in vitro and in vivo. Further research will possibly allow identification of diagnostic tools for erectile dysfunction and of even more selective drugs in its therapy.

Spinal cord lesion: effects of and perspectives for treatment.

Following central motor lesions, two forms of adaptation can be observed which lead to improved mobility: (1) the development of spastic muscle tone, and (2) the activation of spinal locomotor centers induced by specific treadmill training. Tension development during spastic gait is different from that during normal gait and appears to be independent of exaggerated monosynaptic stretch reflexes. Exaggerated stretch reflexes are associated with an absence or reduction of functionally essential polysynaptic reflexes. When supraspinal control of spinal reflexes is impaired, the inhibition of monosynaptic reflexes is missing in addition to a reduced facilitation of polysynaptic reflexes. Therefore, overall leg muscle activity becomes reduced and less well modulated in patients with spasticity. Electrophysiologicai and histological studies have shown that a transformation of motor units takes place following central motor lesions with the consequence that regulation of muscle tone is achieved at a lower level of neuronal organization which in turn enables the patient to walk. Based on observations of the locomotor capacity of the spinal cat, recent studies have indicated that spinal locomotor centers can be activated and trained in patients with complete or incomplete paraplegia when the body is partially unloaded. However, the level of electromyographic activity in the gastrocnemius (the main antigravity muscle during gait) is considerably lower in the patients compared to healthy subjects. During the course of a daily locomotor training program, the amplitude of gastrocnemius, electromyographic activity increases significantly during the stance phase, while inappropriate tibialis anterior activation decreases. Patients with incomplete paraplegia benefit from such training programs such that their walking ability on a stationary surface improves. The pathophysiology and functional significance of spastic muscle tone and the effects of treadmill training on the locomotor pattern underlying new attempts to improve the mobility of patients with paraplegia are reviewed.

EXPRESSION OF DIFFERENT PHOSPHODIESTERASE GENES IN HUMAN CAVERNOUS SMOOTH MUSCLE

Knowledge of intracellular signal propagation in smooth muscle tone regulation is of major importance in the understanding of the physiology of penile erection, and the development of new and selective pharmacological agents for the treatment of related disorders. Since phosphodiesterases (PDE) are key enzymes of the signaling pathway, we elucidate their presence and potential functional relevance in human cavernous tissue. To identify PDE messenger RNA in human cavernous tissue, we constructed primers for 14 published PDE isoforms. Expression of the genes was then analyzed by reverse transcriptase polymerase chain reaction under standard conditions and by subsequent sequencing. Messenger RNA was detected in human corpus cavernosum for the human phosphodiesterase isoenzymes and isoforms PDE1A, PDE1B, PDE1C, PDE2A, PDE3A, PDE4A, PDE4B, PDE4C, PDE4D, PDE5A, PDE7A, PDE8A and PDE9A. A total of 13 PDE genes were expressed in human cavernous tissue, indicating a role of these enzymes in penile erection regulation. The intracellular mechanisms of hydrolyzing cyclic adenosine monophosphate and cyclic guanosine monophosphate by PDEs are more complex than assumed previously. These findings open up new possibilities in the development of drugs for the treatment of erectile dysfunction.

Localization of Prostaglandin E Receptor Subtypes in the Ciliary Body of Mouse Eye

Prostaglandin E2(PGE2) markedly reduces intraocular pressure (IOP) when applied topically and induces strong relaxation of pre-contracted isolated ciliary muscle through PGE2receptor. Because the ciliary muscle relaxation reduces IOP by enhancing uveoscleral aqueous outflow, the ciliary muscle where the existence of PGE2receptors has been demonstrated is thought to be one of the target tissues for PGE2-induced IOP reduction. To investigate the subtypes of PGE2receptors in the ciliary muscle, the regional distribution of four PGE2receptor subtypes (EP1, EP2, EP3and EP4) in the mouse ciliary body was investigated by in situ hybridization using specific probes. Consistent messenger RNA signals for EP1and EP4receptors were expressed in the ciliary muscle, although signal levels for these subtypes were less potent as compared with the kidney, which was used as a reference organ. EP2and EP3signals were not detected. Stimulation of the EP4receptor activates adenylate cyclase, which should induce ciliary muscle relaxation. Therefore, the IOP reduction induced by PGE2analogs may be mediated by the EP4receptor. In contrast, stimulation of the EP1receptor is believed to promote intracellular Ca2+mobilization, and hence should cause ciliary muscle contraction. Thus, the coexistence of EP1and EP4receptors in the ciliary muscle suggests that the regulation of ciliary muscle tone by PGE2is based on a complex mechanism involving multiple receptor subtypes.

Phosphodiesterase inhibitors in the treatment of erectile dysfunction.

Based on knowledge of intracellular signal propagation in cavernous smooth muscle tone regulation and the development of new and selective pharmacological agents, selective phosphodiesterase (PDE) inhibitors were recently introduced in the treatment of erectile dysfunction. The presence of mRNAs specific for 13 different human phosphodiesterase isoenzymes and isoforms in human cavernous tissue was shown by RT-PCR. We detected an expression of the following genes encoding for both cAMP and cGMP hydrolyzing PDEs: all three isogenes of PDE I and PDE IIa, which do hydrolyze cAMP as well as cGMP; the specific cAMP hydrolyzing PDEs PDE IIIa, the four isogenes of PDE IV, PDE VIIa and PDE VIIIa and the cGMP-specific PDEs PDE Va and PDE IXa. By protein chemical methods, PDE-isoenzymes III, IV and V were characterized in the human cavernous smooth muscles. In functional organ bath studies using precontracted human cavernous tissue strips, PDE III and V inhibitors showed the most pronounced relaxant responses. In clinical studies, the use of the orally active PDE V inhibitor sildenafil induced a pronounced and significant erectogenic effect in patients both with predominantly psychogenic and organogenic etiology of erectile dysfunction. The first promising clinical data of the use of an orally active PDE inhibitor for the treatment of erectile dysfunction are well supported by consistent basic scientific findings. Further research will possibly allow to identify diagnostic tools for erectile dysfunction and for even more selective drugs in its therapy.

Raclopride and Chlorpromazine, but not Clozapine, Increase Muscle Rigidity in the Rat: Relationship with D2 Dopamine Receptor Occupancy

The aim of the present study was to investigate the relationship between effects on muscle tone and D2 receptor occupancy of two typical antipsychotic drugs, raclopride and chlorpromazine, and the atypical drug, clozapine. Increased muscle tone (i.e., muscle rigidity), was measured as increases in tonic electromyographic (EMG) activity of the antagonistic muscles of the rat hind limb. D2 dopamine receptor occupancy was assessed in the striatum and substantia nigra, areas involved in the regulation of muscle tone. Raclopride and chlorpromazine produced dose-dependent increases in EMG activity associated with D2 occupancy of 68%–80% in the striatum and 67%–76% in the nigra. No significant increases in EMG were observed with clozapine which showed low D2 occupancy. The results are consistent with those from human studies showing extrapyramidal side effects were associated with striatal D2 occupancy of >70%.

Association of radiologically ascertained pneumonia before age 3 yr with asthmalike symptoms and pulmonary function during childhood: a prospective study.

Epidemiologic evidence suggests an association between reports of pneumonia in early life and the subsequent development of diminished lung function. However, no studies are available in which the diagnosis of pneumonia was based on radiologic evidence. Lower respiratory illnesses with or without a radiologically confirmed diagnosis of pneumonia were assessed in a study of 888 children enrolled at birth. Pulmonary function tests, markers of atopy, asthma diagnosis, and prevalence of respiratory symptoms were assessed at different ages between birth and 11 yr. Incidence of pneumonia during the first 3 yr of life was 7.4%. Respiratory syncytial virus was the most frequent agent identified both in children with pneumonia and in those with lower respiratory tract illness (LRI) without pneumonia (36.4% versus 35.6%, respectively). Children with a diagnosis of pneumonia were more likely to have physician-diagnosed asthma and current wheezing at ages 6 and 11 yr than were those who had no LRIs. When compared with children without LRIs, those with a diagnosis of pneumonia had lower levels of maximal flows at FRC at mean age of 2 mo (albeit not significantly) and at age 6 yr, and lower levels of FEV1 and FEF25-75 at age 11 yr. These deficits were independent of known confounders, including wheezing at the time of study, and were partly and significantly reversed after administration of a bronchodilator. We conclude that children with radiologically confirmed pneumonia have diminished airway function that is probably present shortly after birth. These deficits are at least in part due to alterations in the regulation of airway muscle tone.

Sympathoadrenal hyperactivity and the etiology of neuroleptic malignant syndrome.

The author's goal was to develop a pathophysiological model for neuroleptic malignant syndrome with greater explanatory power than the alternative hypotheses of hypothalamic dopamine antagonism (elevated set point) and direct myotoxicity (malignant hyperthermia variant). Published clinical findings on neuroleptic malignant syndrome were integrated with data from human and animal studies of muscle physiology, thermoregulation, and autonomic nervous system function. The data show that the sympathetic nervous system's latent capacity for autonomous activity is expressed when tonic inhibitory inputs from higher central nervous system centers are disrupted. These tonic inhibitory inputs are relayed to preganglionic sympathetic neurons by way of dopaminergic hypothalamospinal tracts. The sympathetic nervous system mediates hypothalamic coordination of thermoregulatory activity and is a primary regulator of muscle tone and thermogenesis, augmenting both of these when stimulated. In addition, the sympathetic nervous system modulates all of the other end-organs that function abnormally in neuroleptic malignant syndrome. There is substantial evidence to support the hypothesis that dysregulated sympathetic nervous system hyperactivity is responsible for most, if not all, features of neuroleptic malignant syndrome. A predisposition to more extreme sympathetic nervous system activation and/or dysfunction in response to emotional or psychological stress may constitute a trait vulnerability for neuroleptic malignant syndrome, which, when coupled with state variables such as acute psychic distress or dopamine receptor antagonism, produces the clinical syndrome of neuroleptic malignant syndrome. This hypothesis provides a more comprehensive explanation for existing clinical data than do the current alternatives.

Sepsis attenuates the intensity of the neuromuscular blocking effect of d-tubocurarine and the antagonistic actions of neostigmine and edrophonium accompanying depression of muscle contractility of the diaphragm.

Prolonged effects of non-depolarizing muscle relaxants in septic patients have been reported, although the influence of sepsis on neuromuscular transmission has not yet been clarified satisfactorily. These studies were intended to elucidate the influence of sepsis on neuromuscular transmission and on the action of drugs being utilized for regulation of muscle tone (a neuromuscular blocker and anti-cholinesterase (anti-ChE) drugs). The effect of d-tubocurarine (dTc) on neuromuscular transmission and the antagonistic action of anti-ChE drugs (neostigmine and edrophonium) on dTc-induced twitch depression were estimated using sham control and septic rat nerve-hemidiaphragm preparations in vitro. Isometric twitch tension elicited by indirect (phrenic nerve) or direct (muscle) stimulation at 0.1 Hz was evaluated. Sepsis induced by panperitonitis attenuated the twitch tension elicited by indirect or direct stimulation (P < 0.01) without obvious morphological inflammatory damage to the diaphragm. dTc dose-dependently decreased twitch tension elicited by indirect stimulation (P < 0.01) less intensely in the septic group than in the sham group (P < 0.01). The antagonistic actions of the anti-ChE drugs on dTc (1 microM)-induced twitch depression were less intense in the septic group (P < 0.01 or 0.05). These results demonstrate that sepsis in the acute phase attenuates the effects of a neuromuscular blocker and anti-ChE drugs and depresses muscle contractility simultaneously.

Regulation of Muscle Tone &amp; Tension

Regulation of Muscle Tone &amp; Tension

Regulation of Muscle Tone &amp; Tension

Regulation of Muscle Tone &amp; Tension

Effects of neonatal hypoxia on the medulla-spinal cord descending neurons

Hypoxic changes in the medulla-spinal cord descending neurons were studied morphologically using a retrograde neurotracer, choleratoxin B subunit (CTb). On postnatal day 7, Sprague-Dawley rats were subjected to a hypoxic load of 8% oxygen for 5 hours. In the rats that survived, CTb was injected into the lumbar enlargement at postnatal day 26, and they were killed at postnatal day 28 for histologic analysis. Retrograde transported CTb was visualized by immunohistochemistry. The results were compared with those obtained from control rats. In the control rats, CTb-positive cells were observed in the nucleus reticularis gigantocellularis, nucleus reticularis magnocellularis, nucleus raphe magnus, nucleus raphe obscurus, and nucleus raphe pallidus. In the hypoxic rats, although CTb-positive cells were detected in the same areas as the control rats, there was a noteworthy decrease in the number of CTb-positive cells in all areas, and there were many cells with hypoxic degeneration. In all of the nuclei a marked decrease in the number of CTb-positive cells was observed. Because medulla-spinal cord descending neurons have important roles in the regulation of postural muscle tone, these results may account for the pathophysiology of abnormal muscle tonus accompanying hypoxic brain damage.

The effects of an irreversible dopamine receptor antagonist, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), on the regulation of muscle tone in the rat: the role of the substantia nigra

Recent evidence has questioned the view that the increased muscle tone of Parkinson's disease results solely from reduced release of dopamine in the striatum, by emphasising the important role of the substantia nigra. The aim of the current study was to compare the effects on muscle tone of inactivating D 1 and D 2 dopamine receptors throughout the brain with those seen following their inactivation only in the substantia nigra. Inactivation of dopamine receptors by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline injected either intraperitoneally, or bilaterally into the substantia nigra, resulted in similar increases in muscle tone, measured as changes in tonic electromyographic (EMG) activity. The magnitude and onset of EMG increases was related to the level of dopamine receptor inactivation. The results are consistent with the hypothesis that nigral dopamine mechanisms play a key role in the maintenance of muscle tone.

Contribution of the glycine site of NMDA receptors in rostral and intermediate-caudal parts of the striatum to the regulation of muscle tone in rats

The aim of the present study was to assess the contribution of the glycine site of NMDA receptors in the striatum to the regulation of muscle tone. Muscle tone was examined using a combined mechano and electromyographic method, which measured simultaneously the muscle resistance (MMG) of the rat's hind foot to passive extension and flexion in the ankle joint and the electromyographic activity (EMG) of the antagonistic muscles of that joint: gastrocnemius and tibialis anterior. Muscle rigidity was induced by haloperidol (2.5 mg/kg i.p.). 5,7-dichlorokynurenic acid (5,7-DCKA), a selective glycine site antagonist, injected in doses of 2.5 and 4.5 μg/0.5 μl bilaterally, into the rostral region of the striatum, decreased both the haloperidol-induced muscle rigidity (MMG) and the enhanced electromyographic activity (EMG). 5,7-DCKA injected bilaterally in a dose of 4.5 μg/0.5 μl into the intermediate-caudal region of the striatum of rats not pretreated with haloperidol had no effect on the muscle tone. The present results suggest that blockade of the glycine site of NMDA receptors in the rostral part of the striatum may be mainly responsible for the antiparkinsonian action of this drug.

THE EFFECT OF THE SPECIFIC PHOSPHODIESTERASE (PDE) INHIBITORS ON HUMAN AND RABBIT CAVERNOUS TISSUE IN VITRO AND IN VIVO

Purpose Phosphodiesterases (PDE) are key enzymes in the regulation of the smooth muscle tone. Experimental studies showed PDE III and V-isoenzymes to play an important role in the smooth muscle tone regulation of corpus cavernosum. Recently, a specific PDE III-inhibitor (milrinone) and a PDE V-inhibitor (sildenafil) were introduced in clinical studies. An experimental study was done to examine a potential role of PDE-inhibitors in the treatment of erectile dysfunction. Materials and Methods In the organ bath, strips from human and rabbit corpus cavernosum were precontracted and increasing doses of PDE inhibitors were added. In patients with erectile dysfunction as well as in rabbits, intracavernous injections of milrinone were done. Results PDE-inhibitors dose-dependently relaxed human and rabbit corpus cavernosum strips. In the precontracted human cavernous tissue, milrinone and sildenafil were equally potent and efficacious in vitro. In the rabbit, milrinone induced slight tumescence but dramatic circulatory side effects. In patients, penile tumescences as well as full erections were observed. Conclusions Milrinone strongly relaxes human cavernous smooth muscle cells but it exhibits low relaxant effects in the rabbit cavernous tissue. In human tissue, sildenafil was equieffective with milrinone in vitro. In vivo, milrinone induced a good erectile response in humans but a poor erectile effect in rabbits. Our results support a possible potential for selective PDE-III and -V inhibitors in the treatment of impotence and give further evidence that the rabbit is an animal model of limited value to study the effects of drugs on cavernous smooth muscle tone regulation in vivo.

Expression and localization of muscarinic receptors in P19-derived neurons.

The muscarinic acetylcholine receptors are important in a variety of physiological processes such as induction of secretion from various glands and regulation of pacemaker activity, muscle tone, and neurotransmission. To date, the muscarinic receptor family includes five members (designated m1-m5), of which m1-m4 are abundant in brain and in peripheral tissues, and m5 is found exclusively in brain, and even there at very low levels. The expression of m1-m5 receptor subtypes was studied in neurons derived from the murine embryonal carcinoma cell line P19. These cells serve as a model system for differentiation and maturation of neurons resembling CNS neurons. Our results show that P19 neurons express mainly the m2, m3, and m5 subtypes. Low levels of m1 receptors are also detected and m4 subtype is practically absent. Furthermore, muscarinic receptors in P19 neurons are functional in activating second messenger signaling pathways. The localization of m2 receptors is predominantly presynaptic, whereas the m5 subtype is mainly postsynaptic. Consequently, P19 cells provide a model system for the study of pre- and postsynaptic muscarinic acetylcholine-receptor subtypes in a proper neuronal context. This is particularly valid for the rare m5 receptors.