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[Inhibition of acetamide-45 on airway smooth muscle contraction induced by electric field stimulation and methacholine in vitro].

OBJECTIVE: To investigate the effects of the new antiallergic agent N-(pyridin-4-yl)-(indol-3-yl) acetamide-45 (acetamide-45) on electric field stimulation (EFS)-and methacholine-induced contraction of airway smooth muscle in vitro. METHODS: Contractions were induced by EFS in isolated trachea and bronchus of rats or by cumulative methacholine concentrations in isolated trachea of guinea pigs. Changes in isometric force of isolated airway smooth muscle were measured by force transducers and recorded on a multi-channel polygraph recorder. RESULTS: Acetamide-45 inhibited the contraction induced by EFS in isolated rat airway. The IC50 was 10.74 (95% CI 8.87-13.00) micromol.L(-1) and 18.83 (95% CI 14.57-24.33) micromol.L(-1) in tracheae and bronchi, respectively. Acetamide-45 also inhibited methacholine-induced contractile response of isolated guinea pig trachea in a concentration-dependent manner. At concentrations of 3, 10, 30 micromol.L(-1) acetamide-45 significantly decreased maximal contractile response of methacholine by 24.6%-43.2% and increased EC50 of methacholine by 3.1-to 21.4-fold. CONCLUSION: Acetamide-45 inhibits EFS-or methacholine-induced contraction of isolated airway smooth muscle, and these effects might be non-specific inhibition on cholinergic receptor.

Acetamides↗

Dopamine produces muscle contractions and modulates motoneuron-induced contractions in Aplysia gill.

1. Dopamine has been reported to exist in unusually large quantities in Aplysia gill. The physiological role of this neurotransmitter in this organ was examined. 2. The addition of dopamine to a gill perfusate results in the contractions of the lateral and medial external pinnule muscles, the circular and longitudinal muscles of the afferent vessel, and the circular muscles of the efferent vessel. 3. Dopamine-induced contractions persist after chemical synaptic transmission is eliminated in the gill. This suggests that excitatory dopamine receptors are present on gill smooth muscle fibers themselves. 4. Dopamine also potentiates the gill response to action potentials in single identified gill motoneurons. Evidence presented suggests that muscle contractions and modulation of motoneuron contractions are independent phenomena. 5. While modulation may in part be mediated by increases in excitatory junction potential (EJP) amplitude, in many cases large increases in muscle contractions occur while the enhancement of EJPs is disproportionately small. 6. Dopamine's ability to produce muscle contractions suggests that there may be dopaminergic motoneuron innervation of the gill. We suggest that dopamine's modulatory actions may be mediated via modification of excitation-contraction coupling in smooth muscle fibers.

Animals↗

Facilitation of the main generator source of earthworm muscle contraction by a peripheral neuron.

A constant facilitation of responses evoked in the earthworm muscle contraction generator neurons by responses evoked in the neurons of its peripheral nervous system was demonstrated. It is based on the proposal that these two responses are bifurcations of an afferent response evoked by the same peripheral mechanical stimulus but converging again on this central neuron. A single-peaked generator response without facilitation was demonstrated by sectioning the afferent route of the peripheral facilitatory modulatory response, or conditioning response (CR). The multipeaked response could be restored by restimulating the sectioned modulatory neuron with an intracellular substitutive conditioning stimulus (SCS). These multipeaked responses were proposed to be the result of reverberating the original single peaked unconditioned response (UR) through a parallel (P) neuronal circuit which receives the facilitation of the peripheral modulatory neuron. This peripheral modulatory neuron was named "Peri-Kästchen" (PK) neuron because it has about 20 peripheral processes distributed on the surface of a Kästchen of longitudinal muscle cells on the body wall of this preparation as revealed by the Lucifer Yellow-CH-filling method.

Animals↗

A new look at uterine muscle contraction.

Recent progress in our understanding of uterine smooth muscle contraction is reviewed. We no longer believe that actin-myosin interaction in the myometrium occurs through activation of the thin filament; but it is triggered by calcium-dependent phosphorylation of myosin in the thick filament. Calcium is now thought to originate from both extracellular and intracellular sources. Calcium can enter the cell through either a voltage- or a hormone-controlled calcium channel. The intracellular source of calcium is the sarcoplasmic reticulum. The effect of oxytocin in human labor is no longer considered the result of increased circulating oxytocin but rather of increased oxytocin receptors. In contrast, the contractile action of some prostaglandins is related to increased prostaglandin formation at human parturition. The step between hormone binding and cellular action is mediated by second messengers. The uterine-relaxing action of cyclic adenosine monophosphate is now thought to be limited to the inhibition of myosin phosphorylation. Recently discovered second messengers for contraction of the myometrium are phosphoinositides; their turnover causes calcium release from the sarcoplasmic reticulum. Guanine nucleotides are thought to be modulators of these two second messengers.

Adenosine Triphosphatases↗

Measurement of tissue volume during non-steady state high-intensity muscle contraction.

To investigate the pressures driving water into stimulated muscle, water distribution during and after muscle stimulation was studied in isolated cat muscles perfused by recirculating diluted blood. 51Cr-labeled EDTA (51Cr-EDTA) and Evans blue-labeled albumin were used to determine extracellular volume and plasma volume (PV), respectively. Change in tissue volume was calculated as -PV. Interstitial volume (IFV) was determined from the ratio of interstitial solute (51Cr-EDTA and sodium) mass and interstitial concentration. Interstitial mass was determined by mass balance, and interstitial concentration was determined from solute flux and Fick's Law. One group was stimulated at 4 Hz for 2 min, and a second was stimulated by 80-Hz trains (1 train/s, 0.1 s duration). Four Hertz stimulation increased total tissue volume by approximately 3 ml/100 g and decreased IFV by 1 ml/100 g. Train stimulation increased total tissue volume by 6 ml/100 g and decreased IFV by 4. These data indicate that water moves into cells faster than the simultaneous transcapillary flow, suggesting that intracellular osmoles provide the primary driving pressure in stimulation-induced swelling.

Animals↗

[Biomechanics and bio-energetics of smooth muscle contraction. Relation to bronchial hyperreactivity].

Mechanical studies of isolated muscle and analysis of molecular actomyosin interactions have improved our understanding of the pathophysiology of airway smooth muscle. Mechanical properties of airway smooth muscle are similar to those of other smooth muscles. Airway smooth muscle exhibits spontaneous intrinsic tone and its maximum shortening velocity (Vmax) is 10-30 fold lower than in striated muscle. Smooth muscle myosin generates step size and elementary force per crossbridge interaction approximately similar to those of skeletal muscle myosin. Special slow cycling crossbridges, termed latch-bridges, have been attributed to myosin light chain dephosphorylation. From a mechanical point of view, it has been shown that airway hyperresponsiveness is characterized by an increased Vmax and an increased shortening capacity, with no significant change in the force-generating capacity.

Biomechanical Phenomena↗

Calmodulin is intrinsically LESS effective than troponin C in activating skeletal muscle contraction.

Calmodulin (CaM) and troponin C (TnC) are evolutionarily and structurally homologous, yet they are not functionally interchangeable. In particular, CaM cannot effectively substitute for TnC as an activator of skeletal muscle contraction. To determine if this is a consequence of CaM's weak association with troponin T and I or the result of a more fundamental mechanistic defect, we have used CaM and a CaM[TnC] chimera, CaM[3,4 TnC], that stably associates with the thin filament. Replacement of TnC with CaM or CaM[3,4 TnC] reveals that CaM-like molecules reduce the Ca(2+)-sensitivity and cooperativity of activation, as well as the maximal Ca(2+)-activated tension. These observations indicate that CaM-like molecules are unable to continuously maintain the activated state of the thin filament.

Animals↗

31P NMR magnetization-transfer measurements of ATP turnover during steady-state isometric muscle contraction in the rat hind limb in vivo.

31P NMR magnetization-transfer measurements have been used to measure the flux between ATP and inorganic phosphate during steady-state isometric muscle contraction in the rat hind limb in vivo. Steady-state contraction was obtained by supramaximal sciatic nerve stimulation. Increasing the stimulation pulse width from 10 to 90 ms, at a pulse frequency of 1 Hz, or increasing the frequency of a 10-ms pulse from 0.5 to 2 Hz resulted in an increase in the flux which was an approximately linear function of the increase in the tension-time integral. The flux showed an approximately linear dependence on the calculated free cytosolic ADP concentration up to an ADP concentration of about 90 microM. The data are consistent with control of mitochondrial ATP synthesis by the cytosolic ADP concentration and indicate that the apparent Km of the mitochondria for ADP is at least 30 microM.

Adenosine Triphosphate↗

Dependence of the work done by ATP-induced actin-myosin sliding on the initial baseline force: its implications for kinetic properties of myosin heads in muscle contraction.

The properties of the ATP-dependent actin-myosin sliding responsible for muscle contraction was studied using an in vitro force-movement assay system, in which a myosin-coated glass microneedle was made to slide on actin filament arrays (actin cables) in the giant algal cell with iontophoretic application of ATP. With a constant amount of ATP application, the amount of work done by the actin-myosin sliding increased with increasing baseline force from zero to 0.4-0.6 Po, and then decreased with further increasing baseline force, thus giving a bell-shaped work versus baseline force relation. The result that the maximum actin-myosin sliding velocity did not change appreciably with increasing baseline force up to 0.4-0.6 Po implies, together with the limited number of myosin heads involved, that (1) the rate of power output of actin-myosin sliding is determined primarily by the amount of external load rather than the velocity of actin-myosin sliding, and (2) the bell shaped work versus baseline force relation (and also the hyperbolic force-velocity relation) results from the kinetic properties of individual myosin head rather than the change in the number of myosin heads involved.

Actins↗

Skeletal muscle contraction: analysis with use of velocity distributions from phase-contrast MR imaging.

PURPOSE: Velocity gradient data from phase-contrast magnetic resonance (MR) imaging were tested for the ability to calculate tensile strain and shear strain (deformation) during cyclical motion of skeletal muscle. MATERIALS AND METHODS: Strain data were derived from in vitro and in vivo phase-contrast MR velocity maps. A motion phantom designed to cyclically compress and expand a specimen of skeletal muscle provided a standard of reference to validate deformation, translation, and rotation measurements. The authors studied anterior and posterior muscle compartments of the lower extremity in three healthy volunteers during ankle dorsiflexion and plantar flexion against various resistances and the forearms of five healthy volunteers during flexion and extension of the fingers. RESULTS: The mean in vitro tracking error was 0.5 mm. The gastrocnemius muscle area in vivo changed 20% for both the minimum and maximum force conditions and therefore did not appear to be a good predictor of force. CONCLUSION: Phase-contrast MR imaging provides quantitative data on muscle contraction and demonstrates that shear and tensile strain can be measured and separated from translation and rotation of muscle.

Animals↗

[Preventive effect of a novel leukotrienes antagonist ONO-1078 on leukotriene C4- and D4-induced human bronchial smooth muscle contraction].

To study whether a novel leukotrienes antagonist ONO-1078 (4-oxo-8-[4-phenylbutyloxy) benzoylamino]-2-(tetrazol-5-yl)-4H-1-benzopyran hemihydrate) prevents leukotrienes C4- and D4-(LTC4, LTD4) induced human bronchial smooth muscle contraction, we examined the bronchial contractile response to LTC4 and LTD4 in the presence or in the absence of ONO-1078 in human bronchial strips. We prepared 4 strips from each of 5 patients undergoing lobectomy of the lung because of lung cancer. We mounted the strips in organ baths and measured the contractile response to LTC4 and LTD4 from 10(-11) M to 10(-7) M after incubation with ONO-1078 (10(-8) M, 10(-7) M and 10(-6) M) and without ONO-1078. ONO-1078 shifted the dose response curve to LTC4 to higher concentration in dose dependent fashion, and it significantly inhibited the contractile response to LTC4 and LTD4. In the presence of L-serine borate complex (45 mM), an inhibitor of gamma-glutamyl transpeptidase, ONO-1078 significantly inhibited the LTC4-induced contraction. On the other hand, ONO-1078 had no effect on the contractile response to acetylcholine. These results suggest that ONO-1078 is a specific antagonist of LTC4 and LTD4 receptors in human bronchial smooth muscle. Because the effect of LTC4 and LTD4 is thought to be an important part of the pathogenesis of bronchial asthma, our results also suggest that ONO-1078 may be a useful prophylactic drug for bronchial asthma.

Bronchi↗

Excitability of corticospinal neurons during tonic muscle contractions in man.

A magnetic stimulus applied to the human scalp over the motor cortex causes a short latency contraction of contralateral limb muscles. This is presumed to result from the indirect excitation of corticospinal neurons with monosynaptic connections to motoneurons. The excitability of these cortical neurons can be estimated from the magnitude of the postsynaptic potentials produced in spinal motoneurons by a given magnetic stimulus. In man the characteristics of these postsynaptic potentials can be derived from changes in the firing probability of single motor units. When a subject increases the level of a sustained voluntary contraction the excitability of the corticospinal neurons estimated in this way becomes less. We conclude that the additional synaptic input to motoneurons required to maintain a stronger muscle contraction comes from fiber systems other than the population of fast corticospinal neurons activated by magnetic stimulation.

Action Potentials↗

Esophageal striated muscle contractions in patients with gastroesophageal reflux symptoms.

Although there are studies showing that the amplitude of contraction in the distal esophageal body may be lower in gastroesophageal reflux (GER) disease than in asymptomatic subjects, there are no data about proximal striated muscle contraction in this disease. We studied the esophageal contraction 2 or 3 cm below the upper esophageal sphincter in response to swallowing a 5-ml bolus of water in 122 consecutive patients submitted to esophageal manometry who complained of heartburn and acid regurgitation. Sixty-nine had esophagitis seen at endoscopy. Thirty-three also complained of dysphagia. No patients had esophageal stenosis, esophageal motility abnormalities in distal esophagus, chest pain, or extraesophageal manifestations of GER. We also studied 20 patients with systemic sclerosis (SSc), a disease with no involvement of striated muscle. When we measured the amplitude, duration, and area under the curve (AUC) of the proximal esophageal contraction, we did not find any differences (P > 0.05) between patients with esophagitis (N = 69) or without esophagitis (N = 53), with dysphagia (N = 33) or without dysphagia (N = 89), with mild (N = 55) or severe (N = 14) esophagitis, or younger than 40 years (N = 45) or older than 60 years (N = 19). There was also no difference between patients with GER symptoms and patients with SSc (P > 0.05). We conclude that patients with GER symptoms with or without esophagitis and with or without dysphagia have similar esophageal striated muscle contractions.

Adolescent↗

Role of kallikrein-kininogen system in insulin-stimulated glucose transport after muscle contractions.

Serum proteins [molecular weight (MW) > 10,000] are essential for increased insulin-stimulated glucose transport after in vitro muscle contractions. We investigated the role of the kallikrein-kininogen system, including bradykinin, which is derived from kallikrein (MW > 10,000)-catalyzed degradation of serum protein kininogen (MW > 10,000), on this contraction effect. In vitro electrical stimulation of rat epitrochlearis muscles was performed in 1) rat serum +/- kallikrein inhibitors; 2) human plasma (normal or kallikrein-deficient); 3) rat serum +/- bradykinin receptor-2 inhibitors; or 4) serum-free buffer +/- bradykinin. 3-O-methylglucose transport (3-MGT) was measured 3.5 h later. Serum +/- kallikrein inhibitors tended (P = 0.08) to diminish postcontraction insulin-stimulated 3-MGT. Contractions in normal plasma enhanced insulin-stimulated 3-MGT vs. controls, but contractions in kallikrein-deficient plasma did not. Supplementing rat serum with bradykinin receptor antagonist HOE-140 during contraction did not alter insulin-stimulated 3-MGT. Muscles stimulated to contract in serum-free buffer plus bradykinin did not have enhanced insulin-stimulated 3-MGT. Bradykinin was insufficient for postcontraction-enhanced insulin sensitivity. However, results with kallikrein inhibitors and kallikrein-deficient plasma suggest kallikrein plays a role in this improved insulin action.

3-O-Methylglucose↗

Inhibition of spontaneous smooth muscle contractions in rat and rabbit intestine by blockers of the thromboxane A2 pathway.

The effect of inhibitors of the thromboxane A2 pathway on spontaneous contractions of intestinal smooth muscle preparations was studied. The thromboxane A2 antagonists Bay u3405, SK and F 88046 and KW-3635 concentration-dependently inhibited both the amplitude and the frequency of spontaneous contractions of the longitudinal muscle from the rat proximal colon. A concentration-dependent inhibition of the myogenic contractions was also observed with the thromboxane A2 synthase inhibitor U-51605, and with the combined cyclooxygenase/lipoxygenase inhibitor nordihydroguaiaretic acid, whereas indomethacin, a pure cyclooxygenase inhibitor, was ineffective. None of these inhibitors affected the contractile response evoked by the cholinergic agonist carbachol, excluding non-specific actions on intestinal motility. A similar response was observed for the rabbit jejunum, which, in contrast to the rat colon, exhibits more regular, high-frequency spontaneous contractions, which were inhibited by Bay u3405, SK and F 88046 and KW-3635 in a concentration-dependent manner, whereas the response to carbachol remained unaffected. These results suggest a role for thromboxane A2 in the generation and/or facilitation of spontaneous smooth muscle contractions in the gut.

Animals↗

Muscle contraction history: modified Hill versus an exponential decay model.

In recent years, it has been recognised that improvements to classic models of muscle mechanical behaviour are often necessary for properly modelling coordinated multi-joint actions. In this respect, the purpose of the present study was to improve on modelling stretch-induced force enhancement and shortening-induced force depression of muscle contraction. For this purpose, two models were used: a modified Hill model and a model based loosely on mechano-chemistry of the cross-bridge cycle (exponential decay model). The models were compared with a classic Hill modeland experimental data. Parameter values were based, as much as possible, on experimental findings in the literature, and tested with new experiments on the gastrocnemius of the rat. Both models describe many features of slow-ramp movements well during short contractions (300-500 ms), but long-duration behaviour is described only partly. The exponential decay model does not incorporate a force-velocity curve. Therefore, its good performance indicates that the status ofthe classic force-velocity characteristic may have to be reconsidered. Like movement-induced force depression and enhancement, it seems a particular manifestation of time-dependent force behaviour of muscle, rather than a fundamental property of muscle (like the length-tension curve). It is argued that a combination of the exponential decay model (or other models based on the mechano-chemistry of contraction) and structurally based models may be fruitful in explaining this time-dependent contraction behaviour. Furthermore, not in the least because of its relative simplicity, the exponential decay model may prove more suitable for modelling multi-joint movements than the Hill model.

Animals↗