Short-term effects of prednisolone on neuromuscular transmission in the isolated mdx mouse diaphragm.
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To determine the mechanism of the beneficial effects of prednisolone on Duchenne muscular dystrophy (DMD), we examined the short-term effects of prednisolone on neuromuscular transmission by using conventional microelectrode methods in the mdx mice. High (56 micromol/liter) and low (2.8 micromol/liter) concentrations of prednisolone were applied to a bath containing phrenic nerve-diaphragm preparations from mdx mice, and several parameters related to neuromuscular transmission were recorded. The high dose of prednisolone significantly decreased parameter n on quantal release by nerve impulse and decay time-constant of end-plate potentials, which showed adverse effect on neuromuscular transmission. The low dose of prednisolone did not significantly increase quantal content, but could assist the compensatory reaction to maintain the safety margin of neuromuscular transmission in the mdx mice. Our results suggest that the latter effect represents one of the possible mechanisms of the therapeutic effects of prednisolone on DMD. (+info)
Antagonism by hemoglobin of effects induced by L-arginine in neuromuscular preparations from rats.
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Nitric oxide (NO)-synthase is present in diaphragm, phrenic nerve and vascular smooth muscle. It has been shown that the NO precursor L-arginine (L-Arg) at the presynaptic level increases the amplitude of muscular contraction (AMC) and induces tetanic fade when the muscle is indirectly stimulated at low and high frequencies, respectively. However, the precursor in muscle reduces AMC and maximal tetanic fade when the preparations are stimulated directly. In the present study the importance of NO synthesized in different tissues for the L-Arg-induced neuromuscular effects was investigated. Hemoglobin (50 nM) did not produce any neuromuscular effect, but antagonized the increase in AMC and tetanic fade induced by L-Arg (9.4 mM) in rat phrenic nerve-diaphragm preparations. D-Arg (9.4 mM) did not produce any effect when preparations were stimulated indirectly at low or high frequency. Hemoglobin did not inhibit the decrease of AMC or the reduction in maximal tetanic tension induced by L-Arg in preparations previously paralyzed with d-tubocurarine and directly stimulated. Since only the presynaptic effects induced by L-Arg were antagonized by hemoglobin, the present results suggest that NO synthesized in muscle acts on nerve and skeletal muscle. Nevertheless, NO produced in nerve and vascular smooth muscle does not seem to act on skeletal muscle. (+info)
Effect of diaphragm fatigue on neural respiratory drive.
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To test the hypothesis that diaphragm fatigue leads to an increase in neural respiratory drive, we measured the esophageal diaphragm electromyogram (EMG) during CO(2) rebreathing before and after diaphragm fatigue in six normal subjects. The electrode catheter was positioned on the basis of the amplitude and polarity of the diaphragm compound muscle action potential recorded simultaneously from four pairs of electrodes during bilateral anterior magnetic phrenic nerve stimulation (BAMPS) at functional residual capacity. Two minutes of maximum isocapnic voluntary ventilation (MIVV) were performed in six subjects to induce diaphragm fatigue. A maximal voluntary breathing against an inspiratory resistive loading (IRL) was also performed in four subjects. The reduction of transdiaphragmatic pressure elicited by BAMPS was 22% (range 13-27%) after 2 min of MIVV and was similar, 20% (range 13-26%), after IRL. There was a linear relationship between minute ventilation (VE) and the root mean square (RMS) of the EMG during CO(2) rebreathing before and after fatigue. The mean slope of the linear regression of RMS on VE was similar before and after diaphragm fatigue: 2.80 +/- 1.31 vs. 3.29 +/- 1.40 for MIVV and 1.51 +/- 0.31 vs 1.55 +/- 0.31 for IRL, respectively. We conclude that the esophageal diaphragm EMG can be used to assess neural drive and that diaphragm fatigue of the intensity observed in this study does not affect respiratory drive. (+info)
Phrenic long-term facilitation requires 5-HT receptor activation during but not following episodic hypoxia.
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Episodic hypoxia evokes a sustained augmentation of respiratory motor output known as long-term facilitation (LTF). Phrenic LTF is prevented by pretreatment with the 5-hydroxytryptamine (5-HT) receptor antagonist ketanserin. We tested the hypothesis that 5-HT receptor activation is necessary for the induction but not maintenance of phrenic LTF. Peak integrated phrenic nerve activity (integralPhr) was monitored for 1 h after three 5-min episodes of isocapnic hypoxia (arterial PO(2) = 40 +/- 2 Torr; 5-min hyperoxic intervals) in four groups of anesthetized, vagotomized, paralyzed, and ventilated Sprague-Dawley rats [1) control (n = 11), 2) ketanserin pretreatment (2 mg/kg iv; n = 7), and ketanserin treatment 0 and 45 min after episodic hypoxia (n = 7 each)]. Ketanserin transiently decreased integralPhr, but it returned to baseline levels within 10 min. One hour after episodic hypoxia, integralPhr was significantly elevated from baseline in control and in the 0- and 45-min posthypoxia ketanserin groups. Conversely, ketanserin pretreatment abolished phrenic LTF. We conclude that 5-HT receptor activation is necessary to initiate (during hypoxia) but not maintain (following hypoxia) phrenic LTF. (+info)
Potencies of doxapram and hypoxia in stimulating carotid-body chemoreceptors and ventilation in anesthetized cats.
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The effects of doxapram on carotid chemoreceptor activity and on ventilation (phrenic-nerve activity) were tested before and after denervation of the peripheral chemoreceptors in cats. Doxapram was found to be a potent stimulus to the carotid chemoreceptors; the stimulation produced by 1.0 mg/kg doxapram, iv, equalled that produced by a Pao2 of 38 torr. Doxapram also increased phrenic-nerve activity in doses as low as 0.2 mg/kg, iv. After denervation of the peripheral chemoreceptors, doxapram in doses as large as 6 mg/kg failed to stimulate ventilation. It is concluded that (in anesthetized cats) doxapram in doses of less than 6 mg/kg increases ventilation by direct stimulation of the carotid, and, probably, the aortic, chemoreceptors, not by a direct effect on the medullary respiratory center. (+info)
Effect of temperature on endplate potential rundown and recovery in rat diaphragm.
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The amplitude of neuromuscular junction end-plate potentials (EPPs) decreases quickly within a train but recovers nearly completely from train to train during intermittent stimulation. Rundown has been shown to be dependent not only on the rate of transmitter release but also on the rate of replenishment of the depleted neurotransmitter at the site of release. Two groups of processes have been proposed for synaptic vesicle recycling, both of which involve multiple energy-requiring steps and enzymatic reactions and which therefore would be expected to be very temperature-sensitive. The present study tested the hypothesis that low temperature therefore increases the rate of EPP amplitude rundown. Studies were performed in vitro on rat diaphragm and used micro-conotoxin to allow normal-sized EPPs to be recorded from intact fibers. EPP amplitude rundown during intermittent stimulation at 20 and 50 Hz (duty cycle 333 ms) was greater at 20 degrees C than it was at 37 degrees C. Initially, temperature affected only intra-train rundown but, over longer periods of stimulation, both intra- and inter-train rundown were significantly accelerated by cold temperature. Cumulative EPP amplitudes were calculated by successively adding the amplitudes of each EPP during the stimulation period to provide an estimate of total neurotransmitter release in the neuromuscular junction. The cumulative EPP amplitude was significantly lower at 20 degrees C than it was at 37 degrees C during both 20 and 50 Hz stimulation. These data indicate that the mechanism involved in EPP amplitude rundown and recovery is temperature-sensitive, with a greater decrement in EPP amplitude at cold than at warm temperatures. (+info)
Effects of L-arginine on the diaphragm muscle twitches elicited at different frequencies of nerve stimulation.
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In rats, the nitric oxide (NO)-synthase pathway is present in skeletal muscle, vascular smooth muscle, and motor nerve terminals. Effects of NO were previously studied in rat neuromuscular preparations receiving low (0.2 Hz) or high (200 Hz) frequencies of stimulation. The latter frequency has always induced tetanic fade. However, in these previous studies we did not determine whether NO facilitates or impairs the neuromuscular transmission in preparations indirectly stimulated at frequencies which facilitate neuromuscular transmission. Thus, the present study was carried out to examine the effects of NO in rat neuromuscular preparations indirectly stimulated at 5 and 50 Hz. The amplitude of muscular contraction observed at the end (B) of a 10-s stimulation was taken as the ratio (R) of that obtained at the start (A) (R = B/A). S-nitroso-N-acetylpenicillamine (200 microM), superoxide dismutase (78 U/ml) and L-arginine (4.7 mM), but not D-arginine (4.7-9.4 mM), produced an increase in R (facilitation of neurotransmission) at 5 Hz. However, reduction in the R value (fade of transmission) was observed at 50 Hz. N G-nitro-L-arginine (8.0 mM) antagonized both the facilitatory and inhibitory effects of L-arginine (4.7 mM). The results suggest that NO may modulate the release of acetylcholine by motor nerve terminals. (+info)
Altered respiratory activity and respiratory regulations in adult monoamine oxidase A-deficient mice.
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The abnormal metabolism of serotonin during the perinatal period alters respiratory network maturation at birth as revealed by comparing the monoamine oxidase A-deficient transgenic (Tg8) with the control (C3H) mice (Bou-Flores et al., 2000). To know whether these alterations occur only transiently or induce persistent respiratory dysfunction during adulthood, we studied the respiratory activity and regulations in adult C3H and Tg8 mice. First, plethysmographic and pneumotachographic analyses of breathing patterns revealed weaker tidal volumes and shorter inspiratory durations in Tg8 than in C3H mice. Second, electrophysiological studies showed that the firing activity of inspiratory medullary neurons and phrenic motoneurons is higher in Tg8 mice and that of the intercostal motoneurons in C3H mice. Third, histological studies indicated abnormally large cell bodies of Tg8 intercostal but not phrenic motoneurons. Finally, respiratory responses to hypoxia and lung inflation are weaker in Tg8 than in C3H mice. dl-p-chlorophenyl-alanine treatments applied to Tg8 mice depress the high serotonin level present during adulthood; the treated mice recover normal respiratory responses to both hypoxia and lung inflation, but their breathing parameters are not significantly affected. Therefore in Tg8 mice the high serotonin level occurring during the perinatal period alters respiratory network maturation and produces a permanent respiratory dysfunction, whereas the high serotonin level present in adults alters the respiratory regulatory processes. In conclusion, the metabolism of serotonin plays a crucial role in the maturation of the respiratory network and in both the respiratory activity and the respiratory regulations. (+info)