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1.
The enterotoxin of Clostridium perfringens type A, a channel forming protein toxin, inhibited neuromuscular transmission under conditions of low calcium. Twitch tension of isolated phrenic nerve-diaphragm preparations elicited by electrical stimulations to the phrenic nerve was recorded isometrically, and the preparations were exposed to the purified enterotoxin. In Krebs solution containing 0.5 mM calcium, the enterotoxin (20 micrograms/ml) reduced within 10 min the amplitude of the twitch tension to 34 +/- 7% (mean +/- S.D., n = 11) of that recorded before the treatment. The effects of the enterotoxin on the twitch tension were irreversible and proceeded independently of stimulation. The reduction of the twitch tension by the enterotoxin was apparent in Krebs solution containing less than 0.6 mM calcium and the degree of reduction was inversely related to the concentration of calcium. The reduction of the twitch tension by the enterotoxin was also dependent on temperature and concentration of the toxin. At temperatures below 20 degrees C, no obvious reduction of twitch tension was observed with 20 micrograms/ml of the enterotoxin. Enterotoxin at a concentration of 0.4 micrograms/ml caused 16 +/- 2% (mean +/- S.D., n = 4) reduction of twitch tension, and the degree of the reduction in twitch tension increased with toxin concentration, reaching a plateau of 65 +/- 4% (mean +/- S.D., n = 7) at 6.5 micrograms/ml of the enterotoxin. The effects of the enterotoxin were antagonized by 2 microM physostigmine. Unlike curare, pretreatment of the preparation with enterotoxin did not antagonize the neuromuscular block by decamethonium. Neither the tension of muscular twitch elicited by direct electrical stimulation to the muscle nor the resting membrane potentials of muscle fibers recorded intracellularly were affected by the enterotoxin. The enterotoxin (2.2 micrograms/ml) reduced the frequency, but not mean amplitude or amplitude distribution, of miniature end-plate potentials, from 0.91 +/- 0.07/sec to 0.72 +/- 0.07 (mean +/- S.E., n = 5). The results suggest that the enterotoxin will provide a novel tool for the studies on the mechanism of the neuromuscular transmission because of the unique characteristics of the inhibition and of the known mechanism of its action on the cell membrane. 相似文献
2.
F K?ssler 《Journal of applied toxicology : JAT》1991,11(3):189-194
The toxic effect of trichlorethylene (TCE) was investigated on isolated muscles prepared from frog and rats. Twitch and tetanic contractions as well as caffeine-induced contractures, were recorded. Trichloroethylene at a concentration of 0.25-4.0 mM depressed the force development of both twitch and tetanic tension in a dose-dependent manner. This effect was not influenced by the type of muscle. As TCE shortened the time to peak of twitch contractions, it may alter the Ca2+ binding kinetics. Subthreshold caffeine concentrations applied after pre-exposure to TCE (1 or 2mM) induced contractures. The same TCE exposure enhanced regular caffeine contractures through increasing the speed of tension development and the absolute force. Exposure to 5 or 10 mM TCE did not affect the first caffeine-induced contracture but enhanced the potency of the second caffeine dose given 15 min after the first. The results suggest that the interaction of TCE with membrane sites is responsible for Ca2+ release for contractile processes. 相似文献
3.
1. The effects of the calcium agonist, Bay K 8644, on the mechanical output of skeletal muscle were studied in frog semitendinosus fiber bundles and in whole sartorius muscles. 2. Low concentrations of Bay K 8644 (less than or equal to 1 microM) had no significant influence on isometric twitches. Concentrations between 5-20 microM increased peak tension by 28.6 +/- 2.9% while higher concentrations (greater than or equal to 50 microM) initially increased then depressed twitches by 70 +/- 3.5%. 3. 10 microM Bay K 8644 also increased peak tension developed during low frequency stimulation (i.e. less than or equal to 40 Hz), slightly depressed high frequency contractions (i.e. greater than or equal to 80 Hz) but did not reduce maximal tetanic tension which occurred at about 60 Hz. 4. Potentiation of twitches and low frequency tetani and depression of high frequency tetani by Bay K 8644 were partially antagonized by nifedipine (10 microM), low extracellular calcium and D-600 (5 microM). These conditions did not, however, block the depressant actions of greater than or equal to 50 microM Bay K 8644. 5. In skinned fibers, 10 microM Bay K 8644 had no effect on resting or maximal Ca2+ activated tension. Also, 10 microM Bay K 8644 had no effect on caffeine contractures when added to the previous Ca2+ loading solution. 6. These results suggest that Bay K 8644 has both positive and negative inotropic actions on isolated skeletal muscle, which are dependent on drug concentration and muscle activation pattern. 相似文献
4.
Mechanisms controlling caffeine-induced relaxation of coronary artery of the pig. 总被引:1,自引:1,他引:0
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1. We studied the effects of caffeine on coronary artery smooth muscle of the pig by measuring changes in isometric tension, cytosolic free Ca(2+) concentration ( [Ca2+]i) and transmembrane potential. 2. In the absence of tone, caffeine induced a concentration-dependent transient contraction of coronary artery strips, followed by sustained relaxation. Simultaneously with the relaxation, caffeine, 25 mM, hyperpolarized the smooth muscle cells by 7.7 +/- 0.9 mV. 3. Caffeine caused a concentration-dependent relaxation of strips precontracted with 10(-5)M acetylcholine (ACH). A supramaximal relaxing concentration of 25 mM caffeine produced an additional transient increase in [Ca2+]i on the Ca2+ plateau of ACh tonic contraction, which was followed by a decrease in [Ca2+]i to a level slightly below the basal concentration. This relaxation was accompanied by a hyperpolarization of 7.3 +/- 0.9 mV. 4. KCI 120 mM (high K+) contracted the strips with a concomitant depolarization of 38.6 +/- 1.6 mV and sustained increase in [Ca2+]i. Caffeine caused a concentration-dependent relaxation of high K+-induced contraction. Caffeine, 25 mM, decreased the Ca2+ plateau to a level that remained above the basal concentration of Ca2+ but did not change the membrane potential. 5. When strips were placed in a Ca(2+)-free medium with EGTA 2mM, and, in addition, ACh was applied successively three times, both intracellular and extracellular mobilizable Ca2+ pools were depleted. In these conditions, phorbol 12,13 dibutyrate (PDBu) 10(-7) M and prostaglandin F 2 alpha (PGF 2 alpha) 10(-5) M contracted the strips. Caffeine (25 mM) inhibited these contractions with no change in [Ca2+]i.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
5.
Potassium contractures and mechanical activation in rat skeletal muscle: effects of multivalent cations, temperature and tetracaine 总被引:2,自引:0,他引:2
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The effects of cations, temperature and tetracaine on potassium-induced contractures of rat soleus and extensor digitorus longus (e.d.l.) muscles were investigated. In the soleus, the threshold for the potassium contracture was lower (10-20 vs 20-40 mM), the peak amplitude was up to fourteen times larger, and the time course was about one half that in the e.d.l. muscle. The extent of inactivation of a test potassium contracture was directly related to the concentration of potassium in the conditioning solution and the period of exposure. Removal of calcium reduced the amplitude and time course of potassium contractures in both preparations. Addition of cobalt (10 mM) reduced the amplitude but prolonged the time course of contractures. Exposure of muscles to tetracaine (10(-5)-10(-6) M for 30 min) increased, but higher concentrations reduced, the amplitude of potassium contractures. When present for one minute, tetracaine (1 mM) moved the potassium activation curve to higher, and the potassium inactivation curve to lower, potassium concentrations. 相似文献
6.
R C Elliott 《General pharmacology》1987,18(3):331-335
Contractures of the chick biventer cervicis muscle were recorded in vitro in response to exogenous acetylcholine (ACh) and to tetraethylammonium (TEA) and concentration response curves (CRC) produced for these drugs. In BVC muscles equilibrated with lidocaine (1.07 mM), physostigmine (3.63 microM) blocked TEA induced contractures in a reversible non-competitive manner. It had a similar action on ACh induced contractures. Lidocaine (1.07 mM) had no action on the ACh CRC except that it reduced the response to the highest concentration of ACh tested. The data of this and of previous experiments was analyzed and a theory proposed to account for TEA contractures. It suggested that background extravesicular ACh release results in the passage of K+ into the transverse tubular system (TT). In the presence of TEA blocking the K+ channels accumulation of K+ in the TT no longer occurs. Na+/K+ exchange is depressed in favour of Na+/Ca+ exchange and the resulting rise in intracellular Ca2+ acting on the sarcoplasmic reticulum leads to contraction. Lidocaine potentiates the contraction by blocking Ca2+ uptake into the sarcoplasmic reticulum. 相似文献
7.
The effects of 3,4-diaminopyridine (3,4-DAP) were studied on isolated muscle fibres of the frog in concentrations ranging between 0.025 and 5.0 mM. Isometric twitch and tetanus responses were recorded at temperatures between 2.5 and 3.9 degrees. 3,4-DAP caused a concentration-dependent increase in twitch amplitude, maximum effects being obtained at a concentration of 3 mM with a mean increase in tension of 70 +/- 12% of control (n = 7). 3,4-DAP in 3 mM concentration had only a slight increase in initial rate of rise of twitch tension (mean increase 8 +/- 4%) but increased the time to half peak tension by 59 +/- 9% and the time from peak tension to half relaxation by 78 +/- 10%. No significant effect of 3,4-DAP was observed on the initial rate of rise and total amplitude of the isometric tetanus. The twitch potentiating effect of 3,4-DAP developed gradually with the number of times the fibre was stimulated and reached a maximum level after 40-50 stimulations. A gradual increase in the duration of the action potential was also observed. It is suggested that 3,4-DAP, like 4-aminopyridine, potentiates the twitch by means of prolonging the duration of the action potential. 相似文献
8.
Intracellular calcium in canine cultured tracheal smooth muscle cells is regulated by M3 muscarinic receptors. 总被引:3,自引:2,他引:1
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1. The regulation of cytosolic Ca2+ concentrations ([Ca2+]i) during exposure to carbachol was measured directly in canine cultured tracheal smooth muscle cells (TSMCs) loaded with fura-2. Stimulation of muscarinic cholinoceptors (muscarinic AChRs) by carbachol produced a dose-dependent rise in [Ca2+]i which was followed by a stable plateau phase. The EC50 values of carbachol for the peak and sustained plateau responses were 0.34 and 0.33 microM, respectively. 2. Atropine (10 microM) prevented all the responses to carbachol, and when added during a response to carbachol, significantly, but not completely decreased [Ca2+]i within 5 s. Therefore, the changes in [Ca2+]i by carbachol were mediated through the muscarinic AChRs. 3. AF-DX 116 (a selective M2 antagonist) and 4-diphenylacetoxy-N-methylpiperidine (4-DAMP, a selective M3 antagonist) inhibited the carbachol-stimulated increase in [Ca2+]i with pKB values of 6.4 and 9.4, respectively, corresponding to low affinity for AF-DX 119 and high affinity for 4-DAMP in antagonizing this response. 4. The plateau elevation of [Ca2+]i was dependent on the presence of external Ca2+. Removal of Ca2+ by the addition of 2 mM EGTA caused the [Ca2+]i to decline rapidly to the resting level. In the absence of external Ca2+, only an initial transient peak of [Ca2+]i was seen which then declined to the resting level; the sustained elevation of [Ca2+]i could then be evoked by the addition of Ca2+ (1.8 mM) in the continued presence of carbachol.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
9.
A multitissue organ bath was developed to study four isolated muscle preparations simultaneously under identical conditions. The multitissue bath was evaluated by determining the dose-response curves to dobutamine in isolated rabbit right ventricular papillary muscles. Several new procedures were developed to diminish the contracture shortening that often accompanies papillary muscle excision in this species. The excised heart was dissected in a hypothermic (22 degrees C) 'relaxing solution' containing 180 mM NaCl and 5.6 mM glucose, and a 'transfer clip' maintained constant, reproducible resting tension on the isolated muscle after its excision. Rabbit papillary muscles (n = 13) isolated with these procedures and studied in the multitissue bath were stimulated at a frequency of 20/min at 30 degrees C in a modified Krebs solution containing 2.5 mM Ca2+. Mean developed tension was 3.3 +/- 0.5 g/mm2. The dose-response curve for dobutamine demonstrated a maximal increase of dT/dt, an index of contractility, at 10(-4) M (173.6 +/- 35%, p less than 0.01). The multitissue bath may be useful for simultaneous comparison of chronotropic and inotropic effects of interventions on right atrial and ventricular preparations, respectively, or for comparison of intervention effects on selected vascular strips. 相似文献
10.
R C Elliott 《General pharmacology》1987,18(1):7-11
Lidocaine (0.92 mM) potentiated tetraethylammonium (TEA, 0.6-6 mM) induced contractures of the chick biventer cervicis muscle (BVC) in vitro. The dose ratio for TEA (EC50 in lidocaine/EC50 control) was 1.16 X 10(-3). Lidocaine (0.92 mM) blocked nerve and muscle action potentials in the BVC preparation, blocked slow fibre MEPPS, and blocked indirectly elicited muscle contraction. Lidocaine (0.92 mM) non-competitively blocked acetylcholine (ACh) induced contractures of the chick BVC. Gallamine competitively blocked ACh contractures (pA2 6.53) but produced only a relatively weak non-competitive block of TEA induced contractures in lidocaine. TEA induced contractures of the chick BVC in the presence of lidocaine probably do not involve ACh. 相似文献
11.
Contractures elicited by tetraethylammonium in avian muscle treated with methohexitone. 总被引:1,自引:1,他引:0
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R. C. Elliott 《British journal of pharmacology》1979,66(3):391-395
1 The chick biventer cervicis muscle immersed in methohexitone (8.8 x 10(-5) M) responded to tetraethylammonium with contractures which were dose-related. The ED50 for tetraethylammonium was 2.1 x 10(-3) M. 2 In the absence of methohexitone, tetraethylammonium produced contractures only at much higher concentrations: these contractures were accompanied by fasciculations and neuromuscular block of the twitch fibres. 3 The contractures produced by tetraethylammonium in the presence of methohexitone were not reduced by exposure to botulinum toxin which eliminated all response of the muscle to indirect stimulation. 4 Tubocurarine (1.2 x 10(-6) M) displaced the dose-response curve for tetraethylammonium-methohexitone-induced contractures to the right. The dose-ratio was 15.63 +/- 1.98. 5 Physostigmine (1.8 x 10(-6) M) potentiated the activity of tetraethylammonium-methohexitone 3.26 or 3.84 fold, depending on the method of calculation used. 6 Physostigmine potentiated contractures elicited by indirect repetitive stimulation 4.8 to 6.0 fold more than it potentiated contractures due to tetraethylammonium-methohexitone. 7 It is concluded that in the presence of methohexitone, tetraethylammonium produces contractures of the chick muscle by releasing acetylcholine but also by a direct agonist action on the cholinoceptor. 相似文献
12.
The effects of external potassium, multivalent cations and temperature on caffeine contractures in rat skeletal muscle
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The effects of multivalent cations, membrane potential and temperature on caffeine contractures of rat soleus and extensor digitorus longus (e.d.l.) muscles were investigated. The amplitude of the caffeine contracture was depressed by the removal of calcium and by the addition of a high concentration (1 mM) of lanthanum. Low concentrations of lanthanum (0.1-0.5 mM) augmented the caffeine contracture. Low levels of depolarization by potassium (10-40 mM) augmented the amplitude of the caffeine contracture, while higher concentrations of potassium depressed the contracture. Maximum augmentation of the caffeine contracture occurred with a higher concentration of potassium (20 mM vs 10 mM) in the e.d.l. than in the soleus muscle. The amplitude of contractures was directly related to temperature between 22 and 37 degrees C and inversely related to temperature below 22 degrees C. The effects of caffeine in rat skeletal muscle are suggested to be exerted on the sarcolemma and the mechanisms of action are by modification of the processes of activation and inactivation. 相似文献
13.
The response of non-pregnant rat myometrium to oxytocin in Ca-free solution. 总被引:7,自引:6,他引:1
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The contractile response of the longitudinal muscle of non-pregnant rat myometrium to oxytocin (0.2-20 nM) consisted of a phasic and a tonic component. Ca-removal abolished the phasic component but a tonic contraction could be evoked without reduction of amplitude for 50 h. Exceptionally, the tonic contraction also disappeared gradually in Ca-free medium containing 2 mM EGTA. When oxytocin was repeatedly applied in the absence of Ca, the response became at first progressively larger before reaching a steady state. Transient addition of Ca to the medium reduced the size of the subsequent oxytocin contraction. In Ca-free medium, the tissue lost Ca slowly, but it still contained 40 mumol kg-1 after 6 h and roughly 1 mumol kg-1 wet weight after 24 h exposure. 45Ca efflux was marginally increased by oxytocin (20 nM). Caffeine (5-30 mM) produced no contraction, but slightly reduced the resting tension and strongly inhibited the oxytocin response both in the presence and in the absence of Ca. Caffeine also blocked the contraction induced by Ca added to Ca-free 40 mM K solution. However, pretreatment with caffeine (30 mM) had no effect on the following oxytocin response. A calmodulin antagonist, trifluoperazine (1-10 microM) suppressed strongly the Ca-induced contraction, but had only a weak effect on the oxytocin response in Ca-free medium. Chlorpromazine (10-100 microM) and fluphenazine (10-30 microM) had similar effects.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
14.
Leite-Moreira AF Castro-Chaves P Pimentel-Nunes P Lima-Carneiro A Guerra MS Soares JB Ferreira-Martins J 《British journal of pharmacology》2006,147(6):690-697
Acute effects of angiotensin II (AngII) on diastolic properties of the myocardium were investigated. Increasing concentrations of AngII (10(-9) to 10(-5) M) were added to rabbit papillary muscles in the absence (n=11) or presence of: (i) AT1 receptor antagonists, losartan (10(-6) M; n=7) or ZD-7155 (10(-7) M; n=8); (ii) ZD-7155 (10(-7) M) plus AT2 receptor antagonist PD-123,319 (2 x 10(-6) M; n=6); (iii) PKC inhibitor, chelerythrine (10(-5) M; n=8); or (iv) Na(+)/H(+) exchanger (NHE) inhibitor, 5-(N-methyl-N-isobutyl)-amiloride (10(-6) M; n=10). Passive length-tension relations were constructed before and after a single concentration of AngII (10(-5) M, n=6). Effects of AngII infusion (10 microg kg(-1) min(-1)) were evaluated in in situ rabbit hearts. AngII concentration dependently increased inotropy and resting muscle length (RL). At 10(-5) M, active tension increased 43.3+/-6.25% and RL 1.96+/-0.4%. Correcting RL to its initial value resulted in a 46+/-4% decrease of resting tension, indicating decreased muscle stiffness, as confirmed by the right and downward shift of the passive length-tension relation promoted by AngII. In the intact heart, at matched systolic pressures of 112 mmHg, AngII decreased end-diastolic pressures from 10.3+/-0.3 to 5.9+/-0.5 mmHg, and minimal diastolic pressures from 8.4+/-0.5 to 4.6+/-0.6 mmHg. AT1 blockade inhibited AngII effects on myocardial inotropy and stiffness, while PKC or NHE inhibition only significantly attenuated its effects on resting length and tension. In conclusion, AngII decreases myocardial stiffness, an effect that requires AT1 receptor activation and is mediated by PKC and NHE. This represents a novel mechanism of acute neurohumoral modulation of diastolic function, suggesting that AngII is a powerful regulator of cardiac filling. 相似文献
15.
Oshima-Franco Y Leite GB Belo CA Hyslop S Prado-Franceschi J Cintra AC Giglio JR da Cruz-Höfling MA Rodrigues-Simioni L 《Basic & clinical pharmacology & toxicology》2004,95(4):175-182
Bothropstoxin-I from Bothrops jararacussu snake venom is a lysine-49 phospholipase A(2) with myotoxic and neurotoxic activities. In this study, we used mouse phrenic nerve-diaphragm preparations in the absence and presence of manganese (Mn(2+)), a presynaptic blocker, to investigate a possible presynaptic action of bothropstoxin-I. At concentrations of 0.9 mM and 1.8 mM, Mn(2+) produced 50% neuromuscular blockade in less than 4 min., which was spontaneously reversible at the lower concentration. Bothropstoxin-I (1.4 microM) irreversibly inhibited neuromuscular blockade by 50% in 31+/-4 min. (mean+/-S.E.M., n = 9). Pretreating preparations with 0.9 mM Mn(2+) prevented the blockade by bothropstoxin-I. When added after bothropstoxin-I, Mn(2+) produced its characteristic blockade and, after washing, the twitch tension returned to pre-Mn(2+) levels, indicating that bothropstoxin-I caused irreversible damage before the addition of Mn(2+). Electrophysiological measurements showed that a concentration of bothropstoxin-I (0.35 microM), which did not produce neuromuscular blockade, caused the appearance of giant miniature end-plate potentials with no change in the membrane resting potential but increased the quantal content. Preparations preincubated with Mn(2+) (0.9 mM, 30 min.) were protected against the depolarizing action of bothropstoxin-I (0.7 microM). These results show that, in addition to its well-known myotoxic effect, bothropstoxin-I also has a presynaptic action. 相似文献
16.
R C Elliott 《General pharmacology》1986,17(6):655-659
End-plate and miniature end-plate potentials (EPP, MEPP) were recorded in the chick biventer cervicis muscle in vitro. The control frequency of discharge of MEPPs was 5.97 +/- 1.04 min-1, n = 10. Methohexitone (8.8 X 10(-5) M) did not affect the frequency of MEPP discharge, but tetraethylammonium (TEA, 2.4-9.5 mM), reduced the frequency to 32.9 +/- 8.6% of the control. In the presence of neostigmine (3.3 X 10(-6) M) methohexitone (8.8 X 10(-5) M) reduced MEPP frequency to 38.7 +/- 5.4% of the control and TEA (2.4-9.5 mM) further reduced the frequency to 8.7 +/- 2.1% of the control. After a transient facilitation of the EPP, TEA (2.4-9.5 mM) in the presence of methohexitone (8.8 X 10(-5) M) and neostigmine (3.3 X 10(-6) M) markedly reduced EPP amplitude. The contractures which TEA produced in the presence of methohexitone were not due to an increase in the spontaneous release of vesicular ACh. 相似文献
17.
M Adler F J Lebeda F C Kauffman S S Deshpande 《Journal of applied toxicology : JAT》1999,19(6):411-419
The effects of sodium cyanide (NaCN) were investigated on the contractile and electrophysiological properties of rat diaphragm muscles in vitro. Sodium cyanide (0.1-1.0 mM) produced an initial potentiation of directly elicited twitch tensions, followed by a slow progressive depression. The potentiation and depression were both dependent on the NaCN concentration and stimulation frequency. Muscles exposed to NaCN exhibited marked reductions of creatine phosphate concentration, but ATP levels were not significantly lowered. Sodium cyanide had no effect on the resting potential, input resistance or action potential, indicating that the toxicity of the metabolic inhibitor is not mediated by alterations of membrane excitability or passive electrical properties. Sodium cyanide reduced the amplitude of contractures elicited by 70 mM K(2)SO(4), suggesting that the actions of NaCN cannot be explained by a failure of action potentials to propagate across the muscle surface or within t-tubular membranes. Sodium cyanide suppressed the first phase of the caffeine contracture, an observation consistent with an impaired release of, or reduced sensitivity to, sarcoplasmic reticular Ca(2+), but did not alter the amplitude of the second phase, which represents rigor following ATP depletion. These results, in conjunction with those of previous studies, suggest that the depression in muscle tension following exposure to NaCN may result from alterations in Ca(2+) homeostasis, intracellular acidosis or from accumulation of one or more products of phosphocreatine breakdown. 相似文献
18.
1. Dimethyl sulphoxide (DMSO) partially reversed neuromuscular blockade brought about by the action of (+)-tubocurarine or Mg(2+) on the frog sartorius nerve-muscle preparation.2. The amplitude and duration of the endplate potential (e.p.p.) were increased by DMSO at concentrations of 70 mM or greater.3. Miniature endplate potentials were raised in frequency, prolonged in duration and increased in amplitude by DMSO at concentrations of 141 mM or greater, but the increase in amplitude was generally less than in the case of the e.p.p.4. The resting muscle membrane potential was significantly depolarized by DMSO at 70 mM or greater concentrations, both at the endplate and remote from an endplate.5. The reversal of neurmuscular blockade by DMSO can be explained in terms of its previously reported ability to inhibit cholinesterase activity, together with the depolarizing action on muscle. 相似文献
19.
L Lubomirov H Gagov P Petkova-Kirova D Duridanova V U Kalentchuk R Schubert 《British journal of pharmacology》2001,134(7):1564-1570
1. Urocortin is an endogenous vasodilator although the mechanism of vasorelaxation is not completely understood. The hypothesis that an alteration of smooth muscle calcium concentration is involved was tested using isometric tension recording and calcium fluorimetry. The relationship between contraction and intracellular calcium was also estimated. 2. Urocortin produced a concentration dependent relaxation (pD(2) 8.59+/-0.06, n=6) of vessels pre-contracted with a physiological salt solution containing 42 mM KCl (42 mM K-PSS). 3. Removal of the endothelium did not alter the effect of urocortin, pD(2) was 8.49+/-0.11, n=5. 4. Corticotropin-releasing factor relaxed 42 mM K-PSS pre-contracted vessels with less potency compared to urocortin (pD(2) 6.99+/-0.28, n=5). 5. Urocortin at 100 nM relaxed vessels pre-contracted with 42 mM K-PSS by 59.6+/-4.6% (n=8) and vessels pre-contracted with 500 nM noradrenaline by 25.2+/-6.8% (n=6). Both effects were not accompanied by a change in the intracellular calcium concentration. 6. Urocortin at 100 nM produced a significant rightward shift of 0.33+/-0.07 units of normalized intracellular calcium (n=5) of the relationship between tension and intracellular calcium. 7. The urocortin-induced relaxation was considerably reduced in the presence of 0.3 mM Rp-8-CPT-cAMPS, a cyclic AMP-dependent protein kinase (PKA) inhibitor. 8. The PKA-activator Sp-5,6-DCl-cBIMPS relaxed 42 mM K-PSS pre-contracted vessels (pD(2) 4.98+/-0.07, n=6). Sp-5,6-DCl-cBIMPS at 0.1 mM relaxed vessels by 85.3+/-2.5% (n=5), but did not change the intracellular calcium concentration. 9. In conclusion, the data show that urocortin is a potent, endothelium-independent dilator of rat tail arteries and suggest that this effect is mediated by PKA causing a reduction of the sensitivity of the contractile apparatus for calcium. 相似文献
20.
F A Wali 《Pharmacological research communications》1986,18(1):31-48
The effect of lignocaine (0.01-100 micrograms.ml-1) on amplitude of indirectly and directly-elicited twitch contractions and on contractures produced by acetylcholine (ACh) (0.1-10 mM) and tetraethylammonium (TEA) (1.2-12 mM) was studied in isolated biventer cervicis skeletal muscle of the chick. Lignocaine (0.01-0.9 microgram.ml-1) increased the amplitude of the indirectly-elicited twitch contractions. At high concentrations (10-100 micrograms.ml-1), lignocaine decreased or blocked the twitch tension and produced a contracture in the chick skeletal muscle. Lignocaine also reduced or blocked the directly-elicited twitch contractions in a dose-dependent manner. Lignocaine (10 micrograms.ml-1) reduced the ACh-induced contracture whereas it increased that produced by TEA. Physostigmine (2 micrograms.ml-1) increased the stimulating effect of lignocaine, at low concentrations. However, repeated exposures to lignocaine followed by physostigmine resulted in both increase and decrease in the indirectly-elicited twitch contractions. It was concluded that lignocaine had a dual action at the neuromuscular junction. In low concentrations, lignocaine increases the twitch tension, possibly by an anticholinesterase action, and in high concentrations it reduces or blocks the twitch tension, produces a contracture in the muscle, and reduces the ACh-induced contractures, whereas it increases the TEA-induced responses. Some of these effects of lignocaine may be interpreted in terms of effects on excitation-contraction coupling in muscle. 相似文献