SOME BIOCHEMICAL RESPONSES OF RAT SKELETAL MUSCLE TO A SINGLE SUBCUTANEOUS INJECTION OF A TOXIN (NOTEXIN) ISOLATED FROM THE VENOM OF THE AUSTRALIAN TIGER SNAKE NOTECHIS SCUTA TUS SCUTA TUS

1. Some biochemical responses of mammalian skeletal muscle to a single subcutaneous injection of a purified toxin from the venom of the Australian tiger snake, Notechis scutatus scutatus, have been investigated to determine the role of changes in peptide hydrolase enzymes in the muscle wasting caused by notexin administration. 2. Within 6 h of injection, serum creatine kinase activity was increased by five-to ten-fold, and remained elevated for at least 24 h. 3. There was an initial inflammatory response in the muscle adjacent to the site of injection; by 12 h after injection, muscle wet weight increased by 60%. 4. After the initial increase, wet weight fell to about 50% of normal at 7 days. Normal wet weight was achieved by 20 days after the injection. Over the period 1–20 days after the injection of the toxin, the changes in wet weight were mirrored by changes in non-collagen protein content. 5. The activities of cathepsin B and acid proteinase were increased following the injection of the toxin. By 2 days after injection, there was a ten-fold increase in the activity of cathepsin B, and a seven-fold increase in the activity of acid proteinase. The activity of both enzymes became normal by 20 days. 6. Experiments utilizing a variety of cytotoxic drugs suggested that the acid proteinase and cathepsin B are primarily located within invading phagocytic cells. 7. The results are discussed with reference to the previously described pathology of toxin-damaged skeletal muscle.     

中国对虾水提取液对大鼠平滑肌的作用

本文首次报道中国对虾水提取液对大鼠胃条、十二指肠、回肠、输精管、膀胱和子宫平滑肌的收缩作用,并证实其作用机理是兴奋5HT—受体。     

INOTROPIC RESPONSES OF ISOLATED ATRIAL AND VENTRICULAR MUSCLE FROM THE DOG HEART TO INOSINE, GUANOSINE AND ADENOSINE

1. The inotropic effects of inosine, adenosine and guanosine were compared in isolated and blood-perfused canine atrial and ventricular muscle preparations paced at 1.5 2.5 Hz. 2. In isolated atria, guanosine and inosine usually had positive inotropic effects, but adenosine consistently had a marked negative inotropic effect. 3. In ventricular muscles, the three purine compounds examined produced dose-related positive inotropic responses, but adenosine also produced a slight negative inotropic response which preceded the positive inotropic response.     

EFFECT OF DILTIAZEM, VERAPAMIL AND DANTROLENE ON THE CONTRACTILITY OF ISOLATED MALIGNANT HYPERPYREXIA-SUSCEPTIBLE HUMAN SKELETAL MUSCLE

1. Diltiazem (10 mumol/L) and verapamil (10 mumol/L) inhibited the hypercontractility induced by 3% halothane and 2 mmol/L caffeine in malignant hyperpyrexia susceptible (MHS) muscle. Diltiazem also inhibited 80 mmol/L KCl contractures. 2. Like the skeletal muscle relaxant dantrolene sodium (6 mumol/L), diltiazem not only prevented but reversed the abnormal contractures induced by halothane and caffeine. 3. The effect on caffeine contractures of diltiazem and dantrolene in combination was additive. 4. The ability of diltiazem and verapamil to inhibit the hypercontractility of MHS muscle suggests that Ca2+ influx across the transverse tubular membrane may be important in the aetiology of the malignant hyperpyrexia syndrome. 5. These results also suggest an abnormality in transverse tubule-sarcoplasmic reticulum communication.     

STUDIES ON NORMAL HUMAN SKELETAL MUSCLE IN RELATION TO THE PATHOPHARMACOLOGY OF MALIGNANT HYPERPYREXIA

1. The effects of dantrolene on pharmacologically-induced contractures and potentiated isometric twitches in normal human skeletal muscle have been studied in vitro. 2. Dantrolene sodium, at concentrations of 3 μmol/l or less, attenuates basal twitch, inhibits halothane potentiation of basal twitch and inhibits halothane-potentiated potassium contractures, but has less effect on twitch potentiation by 2 mmol/l caffeine. 3. Caffeine contractures are attenuated by dantrolene concentrations of 12 μmol/l or greater. The effect of dantrolene on caffeine contracture is characterized by decreased contracture tension and by prolonged time to peak contracture. 4. The results indicate that halothane and 2 mmol/l caffeine have agonistic effects on the excitation-contraction (E-C) coupling mechanism, and suggest that they may act at separate E-C coupling sites. The relationships of these findings to the pathopharmacology of malignant hyperpyrexia are discussed.     

小檗碱对大鼠肛尾肌多种受体的阻断作用

大鼠肛尾肌对苯福林,乙酰胆碱及5-羟色胺均可引起收缩,而异丙肾上腺素及组织胺则仅在高浓时才引起收缩,苯福林及乙酰胆碱所致的收缩反应可分别被小檗碱及阿托品所阻断,但后者的阻M受体及阻α受体所需剂量相差极大。小檗碱可使苯福林的量效曲线平行右移,最大反应不变,其pA₂值为6.4。阿托品可竞争性地阻断乙酰胆碱的作用,其pA₂值为8.7,小檗碱对乙酰胆碱量效曲线的影响与阿托品不同,属非竞争性拮抗,即使量效曲线右移,最大反应压低,其压低程度与小檗碱浓度成正比,其pD′²值为4.6。     

SELECTIVE DEVELOPMENT OF TOLERANCE TO β-ADRENOCEPTOR AGONISTS IN SKELETAL MUSCLE AS COMPARED WITH AIRWAY SMOOTH MUSCLE FROM THE GUINEA-PIG

1. Guinea-pig were fed with a diet containing terbutaline or placebo for 4--5 days. The trachea, soleus muscle and the extensor digitorum longus (EDL) from these animals were prepared for recording of isometric contractions in vitro. 2. After treatment with terbutaline in vivo, the response of the pilocarpine-contracted trachea to terbutaline and isoprenaline was slightly suppressed with no change in maximum relaxation. 3. After treatment with terbutaline in vivo the maximum depression of the incomplete tetanic contractions of the soleus muscle brought about by terbutaline or isoprenaline was diminished by about 70%. The response of the EDL was also attenuated after previous treatment with terbutaline in vivo. 4. These data indicate a selective development of tolerance to the effects of beta-adrenoceptor agonists in skeletal muscle as compared with tracheal smooth muscle. 5. The present results provide an experimental analogue to the clinical observation that patients being treated with beta-adrenoceptor agonists become tolerant to the tremorogenic rather than to the bronchodilating effect.     

ACTIONS OF THE SYMPATHOMIMETIC BRONCHODILATOR, TRIMETOQUINOL (AQL 208) ON THE CARDIAC, RESPIRATORY AND SKELETAL MUSCLE SYSTEMS IN THE ANAESTHETIZED CAT, AND ON CAT ISOLATED ATRIAL AND TRACHEAL PREPARATIONS

SUMMARY 1. The actions of the sympathomimetic bronchodilator trimetoquinol (AQL 208) have been compared with those of laevoisoprenaline on the cardiac, respiratory and skeletal muscle systems of the cat under chloralose anaesthesia, and on cat isolated atrial and tracheal preparations.
2. Trimetoquinol injected intravenously ranged in potency from two to four times less potent to about four times more potent than laevoisoprenaline in different in vivo experiments. Despite such wide variations in absolute potency the mean effective doses of trimetoquinol in both in vitro and in vivo studies were not significantly different ( P >0.05) from those of laevoisoprenaline.
3. The effect on the soleus muscle is considered to be analogous to the muscle tremor that often occurs in man, and the results suggest that systemic administration of trimetoquinol may produce muscle tremor as an unwanted side effect in some patients.
4. Trimetoquinol, in the cat, shows no evidence of the selectivity for β-adreno-receptors in different tissues reported for it in other species. It is suggested that β-receptors in the cat are less clearly differentiated and that they resemble those in man more closely than do those in other species.     

EFFECTS OF 5HT2 RECEPTOR ANTAGONISTS ON RESPONSES TO POTASSIUM DEPOLARIZATION IN RAT ISOLATED AORTA

1. In order to determine whether 5HT₂ receptor antagonists can modify Ca²⁺ uptake via voltage-operated Ca²⁺ channel (VOC) in arterial smooth muscle, a comparative study of the effects of selected Ca²⁺ uptake blockers and 5HT₂ receptor antagonists on K⁺-induced contractions of rat aortic strip was undertaken. 2. The antagonist drugs studied included the Ca²⁺ uptake blockers verapamil, nifedipine, felodipine, diltiazem and cin-narizine, the 5HT₂ receptor antagonists cyproheptadine, ritanserin, mianserin, and ketanserin and the α₁-adrenoceptor antagonist prazosin. 3. With the notable exception of prazosin, each of these compounds diminished K⁺-induced aortic responses. 4. The following order of potencies (mean IC₅₀ values in mol/L) was established: felodipine (7.0 × 10^-11) >nifedipine (4.8 × 10^-9) >verapamil (5.5 × 10^-8) >cyproheptadine (6.2 × 10^-8) > diltiazem (4.1 × 10^-7) >cinnarizine (1.3 × 10^-6) >ritanserin (1.8 × 10^-6) >ketanserin (9.0 × 10^-6) > mianserin (2.0 × 10^-5). 5. The results suggest that antagonists of 5HT₂ receptors can modulate Ca²⁺ uptake via VOC in rat aorta.     

THE EFFECTS OF THE ATYPICAL ANTIPSYCHOTICS CLOZAPINE, REMOXIPRIDE AND RISPERIDONE ON THE CONTRACTILE CHARACTERISTICS OF RAT SKELETAL MUSCLEIN VITRO

The therapeutic use of the atypical antipsychotics clozapine, remoxipride and risperidone has been reported to be associated with a reduced occurrence of the extrapyramidal side-effects seen during therapy with classical (or typical) antipsychotics such as trifluoperazine and haloperidol. The aim of this study was to determine the effects of the atypical antipsychotics clozapine, remoxipride and risperidone on rat skeletal musclein vitro. Remoxipride and risperidone did not produce contracture in muscle. Clozapine induced a small muscle contracture at high concentrations. Pre-treatment of muscle with trifluoperazine or haloperidolin vitrocaused the muscle to display contracture responses to halothane, and haloperidol also potentiated a contracture response to caffeine. Pre-treatment of muscle with remoxipride and risperidone did not induce contracture in response to halothane and did not potentiate caffeine contracture. Clozapine pre-treatment caused muscle fibre bundles to display a small halothane-induced contracture and caused significant potentiation of caffeine-induced contracture.     

THE EFFECT OF THE CALCIUM ION ANTAGONIST 8-(N,N-DIETHYLAMINO)-OCTYL-3,4,5-TRIMETHOXYBENZOATEON MALIGNANT HYPERPYREXIA-SUSCEPTIBLE PORCINE SKELETAL MUSCLE

In malignant hyperpyrexia susceptible (MHS) porcine skeletal muscle, a low concentration (100 mumol/l) of the calcium ion antagonist 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate (TMB-8) inhibited KCl-induced contractures, but potentiated contractures induced by halothane, caffeine and succinylcholine. Higher concentrations of TMB-8 (333 mumol/l to 1 mmol/l) contracted MHS muscle, but had little effect on muscle tension in control preparations. Treatments which inhibit excitation-contraction coupling abolished TMB-8-induced hyper-reactivity in MHS muscle. TMB-8 (50 mumol/l and 1 mmol/l) did not alter 45Ca2+ levels in actively loaded microsomal preparations from MHS swine. These results suggest that in malignant hyperpyrexia the primary abnormality occurs proximal to the release of calcium from the sarcoplasmic reticulum, probably at the level of excitation-contraction coupling.     

前胡丙素对Ang II致离体血管平滑肌细胞肥厚及胞内钙、NO含量和信号转导的影响

目的前胡丙素(Pra-C)对血管紧张素II(Ang II)致离体培养大鼠血管平滑肌细胞(SMCs)肥厚模型胞内游离钙浓度、NO含量和信号转导的影响。方法以Ang II刺激SMCs形成肥厚模型,用倒置显微镜测定SMCs面积;用Fura-2/AM测定单细胞内［Ca²⁺］i,Griess法测定NO含量;在PMA和ST(PKC激动剂及抑制剂)、PTX(Gi蛋白敏感毒素)作用下观察Pra-C对KCl和NE所致胞内［Ca²⁺］i浓度变化的影响。结果Pra-C组SMCs细胞面积较肥厚组减小39.01%,并接近正常细胞水平;NO含量明显增加;胞内［Ca²⁺］i对KCl和NE激动的反应明显低于肥厚组。PMA使肥厚SMCs［Ca²⁺］i升高,而ST及PTX则使之降低,Pra-C均使之恢复正常。结论Pra-C抑制Ang II致体外培养细胞SMCs肥厚,改善肥厚细胞因PKC和Gi蛋白的信号转导改变所致的［Ca²⁺］i改变。