Clinical and Experimental Pharmacology and Physiology
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FURTHER OBSERVATIONS ON THE PATHOLOGICAL RESPONSES OF RAT SKELETAL MUSCLE TO TOXINS ISOLATED FROM THE VENOM OF THE AUSTRALIAN TIGER SNAKE, NOTECHIS SCUTATUS SCUTATUS SUMMARY 1. Some aspects of the response of mammalian skeletal muscle following the injection of purified toxins from the venom of the Australian tiger snake, Notechis scutatus scutatus , are described. 2. The toxins used were notexin, notechis II‐5, notechis II‐1 and a modified form of notexin (PBP‐notexin). They were injected into the dorso‐lateral aspect of one hind limb so that the soleus muscle would be exposed to the toxins. 3. Within 1 h after the injection of notexin, the soleus muscles were oedematous and by 3–6 h, polymorphonuclear leucocytes had entered the interstitial spaces. The invasion of necrotic muscle fibres was extensive by this time. Muscle spindles appeared relatively unaffected by the toxin. 4. The muscle regenerated via myoblasts at 2–3 days to myotubes at 3–5 days, immature muscle fibres at 7–14 days and fully differentiated muscle fibres by 21–28 days. Even after 6 months, however, the nuclei of many muscle fibres remained in a central position. 5. A second component of Australian tiger snake venom was also found to be myotoxic. It was slightly less potent than notexin, but caused qualitatively similar damage to that caused by notexin. It was identified as notechis II‐5. A third fraction, notechis II‐l, was found to be inactive. 6. Notexin could be neutralized by incubation with tiger snake antivenene; the simultaneous injection of antivenene with notexin did not afford complete protection against muscle damage.
Clinical and Experimental Pharmacology and Physiology - Tập 5 Số 6 - Trang 587-600 - 1978
Pathological responses of rat skeletal muscle to a single subcutaneous injection of a toxin isolated from the venom of the Australian tiger snake, <i>Notechis scutatus scutatus</i> SUMMARY 1. The pathology of mammalian skeletal muscle following a single subcutaneous injection of a purified toxin from the venom of the Australian tiger snake, Notechis scutatus scutatus , has been investigated. 2. The toxin was injected into the antero‐lateral aspect of one hind limb of rats and the effects of the injection on the histology, histo‐chemistry and physiology of the extensor digitorum longus muscles were studied. 3. The muscles underwent degenerative necrosis, with oedema and the infiltration of lymphocytes, polymorphs and macrophages within 12–24 h after the injection. 4. Three days after injection, the oedema had subsided and the necrotic fibres had been completely destroyed by phagocytes. Small uninucleate cells, with basophilic cytoplasm and vesicular nuclei were present at this stage; on the basis of these criteria they were identified as regenerating myoblasts. 5. By 5 days the myoblasts had fused to form myotubes, but differentiation of the myotubes into histochemically distinct muscle fibre types did not commence until around 7 days after the injection. 6. Regeneration and differentiation was virtually complete by 21 days after injection. 7. Between 3 and 5 days, many of the fibres were sensitive to acetylcholine, and muscle fibre action potentials were resistant to tetrodotoxin. Miniature end‐plate potentials were of low amplitude and frequency; they may have been absent from many fibres. 8. By 7–10 days, the proportion of fibres with tetrodotoxin‐resistant action potentials was declining, and acetylcholine sensitivity was less marked; miniature end‐plate potentials, though of normal amplitude, were of reduced frequency. The fibres were virtually normal by 14–21 days. 9. It is considered likely that these physiological properties were recorded from regenerating muscle fibres that reached maturity by 28 days; the possibility that they were recorded from functionally denervated fibres is discussed. 10. The rapid rate of regeneration and differentiation of the toxin‐damaged muscle was sustained only if the peripheral nerve supply was left intact. 11. Preliminary results suggested that mitochondria‐rich fibres were preferentially damaged by the toxin, and that the toxin is less active in vitro than in vivo. These problems are currently being investigated. 12. It is concluded that the toxin has a direct myotoxic effect on muscles; the relationship of this effect to the previously described neurotoxic effect is also currently under investigation.
Clinical and Experimental Pharmacology and Physiology - Tập 2 Số 5 - Trang 383-404 - 1975
Significance of Group <scp>III</scp> and <scp>IV</scp> muscle afferents for the endurance exercising human Summary
With the onset of dynamic whole‐body exercise, contraction‐induced mechanical and biochemical stimuli within locomotor muscle cause an increase in the discharge frequency of thinly myelinated (Group III ) and unmyelinated (Group IV ) nerve fibres located within the muscle. These thin fibre muscle afferents project to various sites within the central nervous system and thereby substantially influence the exercising human. First, Group III /IV muscle afferents are the afferent arm of cardiovascular and ventilatory reflex responses that are mediated in the nucleus tractus solitarius and the ventrolateral medulla. Therefore, neural feedback from working skeletal muscle is a vital component in providing a high capacity for endurance exercise because muscle perfusion and O2 delivery determine the fatigability of skeletal muscle. Second, Group III /IV muscle afferents facilitate ‘central fatigue’ (failure, or unwillingness, of the central nervous system to ‘drive’ motoneurons) by exerting inhibitory influences on central motor drive during exercise. Thus, Group III /IV muscle afferents play a substantial role in a human's susceptibility to fatigue and capacity for endurance exercise.
Clinical and Experimental Pharmacology and Physiology - Tập 39 Số 9 - Trang 831-835 - 2012
Autophagy inhibits the mesenchymal stem cell aging induced by D‐galactose through ROS/JNK/p38 signalling Abstract Autophagy and cellular senescence are two critical responses of mammalian cells to stress and may have a direct relationship given that they respond to the same set of stimuli, including oxidative stress, DNA damage, and telomere shortening. Mesenchymal stem cells (MSCs) have emerged as reliable cell sources for stem cell transplantation and are currently being tested in numerous clinical trials. However, the effects of autophagy on MSC senescence and corresponding mechanisms have not been fully evaluated. Several studies demonstrated that autophagy level increases in aging MSCs and the downregulation of autophagy can delay MSC senescence, which is inconsistent with most studies that showed autophagy could play a protective role in stem cell senescence. To further study the relationship between autophagy and MSC senescence and explore the effects and mechanisms of premodulated autophagy on MSC senescence, we induced the up‐ or down‐regulation of autophagy by using rapamycin (Rapa) or 3‐methyladenine, respectively, before MSC senescence induced by D‐galactose (D‐gal). Results showed that pretreatment with Rapa for 24 hours remarkably alleviated MSC aging induced by D‐gal and inhibited ROS generation. p‐Jun N‐terminal kinases (JNK) and p‐38 expression were also clearly decreased in the Rapa group. Moreover, the protective effect of Rapa on MSC senescence can be abolished by enhancing the level of ROS, and p38 inhibitor can reverse the promoting effect of H2 O2 on MSC senescence. In summary, the present study indicates that autophagy plays a protective role in MSC senescence induced by D‐gal, and ROS/JNK/p38 signalling plays an important mediating role in autophagy‐delaying MSC senescence.
Clinical and Experimental Pharmacology and Physiology - Tập 47 Số 3 - Trang 466-477 - 2020
MicroRNA‐320 EXPRESSION IN MYOCARDIAL MICROVASCULAR ENDOTHELIAL CELLS AND ITS RELATIONSHIP WITH INSULIN‐LIKE GROWTH FACTOR‐1 IN TYPE 2 DIABETIC RATS SUMMARY
The aim of the present study was to determine the role of myocardial microvascular endothelial cells (MMVEC) in impaired angiogenesis of type 2 diabetic Goto‐Kakizaki (GK) rats. A microRNA (miRNA) microarray was used to assess miRNA expression in MMVEC from GK and Wistar rats. Upregulation of miRNA‐320 was observed in MMVEC from GK rats using real‐time reverse transcription–polymerase chain reaction (RT‐PCR). So far, nine miRNAs have been reported to target angiogenic factors and/or receptors, including kinase insert domain containing receptor (Flk‐1), insulin‐like growth factor 1 (IGF‐1) and insulin‐like growth factor 1 receptor (IGF‐1R). The predicted genes targeted by miR‐320 include Flk‐1, IGF‐1 and IGF‐1R. Western blot analysis and RT‐PCR were used to analyse the protein and mRNA expression, respectively, of the putative genes IGF‐1 and IGF‐1R. The expression of IGF‐1 and IGF‐1R proteins decreased significantly in diabetic MMVEC. However, the expression of IGF‐1 mRNA increased rather than decreased. The mRNA expression of IGF‐1R did not differ significantly between diabetic and control MMVEC. Transfection of an miR‐320 inhibitor into MMVEC from GK rats confirmed that miR‐320 impaired angiogenesis. The proliferation and migration of diabetic MMVEC improved after transfection of the miR‐320 inhibitor. In addition, the miR‐320 inhibitor significantly increased the expression of IGF‐1 protein, but had no effect on the expression of IGF‐1R. Eleven miRNAs were upregulated in MMVEC from GK rats compared with those in Wistar rats: let‐7e , miR‐129 , miR‐291‐5p , miR‐320 , miR‐327 , mir‐333 , miR‐363–5p , miR‐370 , miR‐494 , miR‐503 and miR‐664 . The results indicate that upregulation of miR‐320 in MMVEC from GK rats may be responsible for the inconsistency between the expression of IGF‐1 protein and mRNA and therefore related to impaired angiogenesis in diabetes. Transfection of an miR‐320 inhibitor may be a therapeutic approach for the treatment of impaired angiogenesis in diabetes.
Clinical and Experimental Pharmacology and Physiology - Tập 36 Số 2 - Trang 181-188 - 2009
ANTISENSE OLIGONUCLEOTIDES: FROM DESIGN TO THERAPEUTIC APPLICATION
Clinical and Experimental Pharmacology and Physiology - Tập 33 Số 5-6 - Trang 533-540 - 2006
CARDIOVASCULAR EFFECTS OF RILMENIDINE, A NEW α<sub>2</sub>‐ADRENOCEPTOR AGONIST, AND CLONIDINE IN CONSCIOUS SPONTANEOUSLY HYPERTENSIVE RATS SUMMARY 1. The acute and chronic effects of rilmenidine, a partial agonist of α1 ‐ and α2 ‐adrenoceptors with antihypertensive properties, were compared to those of clonidine on blood pressure (BP), heart rate (HR) and the urinary excretion of catecholamines, which was used as an index of sympathetic activity. 2. As these drugs are known to interfere centrally and peripherally with the sympathetic nervous system, long‐term arterial blood pressure recordings in freely moving unstressed adult spontaneously hypertensive rats (SHR) were used. 3. Acute i.v. administrations of rilmenidine (0.3 mg/kg at 1200 h, 1.2 mg/kg at 1700 and 2200 h) and clonidine (12 μg/kg at 1200 h, 50 μg/kg at 1700 and 2200 h) induced short‐lasting increases in BP associated with a decrease in HR, which were followed by prolonged, dose‐dependent decreases in BP without bradycardia. The pressor effect was less marked and the associated bradycardia was more marked in active SHR with physiologically high sympathetic activity than in resting SHR. 4. A 12‐day oral treatment with rilmenidine (6.0 mg/kg daily) or clonidine (150 μg/kg daily) induced moderate decreases in BP without change in HR. Rilmenidine but not clonidine decreased normetanephrine (NMN) excretion in active but not in resting SHR. 5. Finally, during the 24 h following the cessation of the treatments, BP returned to normal, without significantly exceeding that of untreated controls. However, upswings in BP or HR were observed, more markedly and frequently after clonidine than after rilmenidine. 6. In conclusion the effects of α2 ‐adrenoceptor agonists appear to be influenced by the pre‐existing sympathetic tone. The general agreement between these data and those observed in patients demonstrates that the use of conscious unstressed animals is of value to determine the cardiovascular effects of drugs which act on the sympathetic nervous system.
Clinical and Experimental Pharmacology and Physiology - Tập 16 Số 11 - Trang 837-848 - 1989
Dual nitric oxide mechanisms of cholestasis‐induced bradycardia in the rat Summary 1. Cholestatic liver disease is associated with nitric oxide (NO) overproduction and bradycardia. Nitric oxide has a dual effect on sinoatrial node and its effects depend on its concentration. Nitric oxide can increase heart rate by activating hyperpolarization‐activated pacemaker current (If ) but, at high concentrations, it can potentially decrease heart rate by inhibition of L‐type calcium current. In the present study, the responsiveness of isolated atria to CsCl (an inhibitor of the If current) and acetylcholine (ACh; which decreases L‐type calcium current through a NO‐dependent pathway) were evaluated in bile duct‐ligated and sham‐operated control rats. 2. Bile duct ligation induced a significant decrease in the negative chronotropic effect of CsCl (0.2–5 mmol/L), but increased the responsiveness of isolated atria to ACh (10−8 to 10−3 mol/L). These effects were restored after incubation of the atria in the presence of the NO synthase inhibitor N G l ‐arginine methyl ester (0.1 mmol/L). 3. Anaesthetized bile duct‐ligated rats showed bradycardia and the plasma levels of NO2 – /NO3 – were significantly higher in bile duct‐ligated rats compared with sham‐operated animals. 4. Different and opposite responses of atria of cholestatic rats to CsCl and ACh can be explained by NO overproduction in bile duct‐ligated animals. A dual role of NO in the regulation of the sinoatrial node may be responsible for this opposite effect and may have a role in the pathophysiology of cholestasis‐induced bradycardia.
Clinical and Experimental Pharmacology and Physiology - Tập 29 Số 10 - Trang 905-908 - 2002
P2X7 receptor in cardiovascular disease: The heart side Summary The P2X7 receptor is a ligand‐gated purinergic receptor activated by extracellular ATP. The receptor is highly expressed in immune cells and in the brain, and, upon activation, the P2X7 receptor allows a cation flux, leading to the distinct activation of intracellular signalling pathways as the secretion of pro‐inflammatory cytokines, and modulation of cell survival. Through these molecular mechanisms, P2X7 is known to play important roles in physiology and pathophysiology of a wide spectrum of diseases, including cancer, inflammatory diseases, neurological, respiratory and more recently cardiovascular diseases. Recent studies demonstrated that the P2X7 could modulate the assembly of the NLRP3 inflammasome, leading to the secretion of pro‐inflammatory factors and worsen the cardiac disease phenotypes. This review discusses the critical molecular function of P2X7 in the modulation of the onset, progression and resolution of cardiovascular diseases and analyses the putative future use of P2X7‐based therapies that modulate the IL‐1β secretion arm and direct P2X7 antagonists.
Clinical and Experimental Pharmacology and Physiology - Tập 46 Số 6 - Trang 513-526 - 2019
TOTAL BODY SODIUM IN IMMATURE SPONTANEOUSLY HYPERTENSIVE AND WISTAR KYOTO RATS SUMMARY 1. Total body sodium of male and female spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats was estimated weekly during the first 8 weeks of life by measuring exchangeable sodium (ENa). Blood pressure and sodium intake was measured from weeks 4 to 8. 2. SHR had significantly higher blood pressure and sodium intake than WKY from 4 to 8 weeks of age. 3. ENa was higher in SHR than WKY throughout the first 8 weeks of life. 4. Relative sodium retention was observed in SHR during weeks 5 to 8 despite a significant rise in SHR blood pressure and fall in sodium intake. 5. These findings suggest a change in the renal pressure/natriuresis relationship at this age in the SHR.
Clinical and Experimental Pharmacology and Physiology - Tập 12 Số 3 - Trang 315-318 - 1985
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