Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Administration of imipramine plus serotonin (5-HT) to rats has been proposed as an animal model of Duchenne muscular dystrophy. We studied the skeletal muscle necrosis produced in male rats given 5-HT after pretreatment with imipramine, other tricyclic antidepressants, or antihistamines, which like the tricyclic antidepressants, can block neuronal reuptake of 5-HT. Following one of these agents plus 5-HT, 20 mg/kg subcutaneously (s.c.), necrosis was more severe in the soleus muscle than the quadriceps. There was no significant difference in the incidence of necrosis in the soleus and quadriceps muscles following one of these agents plus 5-HT, 100 mg/kg, intraperitoneally (i.p.). After one of these agents plus 5-HT i.p., but not 5-HT s.c., extensive necrosis was significantly more frequent and severe in the quadriceps muscle than after 5-HT s.c. Chlorpheniramine (CP) plus 5-HT, 2.5 mg/kg intravenously, produced less muscle necrosis than CP plus 5-HT s.c. or i.p. The necrosis produced by CP plus 5-HT s.c. was comparable ipsilateral and contralateral to the injection site. The necrosis following CP plus 5-HT i.p. was maximal at 24 hr and remained fairly constant until 5 days. Regeneration was prominent by 7 days. The muscle necrosis produced by CP plus 5-HT is blocked by some 5-HT blockers, e.g., methiotepin and methysergide. It is also partially blocked by denervation. The capacity of tricyclic antidepressants and antihistamines to block neuronal 5-HT reuptake tended to be negatively correlated with the capacity to potentiate the muscle necrosis they produced with 5-HT, which suggests that blockade of 5-HT uptake is not the mechanism of the pathology produced by the combined treatment. The tricyclic antidepressants and the antihistamines are "membrane stabilizers-labilizers". Other drugs which are "membrane stabilizers-labilizers" such as trihexyphenidyl and procaine also promoted skeletal muscle necrosis when given prior to 5-HT. It is proposed that the effects of imipramine plus 5-HT on skeletal muscle are not due to the blockade of neuronal uptake of 5-HT and subsequent vascular-induced ischemia, but reflect direct toxic effects of these agents on skeletal muscle.
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PMID:Skeletal muscle necrosis following membrane-active drugs plus serotonin. 0 32

Dopamine (DA), serotonin (5-HT), tryptophan (TRP), 5-hydroxyindole acetic acid (5-HIAA), and GABA were assayed spectrofluorometrically in various regions of 16 human post-mortem brains with acute and old cerebral infarction. In both recent and older strokes a total depletion of DA and 5-HT in the necrotic tissue was associated with mild reduction of these compounds in remote non-ischemic areas of the injured, and less of the contralateral cerebral hemispheres. 5-HIAA was significantly reduced in acute ischemic necrosis, while the perifocal edema zone showed considerable accumulation of both 5-HT and 5-HIAA. Marked elevation of the 5-HT precursor TRP and of GABA was present in both the necrotic center and perifocal edema of acute infarcts, which also showed a mild reduction of total proteins. The degradation zone surrounding old infarcts showed a mild decrease of both 5-HT and 5-HIAA with normal TRP levels, indicating normalization of the previously increased 5-HT metabolism and turnover after decrease of acute cerebral edema. These data which confirm previous studies in experimental cerebral ischemia and stroke indicate that disorders in the metabolism of brain monoamines and other putative neurotransmitters contribute to the development of postischemic brain damage and the complicating cerebral edema. They are also in keeping with the concept that unilateral focal ischemia produces bilateral effects on brain monoamines.
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PMID:Changes of some putative neurotransmitters in human cerebral infarction. 3 76

Since increased concentration of serotonin (5-HT) has been demonstrated in areas of the brain exposed to ischemia and lesions, and since the elevation might be responsible for the enhanced permeability to proteins across cerebral vessels, studies were carried out to elucidate the effect of the amine, perfused through the cerebral ventricular system, on the transport of horseradish peroxidase (HRP) from blood to brain. The amounts of 5-HT were large (50--800 microgram per mouse). The permeability across cerebral vessels was increased, especially across arterioles. The endothelium was intact. HRP did not form a continuous line between endothelial cells, from the vessel lumen to the subendothelial basement membrane. Furthermore, channels through the endothelium, that could allow HRP to pass, were not observed. However, several vesicles, filled with HRP were observed in the cytoplasm of endothelial cells. They could be open to the vessel lumen or to the subendothelial basement membrane. Freely situated HRP-containing vesicles were also found. Based on the observations it is most reasonable to assume that the 5-HT, perfused through the cerebral ventricles increased the normally occurring vesicular transport of protein from blood to brain.
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PMID:The effect of serotonin on the blood-brain barrier to proteins. 29 Jul 45

Most evidence in the literature concerning the role of serotonin in ischemia originates from brain research. This is partly because the central nervous system is particularly prone to accumulation of 5-HT, due to the neuronal sources of the amine in addition to circulating 5-HT from platelets. In ischemia, platelet invasion, rupture of the blood-brain barrier, liberation of 5-HT from nerve terminals inside the vessel wall, and necrosis of serotonergic neurons favor local increases of the transmitter in the brain. The pathophysiological consequences include amplifications of processes such as vasoconstriction of major and collateral arteries, edema formation, platelet aggregation, and blood sludging. 5-HT2 receptors appear to be the major effector of these actions of serotonin, judging from experimental and clinical pharmacology data with specific or partial 5-HT2 serotonergic antagonists. This review summarizes current knowledge on the key role serotonin plays in the induction or consequences of brain ischemia.
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PMID:Serotonin 5-HT2 receptors and brain circulation. 136 12

Alterations in brain tissue levels of monoamines and monoamine metabolites were studied in gerbils 60 min after cerebral ischemia induced by 10 min carotid ligation after pretreatment with the antiischemic drug DM-9384 (1, 3, 10, 30 mg/kg, PO). The DA levels decreased in striatum after the ischemia, while cortical and hippocampal DA levels increased. The DOPAC levels increased in cortex, but were essentially unaffected in other regions. The HVA levels increased in all forebrain regions studied. NA levels decreased in hippocampus and superior colliculus, while a general increase in MHPG levels was seen. Decreases in 5-HT levels were seen in all forebrain regions except cortex. The 10 mg/kg and 30 mg/kg doses of DM-9384 counteracted the decrease in striatal 5-HT and hypothalamic MHPG/NA ratio, respectively. Thus pretreatment with DM-9384 exerted minor protective effects on the alterations induced in monoamine systems by transient forebrain ischemia.
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PMID:Effects of DM-9384, a pyrrolidone derivative, on ischemia-induced changes in the central monoamine systems. 137 10

The effect of 5-HT3 receptor agonists and antagonists on the hypoxia/hypoglycemia (ischemia)-induced decrease in CA1 field potential elicited by stimulation of Schaffer collaterals was investigated using rat hippocampal slices. Treatment with the 5-HT3 receptor agonist, 2-methyl-5-HT (1-10 microM), exacerbated the ischemia-induced decreased in CA1 field potential, whereas treatment with the 5-HT3 receptor antagonist, Y-25130 (0.1-100 microM), or the 5-HT2 receptor antagonist, ketanserin (10, 100 microM), produced dose-dependent neuroprotection against the ischemia-induced decrease. However, in normal non-ischemic solution these treatments did not significantly change the CA1 field potential. The protective action of Y-25130 was blocked by co-treatment with 2-methyl-5-HT. The magnitude of protection in the Y-25130-treated group (EC50, 1.8 microM) was about 20 times greater than that in the ketanserin-treated group (EC50, 33 microM). The present study demonstrated that stimulation of 5-HT3 receptors plays a detrimental role in the development of ischemic damage, whereas blockade of the 5-HT3 receptor plays a neuroprotective role in ischemic damage, suggesting a facilitatory role of 5-HT neurons in ischemia-induced neuronal deficits.
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PMID:Neuroprotective effect of 5-HT3 receptor antagonist on ischemia-induced decrease in CA1 field potential in rat hippocampal slices. 145 43

Excessive neuronal activity combined with an increased release of neurotransmitters is supposed to contribute to the delayed neuronal degeneration in animal models of transient cerebral ischemia. Since evidence is accumulating that serotonin (5-HT) exerts an excitatory effect on neurons via 5-HT2 receptors we tested the hypothesis that 5-HT2 receptor antagonists could protect neurons in the gerbil after transient bilateral carotid occlusion. In a first series of experiments, the 5-HT2 receptor antagonist ketanserin was injected intraperitoneally 15 min prior to 5 min of forebrain ischemia and given twice daily on the following 3 days. At a dose of 10 mg/kg i.p., the number of intact hippocampal CA1 neurons was significantly higher than in the saline-treated group and reached 74% of the sham-operated controls. In addition, the degree of neuronal damage correlated with an increased intracellular Ca2+ content in CA1 pyramidal neurons as revealed by arsenazo(III) staining with a procedure modified for paraffin sections. In a second series of experiments, ketanserin (10 mg/kg) was injected at various times after onset of ischemia. Up to a period of 90 min after ischemia, the number of intact CA1 pyramidal cells in ketanserin-treated animals was still significantly higher than in the saline-treated group. These results indicate that 5-HT2 receptor antagonists may protect neurons against ischemic damage even when the treatment is started after onset of ischemia. It remains to be investigated whether the neuroprotective effect of ketanserin is due to a neuronal action or to an inhibition of cerebrovascular vasospasm.
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PMID:Ketanserin reduces neuronal calcium accumulation and cell death in the hippocampus of the Mongolian gerbil after transient forebrain ischemia. 151 Dec 66

Recent studies revealed a role for dopamine and noradrenaline in the etiology of ischemia-induced neuronal cell death. In the present investigation, the modulation by clozapine, an atypical antipsychotic agent that interacts with adrenergic receptors, of N-methyl-D-aspartate (NMDA) receptor complex-mediated events were studied by examining its effects on levels of cGMP in the cerebellum. Clozapine decreased basal levels of cGMP in the cerebellum and antagonized harmaline-, methamphetamine-, pentylenetetrazol- and D-serine-induced increases in levels of cGMP with ED50 values of 3.9, 2.36, 2.13 and 2.1 mg/kg (i.p.). However, clozapine (1.25-25 mg/kg) did not attenuate the quisqualate-induced increases in levels of cGMP, indicating a specific modulation of events modulated by the NMDA receptor complex. Antagonists of dopamine (D2), serotonin (5-HT)-5-HT1, 5-HT2 and 5-HT3 [haloperidol, propranolol, ritanserin, ICS 205-930 [(3-tropanyl-indole-3-carboxylate methiodide)] respectively], did not reverse the response to harmaline. However, WB-4101 [(2,6-dimethoxy-phenoxyethyl)aminomethyl-1,4-benzodioxane HCl], and alpha 1-adrenergic antagonist, reversed harmaline-, D-serine-, PTZ- and MA-induced increases in levels of cGMP, indicating an adrenergic modulation of the events mediated by the NMDA receptor complex. Intracerebellar and intracerebroventricular administration of clozapine and intracerebellar administration of WB-4101 reversed the D-serine-induced response, indicating a central locus of action. These results indicated that clozapine modulates levels of cGMP predominantly through its interactions with central adrenergic receptors.
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PMID:Clozapine attenuates N-methyl-D-aspartate receptor complex-mediated responses in vivo: tentative evidence for a functional modulation by a noradrenergic mechanism. 168 42

Denervation of the gut, resulting in altered bowel function, has been viewed as an impediment to the clinical success of small intestinal transplantation. This study examined the effect of complete extrinsic denervation of the jejunum and ileum on tissue levels of VIP, SP, and 5-HT in a rat model of small intestinal transplantation. Orthotopic total small bowel isograft transplants were performed in 18 Lewis inbred rats. Sham operations consisted of occluding the superior mesenteric artery of 18 Lewis rats for 10 minutes to provide comparable degrees of ischemia. Six rats from each group were sacrificed 1, 2, and 4 weeks following transplantation or sham operation. The jejunum and ileum were removed and extracted in acid for measurement of VIP, SP, and 5-HT by radioimmunoassay. There were no statistically significant differences in the jejunal or ileal content of VIP or 5-HT or the jejunal content of SP between the transplant and sham groups. An initial decrease in ileal SP content at 1 week following transplantation was no longer evident by the fourth week. We conclude that the extrinsic denervation of small intestinal transplantation has minimal effects on the intestinal content of VIP, SP, and 5-HT and should not significantly affect physiologic function controlled by these gastrointestinal hormones.
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PMID:Effect of transplantation on tissue levels of substance P, vasoactive intestinal polypeptide, and serotonin in rat small intestine. 169 79

Gastric mucosal blood flow and its regulating factors were studied in normal and stressed rats. In addition, vascular regulating factors and the role of CoQ10 anion radical and SOD (superoxide dismutase) level in gastric mucosa were also investigated as well as the influence of 5-HT (5-hydroxytryptamine) on gastric mucosal blood flow. Gastric mucosal blood flow was measured by the hydrogen gas clearance method. The vascular pattern of the stomach was investigated by the infusion method with two-colored silicon rubber. CoQ10 anion radical and SOD levels in gastric tissue were assayed by electron spin resonance (ESR) and radioimmunoassay. The gastric mucosal blood flow decreased significantly early after the induction of stress. Impairment of gastric mucosal blood flow was highly correlated with 5-HT and CoQ10 anion radical and SOD levels. Reduction in gastric mucosal blood flow was consequently due to opening of arteriovenular shunt and hyperpermeability of true capillaries influenced by 5-HT. These results demonstrate that ischemia and reperfusion after reduction of the gastric mucosal blood flow resulted in the sequence of events that led to formation of acute gastric mucosal lesions.
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PMID:Gastric microcirculation and its regulating factors in stress. 194 Feb 4


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