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

Using Zucker fatty rats, a strain characterized by diabetes and hyperlipidemia, we investigated the diabetes- and hyperlipidemia-related impairment of bone marrow mononuclear cells (BMCs) for inducing therapeutic angiogenesis. BMCs from Zucker fatty and normal Zucker lean rats were collected and cultured. Although the characterization and cell survival of BMCs did not differ, the VEGF production, endothelial differentiation, and endothelial cell colony-forming potential of BMCs from Zucker fatty rats were significantly lower than those of BMCs from lean rats. By using an ischemic hindlimb model, we found that the native recovery of induced limb ischemia in the Zucker fatty rats was also significantly worse than that in the lean rats. Furthermore, the expression of 5-hydroxytryptamine (5-HT(2A)) receptors was obviously higher in the Zucker fatty rats than that in the lean rats and was enhanced after limb ischemia. Although the therapeutic potency was lower than with the implantation of BMCs from normal lean rats, the implantation of BMCs from fatty rats could also induce angiogenesis and increase blood flow significantly in the ischemic hindlimbs of Zucker fatty rats. Furthermore, the blood flow in the ischemic hindlimbs was increased by the administration of sarpogrelate, a selective 5-HT(2A)-receptor antagonist. Our results clearly show diabetes- and hyperlipidemia-related dysfunction and impaired potency for inducing angiogenesis of BMCs. However, the implantation of autologous BMCs into ischemic limbs of diabetic and hyperlipidemic rats has induced therapeutic angiogenesis effectively, and blood flow would be enhanced by the administration of a 5-HT(2A)-receptor antagonist.
 ...
PMID:Impaired potency of bone marrow mononuclear cells for inducing therapeutic angiogenesis in obese diabetic rats. 1622 42

Upregulation of endothelin B (ET(B)) and 5-hydroxytryptamine 1B (5-HT(1B)) receptors via transcription has been found after experimental subarachnoid hemorrhage (SAH), and this is associated with enhanced phosphorylation of the mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (ERK1/2). In the present study, we hypothesized that inhibition of ERK1/2 alters the ET(B) and 5-HT(1B) receptor upregulation and at the same time prevents the sustained cerebral blood flow (CBF) reduction associated with SAH. The ERK1/2 inhibitor SB386023-b was injected intracisternally in conjunction with and after the induced SAH in rats. At 2 days after the SAH, cerebral arteries were harvested for quantitative real-time polymerase chain reaction, immunohistochemistry and analysis of contractile responses to endothelin-1 (ET-1; ET(A) and ET(B) receptor agonist) and 5-carboxamidotryptamine (5-CT; 5-HT1 receptor agonist) in a sensitive myograph. To investigate if ERK1/2 inhibition had an influence on the local and global CBF after SAH, an autoradiographic technique was used. At 48 h after induced SAH, global and regional CBF were reduced by 50%. This reduction was prevented by treatment with SB386023-b. The ERK1/2 inhibition also decreased the maximum contraction elicited by application of ET-1 and 5-CT in cerebral arteries compared with SAH. In parallel, ERK1/2 inhibition downregulated ET(B) and 5-HT(1B) receptor messenger ribonucleic acid and protein levels compared with the SAH. Cerebral ischemia after SAH involves vasoconstriction and subsequent reduction in the CBF. The results suggest that ERK1/2 inhibition might be a potential treatment for the prevention of cerebral vasospasm and ischemia associated with SAH.
 ...
PMID:ERK1/2 inhibition attenuates cerebral blood flow reduction and abolishes ET(B) and 5-HT(1B) receptor upregulation after subarachnoid hemorrhage in rat. 1625 86

The recovery (%) of the left ventricular developed pressure by (S)-(-)-pyrapyridolol (5 x 10(-8) M) (90.7%), an optical isomer of a new 5-HT1A receptor antagonist, was greater than that by (R)-(+)-pyrapyridolol (66.2%, control: 34.4%) against ischemia-reperfusion injury in perfused Langendorff guinea-pig hearts. In the perfused mitochondrial preparation, (S)-(-)-pyrapyridolol inhibited the mitochondrial Ca2+ (Cam) elevation that was brought about by the change of Ca2+ content or pH of perfusate, similar to findings with cyclosporin A, well known to be an inhibitor of the mitochondrial permeability transition pore (MPTP). The mitochondrial K(ATP) channel opener, diazoxide, also inhibited the Cam elevation, but the mitochondrial K(ATP) channel antagonist, 5-hydroxydecanoic acid, attenuated it. There were significantly fewer numbers of TUNEL-positive cells in these (S)-(-)-pyrapyridolol-treated hearts than the control or (R)-(+)-pyrapyridolol, with decreases of the caspase-3 activity. Therefore, these results suggest that (S)-(-)-pyrapyridolol likely inhibits the opening of the MPTP by preventing the Cam overload induced apoptosis related to endogenous 5-HT accumulation in ischemia-reperfusion hearts.
 ...
PMID:Different effects of optical isomers of the 5-HT1A receptor antagonist pyrapyridolol against postischemic guinea-pig myocardial dysfunction and apoptosis through the mitochondrial permeability transition pore. 1661 42

Equine laminitis is the painful and debilitating condition resulting from cellular damage and inflammation of the tissues comprising the bonds supporting the pedal bone within the hoof capsule. One of the reasons why this condition is so complicated and enigmatic is its association with gastrointestinal disturbances, particularly a diet of lush grass at certain times of the year. Determining the link between disturbances to the hindgut flora and pathophysiology in the foot is one of the keys to preventing this condition. Therefore, one of the biggest challenges in equine laminitis research is to determine those events that precede the onset of the classical clinical signs of lameness, bounding digital pulses, and warm feet. A main theory for the pathogenesis of acute laminitis involves the development of vasoconstriction within the foot, which leads to ischemic and/or inflammatory tissue damage. Serotonin is an important constrictor mediator controlling digital blood flow. Certain equine hindgut bacteria produce amino acid decarboxylase enzymes that convert free amino acids into monoamines. Therefore, amines formed and released from the gastrointestinal tract are hypothesized to act as the link between the ingestion of lush grass and the digital ischemia thought to precede laminitis. Equine cecal contents contain a range of amines that are present in micromolar concentrations. Tryptamine is the most potent cecum-derived amine, causing vasoconstriction in vitro and in vivo through direct activation of serotonin receptors and displacing serotonin from platelets. Monoamines found in the cecum of the horse could potentially induce hemodynamic disturbances in the digit that result in laminar ischaemia, and so trigger laminitis.
 ...
PMID:Gastrointestinal derived factors are potential triggers for the development of acute equine laminitis. 1677 11

Even though reperfusion is the treatment of choice in patients admitted with acute myocardial infarction, reperfusion itself has been demonstrated to activate various pathological factors especially following procedures of cardiac revascularization. 5-hydroxytryptamine (5HT) is one such factor activated during reperfusion and is known to trigger the post ischemic contractile dysfunction and pathological apoptosis. Here we demonstrate the potential effects of the 5-HT(2)A antagonist sarpogrelate in protecting the myocardium against reperfusion injury of heart. Male Wistar rats weighing between 220 and 240 g were subjected to 30 min left coronary artery (LCA) occlusion and 120 min reperfusion. Sarpogrelate (4 mg/kg) was infused intravenously for 30 min either before LCA occlusion or at reperfusion. Following reperfusion the samples were collected for infarction area, immunohistochemistry, western blotting and myocardial metabolite analysis. Sarpogrelate infusion before ischemia resulted in (a) significant recovery of post ischemic cardiac functions (LVDP, EDP), (b) significant reduction in the infarct size among the risk area after triphenyl tetrazolium chloride staining (p<0.001), (c) decreased tissue water content (p<0.05), (d) well preserved myocardial ATP (p<0.05), (e) reduction in Bcl-2 downregulation and caspase 3 activation and (g) less prevalence of apoptotic cells (3.1+/-0.4% to 15.2+/-0.6%, drug versus control). Treating the rats with sarpogrelate during reperfusion also showed similar results. This study thus demonstrates the protective effects of sarpogrelate and supports the role for 5-HT2A inhibition in preventing the reperfusion injury of the heart.
 ...
PMID:5-HT2 receptor blocker sarpogrelate prevents downregulation of antiapoptotic protein Bcl-2 and protects the heart against ischemia-reperfusion injury. 1687 2

We have investigated the gene expression in human middle cerebral artery (MCA) after ischemia. Ischemic stroke affects the perfusion in the affected area and experimental cerebral ischemia results in upregulation of vasopressor receptors in the MCA leading to the ischemic area. We obtained human MCA samples distributing to the ischemic area, 7-10 days post-stroke. The gene expression was examined with real-time polymerase chain reaction (PCR) and microarray, proteins were studied with immunohistochemistry. We investigated genes previously shown to be upregulated in animal models of cerebral ischemia (e.g. ET(A), ET(B), AT1, AT2, and 5-HT(2A/1B/1D)). Their mRNA expression was increased compared with controls, consistent with findings in experimental stroke. Immunohistochemistry showed upregulation of the receptors localized on the smooth muscle cells. The gene expression was profiled with microarray and seven genes chosen for further investigation with real-time PCR; ELK3, LY64, Metallothionin IG, POU3F4, Actin alpha2, RhoA and smoothelin. Six of these were regulated the same way when confirming array expression with real-time PCR. Gene expression studies in the human MCA leading to the ischemic region is similar to that seen after MCA occlusion in rats. We found new genes that support the dynamic changes that occur in the MCA distributing to the ischemic region.
 ...
PMID:Gene expression profiling in the human middle cerebral artery after cerebral ischemia. 1711 15

Selective dopamine (D) receptor agonists either slightly improve (D2 and D3) or do not affect (D1 and D4) the tolerance of the brain to global ischemia. As for D and 5-HT (hydroxytryptamine) antagonists, only D1 antagonist SCH 23390 and 5-HT2 antagonist ketanserin produce a small neuroprotective effect, while D2, D4, 5-HT(2B) and 5-HT(2C) antagonists are not active. Simultaneous injection of D2 (raclopride), D3 (GR 103691), and D4 (L 745870) receptor blockers also does not protect the brain. These results are not at variance with a widespread hypothesis that the accumulation of extracellular 5-HT and especially D in the brain causes the neuron damage. The effect of ketanserine is not increased by D2 or D4 blockers, but the introduction of D3 blocker GR 103691 (+88%) and especially the simultaneous injection of D2,3,4 antagonists improve the effect of ketanserine (+134%). The neuroprotective effect of the last combination is not lower but even exceeds that of some neuroleptics. This fact shows the possibility to increase the tolerance to cerebral ischemia by simultaneously blocking D and 5-HT-receptors.
 ...
PMID:[Influence of the selective ligands of dopamine and 5-hydroxytryptamine receptors on the tolerance to global cerebral ischemia]. 1720 58

Biogenic amines like serotonin (5-HT) and catecholamines usually act through stimulation of G-protein coupled receptors (GPCRs). We now have strong evidence that they can signal through receptor-independent mechanisms. One well described pathway is the degradation of biogenic amine by monoamine oxidases (MAOs) after transport into the cells by selective transporters. The oxidation of biogenic amines generates hydrogen peroxide, H(2)O(2), that can act as a signalling intermediate in the cell. This original mechanism of action of 5-HT is relevant in the heart since it is responsible for both cardiomyocyte hypertrophy and apoptosis. Moreover, in vivo experiments indicate a physiological significance for MAO in the damage during ischemia-reperfusion in the heart. Since functional 5-HT receptors are present in the heart and have also been demonstrated to contribute to cardiomyocyte growth and apoptosis, it is of major interest to evaluate respective contribution and cross-regulations between 5-HT receptors and MAO in cardiac function.
 ...
PMID:New insights on receptor-dependent and monoamine oxidase-dependent effects of serotonin in the heart. 1747 6

In severe hypoxia or ischemia, normal eupneic breathing fails and is replaced by gasping. Gasping serves as part of a process of autoresuscitation by which eupnea is reestablished. Medullary neurons, having a burster, pacemaker discharge, underlie gasping. Conductance through persistent sodium channels is essential for the burster discharge. This conductance is modulated by norepinephrine, acting on alpha 1-adrenergic receptors, and serotonin, acting on 5-HT2 receptors. We hypothesized that blockers of 5-HT2 receptors and alpha 1-adrenergic receptors would alter autoresuscitation. The in situ perfused preparation of the juvenile rat was used. Integrated phrenic discharge was switched from an incrementing pattern, akin to eupnea, to the decrementing pattern comparable to gasping in hypoxic hypercapnia. With a restoration of hyperoxic normocapnia, rhythmic, incrementing phrenic discharge returned within 10 s in most preparations. Following addition of blockers of alpha 1-adrenergic receptors (WB-4101, 0.0625-0.500 microM) and/or blockers of 5-HT2 (ketanserin, 1.25-10 microM) or multiple 5-HT receptors (methysergide, 3.0-10 microM) to the perfusate, incrementing phrenic discharge continued. Fictive gasping was still induced, although it ceased after significantly fewer decrementing bursts than in preparations than received no blockers. Moreover, the time for recovery of rhythmic activity was significantly prolonged. This prolongation was in excess of 100 s in all preparations that received both WB-4101 (above 0.125 microM) and methysergide (above 2.5 microM). We conclude that activation of adrenergic and 5-HT2 receptors is important to sustain gasping and to restore rhythmic respiratory activity after hypoxia-induced depression.
 ...
PMID:Maintenance of gasping and restoration of eupnea after hypoxia is impaired following blockers of alpha1-adrenergic receptors and serotonin 5-HT2 receptors. 1816 82

It is known that the activation of 5-hydroxytryptamine receptor type 1A (5HT(1A) receptor) may protect against brain damage induced by transient global ischemia. The biochemical mechanisms that underlie this neuroprotective effect remain however to be fully elucidated. Given that serotonergic drugs may regulate N-methyl-d-aspartate (NMDA) receptor function, which is implicated in events leading to ischemia-induced neuronal cell death, and also stimulate the expression of brain-derived neurotrophic factor (BDNF), which is down-regulated in cerebral ischemia, we sought to determine the effects of the selective 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), on the levels of NMDA receptor NR1 subunit and BDNF in gerbil hippocampus after transient global cerebral ischemia. Pretreatment with 8-OH-DPAT (1 mg/kg) prevented the neuronal loss in CA1 subfield 72 h after ischemia and also the dramatic decrease in BDNF immunoreactivity observed in this area at an earlier time. NMDA receptor NR1 levels in whole hippocampus were not affected 24 h after ischemia, but the levels of the subunit phosphorylated at the protein kinase A (PKA) site, pNR1(Ser897), were significantly increased, and this increase was prevented by the same 8-OH-DPAT dose, a probable consequence of the increased phosphatase 1 (PP1) enzyme activity found in ischemic gerbils pretreated with the 5-HT(1A) receptor agonist. The results indicate that both NR1 subunit phosphorylation and the neurotrophin BDNF account, at least in part, for the neuroprotective effect of 8-OH-DPAT on cell damage induced by global ischemia in the gerbil hippocampus and support the potential interest of 5-HT1A receptor activation in the search for neuroprotective strategies.
 ...
PMID:Neuroprotective effects of serotonin 5-HT 1A receptor activation against ischemic cell damage in gerbil hippocampus: Involvement of NMDA receptor NR1 subunit and BDNF. 1826 31


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>