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)

In conscious rats, we tested the hypothesis that prostaglandins attenuate regional vasoconstriction caused by acute infusion of angiotensin II. Mean arterial pressure, regional blood flow, and vascular conductance in response to 2-minute infusions of 0.05 or 1 microg/kg/min Ang II were assessed before and during indomethacin treatment (5 mg/kg). Effects of the lower dose of Ang II (n=8) on regional blood flow were not altered by indomethacin, but conductance in the kidney (2.98+/-0.35 vs. 2.19+/-0.32), stomach (1.15+/-0.13 vs. 0.83+/-0.13), and white gastrocnemius muscle (0.11+/-0.02 vs. 0.07+/-0.01 mL/min/100g/mm Hg) were reduced. Changes in conductance were not seen in the pancreas or spleen. In response to the higher dose of Ang II (n=7), indomethacin reduced blood flow in the kidney, red and white gastrocnemius, and soleus muscles. Reductions in conductance were found in the kidney, stomach and small intestine, and in the red and white gastrocnemius, and soleus muscles (2.27+/-0.9 vs. 1.79+/-0.14, 0.44+/-0.07 vs. 0.27+/-0.03, 0.68+/-0.11 vs. 0.60+/-0.07, 0.43+/-0.08 vs. 0.16+/-0.03, 0.10+/-0.02 vs. 0.05+/-0.01, and 0.26+/-0.03 vs. 0.15+/-0.02 mL/min/100g, respectively). No changes occurred in the pancreas and spleen. Indomethacin had no effect on baseline blood flow or conductance in any of these organs. These results suggest that prostaglandins attenuate vasoconstriction caused by Ang II in a manner that is organ-specific and dependent on the dose of Ang II. Consequently, prostaglandins may limit vasoconstriction and potential ischemia caused by elevated levels of this hormone.
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PMID:Endogenous prostaglandins limit angiotensin-II induced regional vasoconstriction in conscious rats. 1282 20

This study explored the effect of chronic hypoxia on the elevation of pulmonary vascular resistance caused by ischemia-reperfusion (IR) in anesthetized rats. Experiments were separated into five parts. In Part 1, we examined the increase in left pulmonary vascular resistance (Rpl) after ischemia of the left lung and localized the major site for the increased resistance of the left pulmonary vasculature in both the normoxic and chronic hypoxia groups. Here, IR induced a significant increase in Rpl in the normoxic but not the chronic hypoxia group. This increased Rpl in the normoxic group was attributed to contraction of pulmonary arterial segments. Part 2 and Part 3 were focused on the changes in plasma nitrate/nitrite (NOx) and thromboxane B(2) (TxB(2)) levels. TxB(2) increased significantly in the normoxic group, whereas NOx increased significantly in the chronic hypoxia group, following ischemia. Indomethacin (Part 4) prevented IR-induced increase in Rpl in the normoxic group, whereas the IR-induced increase in Rpl appeared in the chronic hypoxia group after N(G)-nitro-L-arginine methyl ester treatment (Part 5). We conclude that IR elicited increases in the cyclooxygenase products such as TxB(2), which in turn caused an increase in Rpl. However, this increased Rpl was attenuated by elevated NOx in the chronic hypoxia group.
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PMID:Chronic hypoxia attenuates ischemia-reperfusion-induced increase in pulmonary vascular resistance. 1292 88

Ischemia-reperfusion injury (IRI) is a common event in organ transplantation, being implicated as a potential contributor for the development of chronic allograft nephropathy. There are new evidences showing a tissue inflammatory response following renal IRI. Cyclooxygenases (COX) 1 and 2 can be detected in tissue submitted to IRI and may have impact on organ function outcome. We evaluated the role of COX inhibition on the renal tissue damage that follows IRI. Mice were submitted to 45 min of renal pedicle ligature and allowed to reperfuse for 24, 48, 72 and 120 h. Blood and kidney samples were collected at reperfusion times. mRNA was extracted from the kidney samples to amplify COX-1, COX-2 and beta-actin genes. Animals were pretreated with indomethacin or rofecoxib before the surgery. Indomethacin treatment induced a better renal function (serum urea) when compared to control animals at 24, 48 and 72 h (219+/-54.5 vs. 338+/-51 mg/dl; 106+/-51 vs. 326+/-86 mg/dl; 94+/-14 vs. 138+/-38 mg/dl, respectively). Surprisingly, rofecoxib use was associated with even better renal improvement following IR. Animals treated with the later drug showed lower urea values at 24 h post reperfusion compared to indomethacin-treated animals (128+/-33 vs. 219+/-54.5 mg/dl, P<0.05). Blockade of COX-1 and -2 resulted in a decrease of tubular necrosis. mRNA COX-2 was up-regulated post IRI and considerable inhibited after indomethacin or rofecoxib treatment. Our data show COX-1/-2 participates in the inflammatory tissue response to IR injury and its inhibition is associated with an improvement in renal function.
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PMID:Cyclooxygenase 1 and/or 2 blockade ameliorates the renal tissue damage triggered by ischemia and reperfusion injury. 1558 63

Failure of ductal closure is common in extremely low birth weight infants with significant postnatal morbidities from both pulmonary overcirculation (i.e. chronic lung disease) and/or systemic hypoperfusion (i.e. necrotizing enterocolitis). Early clinical signs of a hemodymanically significant ductus may be non-specific (i.e. hypotension, increasing ventilator requirements, metabolic acidosis) necessitating early screening by echocardiography. Cyclooxygenase inhibitors remain the first-line treatment option. Indomethacin remains the most commonly used agent, despite comparable efficacy and reduced risk of adverse events with ibuprofen. Surgical intervention is recommended after failure of medical therapy, contraindications to medical treatment or fulminating duct-related cardiorespiratory deterioration. Wherever possible, surgical intervention in ELBW infants should be avoided in the first week of life due to the potential risks of ischemia-reperfusion cerebral hemorrhage. The postoperative course is often complicated by left ventricular failure, pulmonary edema, and/or hemodynamic instability requiring close monitoring and physiologically relevant therapeutic interventions.
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PMID:Enhanced intensive care for the neonatal ductus arteriosus. 1672 Apr 84

Ghrelin is involved in the control of food intake, but its role in gastroprotection against the formation of gastric mucosal injury has been little elucidated. We studied the effects of peripheral (i.p.) and central (i.c.v.) administration of ghrelin on gastric secretion and gastric mucosal lesions induced by 3 h of ischemia/reperfusion (I/R) with or without inhibition of ghrelin growth hormone secretagogue type 1a receptor (GHS-R1a) by using ghrelin antagonist, d-Lys(3)-GHRP-6; blockade of cyclooxygenase (COX)-1 (indomethacin, SC560 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole]) and COX-2 (rofecoxib); and bilateral vagotomy or capsaicin denervation. I/R produced typical gastric erosions, a significant fall in the gastric blood flow (GBF), an increase in gastric myeloperoxidase (MPO) activity and malonyldialdehyde (MDA) content, and the up-regulation of mucosal ghrelin mRNA. Ghrelin dose-dependently increased gastric acid secretion and significantly reduced I/R-induced gastric erosions, while producing a significant rise in the GBF and mucosal PGE(2) generation and a significant fall in MPO activity and MDA content. The protective and hyperemic activities of ghrelin were significantly attenuated in rats pretreated with d-Lys(3)-GHRP-6 and capsaicin denervation and completely abolished by vagotomy. Indomethacin, SC560, and rofecoxib, selective COX-1 and COX-2 inhibitors, attenuated ghrelin-induced protection that was restored by supplying the methyl analog of prostaglandin (PG) E(2). The expression of mRNA for COX-1 was unaffected by ghrelin, but COX-2 mRNA and COX-2 protein were detectable in I/R injured mucosa and further up-regulated by exogenous ghrelin. We conclude that ghrelin exhibits gastroprotective and hyperemic activities against I/R-induced erosions, the effects that are mediated by hormone activation of GHS-R1a receptors, COX-PG system, and vagal-sensory nerves.
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PMID:Prostaglandin/cyclooxygenase pathway in ghrelin-induced gastroprotection against ischemia-reperfusion injury. 1686 36

Prior work in animals and humans suggests that muscle mechanoreceptor control of sympathetic activation [muscle sympathetic nerve activity (MSNA)] during exercise in heart failure (HF) patients is heightened compared with that of healthy humans and that muscle mechanoreceptors are sensitized by metabolic by-products. We sought to determine whether cyclooxygenase products and/or endogenous adenosine, two metabolites of ischemic exercise, sensitize muscle mechanoreceptors during rhythmic handgrip (RHG) exercise in HF patients. Indomethacin, which inhibits the production of prostaglandins, and saline control were infused in 12 HF patients. In a different protocol, aminophylline, which inhibits adenosine receptors, and saline control were infused in 12 different HF patients. MSNA was recorded (microneurography). During exercise following saline, MSNA increased in the first minute of exercise, consistent with baseline heightened mechanoreceptor sensitivity. MSNA continued to increase during 3 min of RHG, indicative that muscle mechanoreceptors are sensitized by ischemia metabolites. Indomethacin, but not aminophylline, markedly attenuated the increase in MSNA during the entire 3 min of low-level rhythmic exercise, consistent with the sensitization of muscle mechanoreceptors by cyclooxygenase products. Interestingly, even the early increase in MSNA was abolished by indomethacin infusion, indicative of the very early generation of cyclooxygenase products after the onset of exercise in HF patients. In conclusion, muscle mechanoreceptors mediate the increase in MSNA during low-level RHG exercise in HF. Cyclooxygenase products, but not endogenous adenosine, play a central role in muscle mechanoreceptor sensitization. Finally, muscle mechanoreceptors in patients with HF have heightened basal sensitivity to mechanical stimuli, which also appears to be mediated by the early generation of cyclooxygenase products, resulting in exaggerated early increases in MSNA.
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PMID:Cyclooxygenase products sensitize muscle mechanoreceptors in humans with heart failure. 1829 64

Decreases in fetal blood pressure stimulate homeostatic stress responses that help return blood pressure to normal levels. Fetal hypothalamus-pituitary-adrenal (HPA) axis responses to hypotension are mediated by chemoreceptor and baroreceptor reflexes and ischemia of the fetal central nervous system. Indomethacin, a nonselective inhibitor of prostaglandin endoperoxide synthase (PGHS)-1 and -2, attenuates the HPA response to hypotension in the fetus. The present study was designed to test the hypothesis that selective inhibition of PGHS-2 also inhibits the HPA response to cerebral hypoperfusion. We studied 13 chronically catheterized fetal sheep (126-136 days gestation). Five fetal sheep were subjected to intracerebroventricular infusion of nimesulide (0.01 mg/day), a specific inhibitor of PGHS-2, and eight were treated with vehicle (DMSO in water) for 5 days. Each fetus was subjected to a 10-min period of brachiocephalic occlusion, which decreased carotid arterial pressure approximately 75% and reflexively increased fetal plasma concentrations of ACTH, POMC, cortisol, and femoral arterial pressure, and decreased fetal heart rate. Nimesulide significantly inhibited the ACTH response to the BCO, while significantly augmenting the reflex cardiovascular response and altering fetal heart rate variability consistent with increased sympathetic nervous system activity. The results of this study demonstrate that the activity of PGHS-2 in the brain is a necessary component of the fetal HPA response to cerebral hypoperfusion in the late-gestation fetal sheep. These results are consistent with those of recent study, in which we demonstrated that the preparturient increase in fetal ACTH secretion depends upon PGHS-2 activity within the fetal brain.
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PMID:Blockade of PGHS-2 inhibits the hypothalamus-pituitary-adrenal axis response to cerebral hypoperfusion in the sheep fetus. 1929 37

We have previously shown that expression of renal organic anion transporters Oat1 and Oat3 is diminished by prostaglandin E(2) (PGE(2)) and that both transporters are downregulated after renal ischemia. Because PGE(2) is increased after renal ischemia and is generated by cyclooxygenases (COX), we investigated the effect of the COX inhibitor indomethacin on expression of Oat1/3 after ischemic acute kidney injury (iAKI). iAKI was induced in rats by bilateral clamping of renal arteries for 45 min. Indomethacin (1 mg/kg) was given intraperitoneally as soon as reperfusion started. Sham-treated animals served as controls. Oat1/3 were determined by qPCR and Western blot. PGE(2) in blood and urine was measured by enzyme-linked immunosorbent assay. Invasion of monocytes/macrophages was determined. Glomerular filtration rate and renal plasma flow were determined. All parameters were detected 24 h after ischemia. PAH net secretion, as well as clearance and secretion of PGE(2) were calculated. In clamped animals, indomethacin restored expression of Oat1/3, as well as PAH net secretion, PGE(2) clearance, or PGE(2) secretion. Additionally, indomethacin substantially improved kidney function as measured by glomerular filtration and PAH clearance. Indomethacin did not affect ischemia-induced invasion of monocytes/macrophages. In conclusion, our study indicates that low-dose indomethacin applied after ischemia prevents ischemia-induced downregulation of Oat1/3 during reperfusion and has a substantial protective effect on kidney function after iAKI. The beneficial effect of low-dose indomethacin on renal outcome is likely due to an effect different from inhibition of inflammation. In accordance to the decreased PAH net secretion, renal excretion of an endogenous organic anion (PGE(2)) is also impaired after ischemia and reperfusion.
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PMID:Low-dose indomethacin after ischemic acute kidney injury prevents downregulation of Oat1/3 and improves renal outcome. 1979 9

We examined the role of cysteinyl leukotrienes (CysLTs) in the gastric ulcerogenic response to ischemia/reperfusion (I/R) in mice. Experiments were performed in male C57BL/6J mice after 18-h fasting. Under urethane anesthesia, the celiac artery was clamped for 30 min, and then reperfusion was achieved by removing the clamp. The stomach was examined for lesions 60 min thereafter. The severity of I/R-induced gastric damage was reduced by prior administration of pranlukast [CysLT receptor type 1 (CysLT(1)R) antagonist] as well as 1-[[5'-(3''-methoxy-4''-ethoxycarbonyl-oxyphenyl)-2',4'-pentadienoyl]aminoethyl]-4-diphenylmethoxypiperidine [TMK688; 5-lipoxygenase (5-LOX) inhibitor]. On the contrary, these lesions were markedly worsened by pretreatment with indomethacin, and this response was abrogated by the coadministration of TMK688 or pranlukast. The gene expression of CysLT(1)R but not 5-LOX was up-regulated in the stomach after I/R, but both expressions were increased under I/R in the presence of indomethacin. I/R slightly increased the mucosal CysLT content of the stomach, yet this increase was markedly enhanced when the animals were pretreated with indomethacin. The increased CysLT biosynthetic response to indomethacin during I/R was attenuated by TMK688. Indomethacin alone caused a slight increase of CysLT(1)R expression and markedly up-regulated 5-LOX expression in the stomach. We concluded that I/R up-regulated the expression of CysLT(1)R in the stomach; CysLTs play a role in the pathogenesis of I/R-induced gastric damage through the activation of CysLT(1)R; and the aggravation by indomethacin of these lesions may be brought about by the increase of CysLT production and the up-regulation of 5-LOX expression, in addition to the decreased prostaglandin production.
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PMID:Pathogenic importance of cysteinyl leukotrienes in development of gastric lesions induced by ischemia/reperfusion in mice. 2004 30

Although exogenous administration of Angiotensin-(1-7) [Ang-(1-7)] can prevent development of diabetes induced end-organ damage, little is known about the role of endogenous Ang-(1-7) in diabetes and requires further characterization. Here, we studied the effects of chronically inhibiting endogenous Ang-(1-7) formation with DX600, a selective angiotensin converting enzyme-2 (ACE2) inhibitor, on renal and cardiac NADPH oxidase (NOX) activity, vascular reactivity and cardiac function in a model of Type-1 diabetes. The contribution of endogenous Ang-(1-7) to the protective effects of Losartan and Captopril and that of prostaglandins to the cardiovascular effects of exogenous Ang-(1-7) were also examined. Cardiac and renal NOX activity, vascular reactivity to endothelin-1 (ET-1) and cardiac recovery from ischemia/reperfusion (I/R) injury were evaluated in streptozotocin-treated rats. Chronic treatment with DX600 exacerbated diabetes-induced increase in cardiac and renal NOX activity. Diabetes-induced abnormal vascular reactivity to ET-1 and cardiac dysfunction were improved by treatment with Ang-(1-7) and worsened by treatment with DX600 or A779, a Mas receptor antagonist. Ang-(1-7)-mediated improvement in cardiac recovery or vascular reactivity was attenuated by Indomethacin. Captopril and Losartan-induced improvement in cardiovascular function was attenuated when these drugs were co-administered with A779. Ang-(1-7)-mediated decrease in renal NOX activity was prevented by indomethacin. Losartan also decreased renal NOX activity that could be attenuated with A779 co-treatment. In conclusion, endogenous Ang-(1-7) inhibits diabetes-induced cardiac/renal NOX activity and end-organ damage, and mediates the actions of Captopril and Losartan. Further, prostaglandins are important intermediaries in the beneficial effects of Ang-(1-7) in diabetes. Combining either Losartan or Captopril with Ang-(1-7) had additional beneficial effects in preventing diabetes-induced cardiac dysfunction and this may represent a novel therapeutic strategy. Collectively, these data shed new insights into the likely mechanism of action through which the ACE2/Ang-(1-7)/Mas receptor axis prevents Type 1 diabetes-induced cardiovascular dysfunction.
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PMID:Characterization of Angiotensin-(1-7) effects on the cardiovascular system in an experimental model of type-1 diabetes. 2258 Feb 36


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