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)

Microvascular dysfunction is a prominent feature of the lung injury associated with intestinal reperfusion (IR). This study examines the hypothesis that IR induces pulmonary thromboxane A2 (TxA2) release, which contributes to pulmonary microvascular dysfunction. Sprague-Dawley rats underwent 120 min of intestinal ischemia and 60 min of reperfusion (IR). Sham-operated animals served as controls (SHAM). Following IR or SHAM, the lungs were perfused in vitro with a modified Krebs buffer and ventilated with room air. Eicosanoid levels within the pulmonary venous effluent and bronchoalveolar lavage (BAL) fluid were determined (TxB2, 6-keto-PGF1a, and PGE2). Pulmonary artery pressure (PAP) was measured continuously and expressed as change from baseline in mm Hg. The dominant eicosanoid generated by the lungs in response to IR was TxB2. TxB2 levels in the pulmonary venous effluent of IR lungs were 75% greater than controls (P = 0.005). Similarly, TxB2 levels in the BAL were more than 2.5 times controls (P = 0.001). The change in PAP of lungs from IR animals was significantly greater than that of controls (4.1 +/- 1.5 vs 0.3 +/- 0.54 mm Hg, IR vs SHAM, P = 0.01). The increased PAP associated with IR lungs was prevented by cyclooxygenase inhibition with indomethacin (-1.28 +/- 0.29 mm Hg, P < 0.05) and thromboxane synthetase inhibition with imidazole (-1.75 +/- 0.95 mm Hg, P < 0.05). These experiments support the hypothesis that IR up-regulates endogenous pulmonary TxA2 release. Furthermore, the local release of TxA2 by the lung may contribute to the microvascular dysfunction characteristic of IR-induced lung injury.
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PMID:Pulmonary thromboxane release following intestinal reperfusion. 779 27

This study examines the hypothesis that reduced splanchnic blood flow during intestinal reperfusion (IR) is associated with impaired release of the vasodilatory prostanoid PGI2. Sprague-Dawley rats underwent occlusion of the superior mesenteric artery (SMA) for 120 min and reperfusion for up to 60 min. SMA blood flow was measured by transonic flow probe and radiolabeled microspheres (141Ce and 103Ru). Sham-operated animals served as controls (SHAM). Splanchnic eicosanoid release was quantitated by measuring thromboxane B2 (TxB2, stable metabolite of TxA2), 6-keto-PGF1a (6-keto, stable metabolite of PGI2), and PGE2 within the portal vein (PV) and inferior vena cava (IVC) of animals sustaining IR and SHAM. SMA flow in IR animals was < 10% of baseline and 27% of SHAM when measured by transonic flow probe (8 +/- 2% and 29 +/- 3%, IR and SHAM, respectively, P < 0.05). Similar results were obtained when intestinal blood flow was measured with microspheres (0.33 +/- 0.12 vs 1.34 +/- 0.13 ml/min/g, IR vs SHAM, P < 0.05). The greatest change in IR-induced splanchnic eicosanoid release occurred with 6-keto. Following ischemia, 6-keto levels in the PV were twice those of SHAM (P < 0.05). Five minutes after reperfusion, PV 6-keto levels were 22 times those of controls (P < 0.05) and 4 times greater than those of the IVC (P < 0.05). By 60 min of reperfusion, levels of 6-keto were reduced to those in the IVC. These data support the hypothesis that splanchnic blood flow is critically reduced by severe IR.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Splanchnic PGI2 release and "no reflow" following intestinal reperfusion. 779 28

The present study measured the production of eicosanoids in the gerbil brain during early reperfusion after either a 3-h unilateral carotid occlusion (UCO, model of focal ischemia) or a 10-min bilateral carotid occlusion (BCO, model of global ischemia). Arachidonic acid (AA) metabolites were examined to determine if pretreatment with the 21-aminosteroid lipid peroxidation inhibitor U-74006F (tirilazad mesylate) could influence postreperfusion synthesis of brain eicosanoids. In the 3-h UCO focal ischemia model, there was an early (5-min) postreperfusion elevation in brain levels of PGF2 alpha, TXB2 and LTC4 (P < 0.05 vs. sham for all three eicosanoids). LTB4 also rose but not significantly. On the other hand, PGE2 and 6-keto-PGF1 alpha tended to decrease during ischemia and at 5-min postreperfusion (P < 0.05 vs. sham for PGE2). Pretreatment with known neuroprotective doses of U-74006F in this model (10 mg/kg i.p. 10 min before and again immediately upon reperfusion) did not affect the increase in PGF2 alpha or TXB2 but significantly blunted the elevations in LTC4 and LTB4. The postreperfusion decrease in PGE2 was also attenuated. In the 10-min BCO global ischemia model, there was also an increase in each of the measured eicosanoids, except LTB4, at 5 min after reperfusion. Pretreatment with U-74006F (10 mg/kg i.p. 10 min before ischemia) selectively decreased the rise in LTC4 but did not significantly affect the other eicosanoids. In contrast, the antioxidant actually caused a significant enhancement of the postreperfusion increase in PGE2 vs. vehicle-treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of the lipid peroxidation inhibitor tirilazad mesylate (U-74006F) on gerbil brain eicosanoid levels following ischemia and reperfusion. 782 Jun 53

Acute occlusion of the renal circulation in the anesthetized rabbit results in a neurally mediated, reflex increase in hind-limb vascular resistance, which is flow rather than pressure dependent. This suggests that the activating stimulus could be ischemia. In the present study vascularly isolated kidneys were perfused with hypoxemic or hypercapnic blood, and the hind-limb vascular response was measured. Renal perfusion with hypoxemic blood resulted in an increase in femoral perfusion pressure (FPP), which was negatively correlated with the oxygen tension of the blood. At a PO2 of 36.4 +/- 0.9 mmHg (1 mmHg = 133.3 Pa), FPP rose by 34.4 +/- 5.7 mmHg. Renal denervation abolished this effect. Renal perfusion with hypercapnic blood had no effect on FPP. Prostaglandin E2, bradykinin, and adenosine are released during renal ischemia and have been implicated in the mediation of afferent renal nerve activity; intrarenal administration (prostaglandin E2, 10 micrograms; bradykinin, 5 micrograms; adenosine, 20 micrograms; as a 1-mL bolus) during renal perfusion with normoxemic blood elicited increases in FPP of 32.4 +/- 13.2, 19.2 +/- 3.7, and 55.6 +/- 17.8 mmHg, respectively. Intrarenal indomethacin, aprotonin, and aminophylline all inhibited the increase in FPP observed during renal perfusion with hypoxemic blood. These data indicate that renal hypoxemia stimulates an afferent renal nerve mediated increase in FPP and suggest that prostaglandin E2, bradykinin, and adenosine may all be involved in the activation of ischemically sensitive R1 chemoreceptors.
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PMID:Mechanisms involved in the activation of ischemically sensitive, afferent renal nerve mediated reflex increases in hind-limb vascular resistance in the anesthetized rabbit. 795 95

This study examines the hypothesis that pentoxifylline protects splanchnic PGI2 synthesis during severe mesenteric ischemia/reperfusion injury. Anesthetized Sprague-Dawley rats (300 grams) were subjected to sham or superior mesenteric artery occlusion for 20 minutes followed by 30 minutes of reperfusion. The ischemia/reperfusion groups received either enteral allopurinol (10 mg/kg) daily for 5 days prior to ischemia, PTX (50 mg/kg) 10 minutes prior to ischemia or carrier. The superior mesenteric artery was cannulated and removed with its intact intestine (SV + SI). The SV + SI was perfused in vitro with oxygenated Krebs buffer. The venous effluent was collected and assayed for release of 6-keto-PGF1 alpha, PGE2 and thromboxane B2 by enzyme immunoassay. Severe mesenteric ischemia/reperfusion decreased SV + SI 6-keto-PGF1 alpha release by 40% compared to the sham group but did not alter release of PGE2 or thromboxane B2. Pretreatment of the animals with PTX and not allopurinol preserved SV + SI 6-keto-PGF1 alpha release at all times of perfusion to a level similar to the sham group. These data showed that severe mesenteric ischemia/reperfusion injury abolished release of endogenous splanchnic PGI2. PTX exerted a protective effect against severe mesenteric ischemia/reperfusion injury by maintaining release of splanchnic PGI2, a potent endogenous splanchnic vasodilator.
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PMID:Pentoxifylline protects splanchnic prostacyclin synthesis during mesenteric ischemia/reperfusion. 801 84

Abnormal smooth muscle cell (SMC) proliferation is observed in several pathological situations such as atherosclerosis, pulmonary hypertension, and venous pathologies, resulting in a thickening of the vessel wall. If endothelial cells have been assumed to play a role in the triggering of this proliferation, no direct evidence is available. As ischemia is often linked to these situations, we exposed human umbilical vein endothelial cells (HUVEC) to hypoxia. The HUVEC-conditioned medium was then added to SMC and the proliferation of these cells was measured. We observed a pro-proliferative activity for SMC of the hypoxic HUVEC-conditioned medium but not of the normoxic HUVEC one. This pro-proliferative activity could not be inhibited if HUVEC were treated with cycloheximide but was blocked if the synthesis of prostaglandins by HUVEC was inhibited during hypoxia. PGD2, and especially PGF2 alpha at the concentration found in the hypoxic HUVEC-conditioned medium, were demonstrated to have a mitogenic effect on SMC. PGE2 also showed a pro-proliferative activity but at higher concentrations. In addition, the kinetics of increase in SMC proliferation induced by a mixture of the four prostaglandins at the corresponding concentrations was the same as the one observed with hypoxic HUVEC-conditioned medium. However, when tested on fibroblasts which do not respond to PGF2 alpha, hypoxic HUVEC-conditioned medium also had a pro-proliferative activity. In addition, anti-bFGF antibodies but not anti-PDGF blocked the mitogenic activity of this conditioned medium for SMC. Finally, the mitogenic effects of PGF2 alpha and of bFGF on SMC are additive. These results indicate that bFGF is probably also involved. These results indicate that these prostaglandins act in synergy with bFGF and are the molecules responsible for the pro-proliferative activity observed in hypoxic HUVEC-conditioned medium. We propose that these findings can explain the excessive growth of SMC in blood vessels following chronic ischemic situations.
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PMID:Hypoxia stimulates human endothelial cells to release smooth muscle cell mitogens: role of prostaglandins and bFGF. 802 Jun 5

In an attempt to search for neuronal models to investigate the molecular pharmacology of central nervous system ischemia, we have focused on PC12 pheochromocytoma cultures which are now popular in neuroscience research. These chromaffinergic transformed cells, originary from the adrenal medulla, synthesize and release catecholamines and, upon treatment with nerve growth factor (NGF), differentiate to a sympathetic phenotype expressing neurites and excitability. To measure eicosanoid production, undifferentiated or NGF-treated PC12 cultures have been exposed for 1 h to a mixture of N2/CO2 (95:5%), resulting in hypoxia (5 +/- 1% O2), followed by 1 h reoxygenation (21% O2) using a special ischemic device. Hypoxia, up to 2 h, was not followed by significant cytotoxicity or significant production of prostaglandin PGE2. However, upon reoxygenation, a specific release of PGE2 (2-3 fold over control) was measured. A similar PGE2-enhanced release could be induced by 'chemical hypoxia' using 2-deoxyglucose and oligomycin to reduce cellular adenosine triphosphate (ATP). Anoxia (0.1-1% O2, 1 h) achieved by a reduction of culture incubation volume and the reduction in ATP level have been found as critical parameters leading to PC12 cells cytotoxicity. These results emphasize the simplicity and applicability of the tissue culture ischemic device proposed to investigate hypoxia and ischemia at a cellular level.
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PMID:A tissue culture ischemic device to study eicosanoid release by pheochromocytoma PC12 cultures. 810 1

Prostanoids are derivative of arachidonic acid and arising from a common endoperoxide and they possess multiple and even opposing effects. Their main function is to control haemostasis and to maintain vascular homeostasis. Among these compounds thromboxane, generated by platelets, is a powerful vasoconstrictor and an inducer of platelet aggregation; prostaglandin E1 (PGE1) and prostacyclin (PGI2) are potent vasodilator and inhibitor of platelet aggregation. For these properties PGE1 and PGE2 are object of interest for the potential therapeutical use in treatment of atherosclerotic diseases, where mechanisms of vascular defense are altered and amplified. Pharmacokinetic and pharmacodynamic characteristics of these compound have been per se a good rationale for plenty of experimental studies which generated enthusiasm and hope of new therapeutic means in patients with surgically unreconstructible peripheral arterial disease. Nevertheless clinical trials have to face many difficulties deriving from their properties themselves. PGE1 and PGI2 are unstable hormones with local action and it is difficult to employ them in clinical practice. Moreover their protean action is often implicated in not unusual adverse effects. The development of compounds with a prostacyclin-type of action, but long lasting and therefore easier to handle, undoubtedly facilitated clinical research. But we still lack firm indications for a correct therapeutic use. Limb ischemia is the condition in which prostanoids were mostly studied. Although anecdotal reports or uncontrolled studies provided encouraging results, several controlled trials failed to demonstrate a consistent efficacy of either PGE1 or PGI2, whilst metanalytic review of controlled trials on iloprost demonstrated an efficacy on critical and less severe limb ischemia, thromboangiitis obliterans and Raynaud's phenomenon.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[The pharmacology and clinical aspects of the prostanoids]. 811 24

Mesenteric ischemia of short duration (5-10 min) can stimulate A delta- and C-fiber afferent nerve endings in the viscera to reflexly activate the cardiovascular system. The mechanism of activation of abdominal visceral afferents is probably multifactorial and may involve prostaglandins (PGs), which have been shown to directly stimulate and/or sensitive visceral afferents when administered exogenously. We hypothesized that brief visceral ischemia is accompanied by release of PGI2 and PGE2 into the interstitium, where these cyclooxygenase products could stimulate or sensitize visceral afferent nerve endings. Accordingly, we measured immunoreactive PGE2 (iPGE2) and 6-keto-PGF1 alpha (i6-keto-PGF1 alpha), the stable metabolite of PGI2, in lymph draining the ischemic viscera as well as in portal venous blood. An intestinal lymph duct distal to the lymph node was cannulated in pentobarbital sodium-anesthetized cats. Lymph and plasma iPGE2 and i6-keto-PGF1 alpha concentrations were measured by radioimmunoassay before, during, and immediately after a 5- to 10-min occlusion of the descending aorta. The i6-keto-PGF1 alpha concentration increased significantly (P < 0.001) in portal venous plasma (61 +/- 12 to 107 +/- 18 pg/0.1 ml; n = 14) but not in lymph (148 +/- 30 to 159 +/- 24 pg/0.1 ml; n = 16). In contrast, iPGE2 concentration was significantly (P < 0.01) elevated in both venous plasma (156 +/- 16 to 207 +/- 26 pg/0.1 ml; n = 19) and lymph (520 +/- 48 to 590 +/- 52 pg/0.1 ml; n = 20).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Brief mesenteric ischemia increases PGE2, but not PGI2, in intestinal lymph of cats. 820 52

This study examined the hypothesis that burn injury inhibits the release of splanchnic PGI2, a potent endogenous vasodilator of the splanchnic vascular bed. Male Hartley Guinea Pigs (350 grams) were anesthetized, shaved and subjected to a full thickness scald burn comprising 45% of the total body surface area (or sham burn). The animals were treated with intravenous or topical lazaroid, a 21-aminosteroid U75412E. After recovery for 24 hours, the animals were anesthetized, and the superior mesenteric artery was cannulated and removed with its intact intestine (SV + SI). The SV + SI was perfused in vitro with oxygenated Krebs buffer. The venous effluent was assayed for 6-keto-PGF1 alpha, PGE2 and thromboxane B2 by enzyme immunoassay. Acute burn injury decreased SV + SI release of 6-keto-PGF1 alpha by 57% but did not alter release of PGE2 or thromboxane B2. Treatment of the animals with topical lazaroid and not intravenous lazaroid restored SV+SI 6-keto-PGF1 alpha release to control levels. These data showed that topical lazaroid therapy maintained endogenous splanchnic PGI2 release following acute burn injury. Maintaining endogenous splanchnic PGI2 release by topical lazaroid treatment may be one strategy to avoid splanchnic ischemia following acute thermal injury.
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PMID:Burn injury decreased splanchnic PGI2 release is restored by treatment with lazaroid. 833 13


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