UMLS:C0432222 - FACTA Search

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A quantitative method for testing antiinflammatory agents in beagles has been developed, based on measurement of paw inflammation induced by a local injection of carrageenin. Carrageenin [0.5 mL of 2% (wt/vol) in saline] was injected into the plantar region of the hindpaws of pentobarbital-anesthetized beagles. Paw pressure changes registered from a water-filled balloon held on the top of the paw by a light adhesive tape wrapping were monitored for 240 min. In control dogs given 0.5% (wt/vol) methylcellulose (10 mL/kg orally) just before carrageenin, paw pressure increased significantly (p less than 0.05) over eightfold, from 2.9 +/- 0.8 mm Hg (mean +/- SEM, n = 29 paws) at 75 min to 26.0 +/- 3.5 mmHg at 240 min. The increase in paw pressure was significantly inhibited by the cyclooxygenase inhibitors, ibuprofen, indomethacin, and orpanoxin, and partially inhibited by the lipoxygenase inhibitor, phenidone, administered orally before carrageenin injection. Thus this model, with further characterization, could provide a convenient, quantitative way of assessing the efficacy of nonsteroidal antiinflammatory agents in dogs.
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PMID:Canine carrageenin-induced acute paw inflammation model and its response to nonsteroidal antiinflammatory drugs. 190 6

Inhibitors of the arachidonic acid metabolism (AA) as well as scavengers of oxygen free radicals (OFR) have been shown to reduce myocardial infarct size. We investigated the effects of two inhibitors of AA metabolism on the cardiac effects of OFR. Isolated rat hearts were retrogradely perfused for 10 min with buffer containing hypoxanthine (HX, 1 mmol l-1) and xanthine oxidase (XOD: 24 U l-1) alone (n = 11), or with the addition of ibuprofen (IBU) (n = 6) (a cyclooxygenase inhibitor) or BW 755C (n = 6) (a dual inhibitor of cyclo-oxygenase and lipoxygenase). The hearts were observed for 30 min thereafter (total observation time 40 min). Left-ventricular pressures were measured by a balloon in the left ventricle. HX + XOD significantly reduced left-ventricular developed pressure (LVDP) and coronary flow (CF), but not heart rate. The reduction of LVDP and CF was not significantly ameliorated by the addition of IBU (7.6 x 10(-4) mol l-1) or BW 755C (2 x 10(-3) mmol l-1). OFR increased left-ventricular end-diastolic pressure (LVEDP) from (mean +/- SEM) 0 to 22 +/- 4 mmHg (10 min) and 30 +/- 5 mmHg (40 min). Upon addition of IBU, LVEDP increased from 0 to 24 +/- 8 mmHg and 17 +/- 6 mmHg at 10 and 40 min respectively. The addition of BW 755C almost completely inhibited the increase in LVEDP (1 +/- 1 mmHg and 3 +/- 3 mmHg at 10 min and 40 min). In conclusion, except for inhibition of OFR-induced diastolic dysfunction by BW 755C, neither BW 755C nor IBU appear to inhibit cardiac injury induced by OFR.
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PMID:Oxygen free radical-induced injury in isolated rat hearts: effects of ibuprofen and BW 755c. 194 22

The role of bradykinin in the ovulatory process was investigated using an in vitro-perfused rat ovary model. Stimulation with LH (0.1 micrograms/ml) resulted in 2.6 +/- 0.5 (mean +/- SEM) ovulations per ovary, whereas no ovulations occurred in the nonstimulated control group. Bradykinin (5 microM) added to the perfusion system hourly for 10 h induced 2 of 5 ovaries to ovulate, with 2 and 3 ovulations, respectively. When bradykinin (5 microM) was given as a single dose at 5 or 10 h after LH, the ovulation rate was significantly increased to 11.0 +/- 2.8 and 8.6 +/- 2.0 ovulations per ovary, respectively. A competitive bradykinin antagonist, phenylalanine bradykinin, inhibited the bradykinin-induced increase in LH-stimulated ovulations. The addition of LH, but not of bradykinin, increased the levels of prostaglandin endoperoxide synthase in granulosa cells, but the levels of the enzyme in the residual ovarian tissue were negligible. In contrast, prostacyclin synthase was predominantly located in the residual ovarian tissue. This enzyme was not affected by LH or bradykinin. LH increased the tissue levels of prostaglandins, predominantly prostaglandin E2 (PGE2), at 7 h, whereas the stimulatory effect of bradykinin was smaller, with a preferential increase in prostacyclin (prostaglandin I2) levels. This study indicates a modulatory role of bradykinin, possibly involving prostacyclin late in the ovulatory process, in the rat.
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PMID:Stimulatory effects of bradykinin on the ovulatory process in the in vitro-perfused rat ovary. 200 29

This study demonstrates that the hexapeptide angiotensin II-(3-8) and L-arginine, generated through enzymatic degradation of angiotensin, mediate endothelium-dependent dilation in rabbit brain arterioles. Topical application of angiotensin II (10(-5) M) on the brain surface of anesthetized rabbits caused 21.6 +/- 4.5% (mean +/- SEM) cerebral arteriolar dilation. The cyclooxygenase inhibitor indomethacin did not change this dilation. The natural degradation product of angiotensin II in the brain, angiotensin III, also induced vasodilation at concentrations of 10(-7) to 10(-5) M. The dilation to angiotensin II and angiotensin III was eliminated in the presence of 10(-5) M methylene blue, a known inhibitor of endothelium-dependent vasodilation. Amastatin, an aminopeptidase inhibitor and blocker of enzymatic angiotensin degradation, also inhibited the response to angiotensin II and angiotensin III. The angiotensin fragment angiotensin II-(3-8), which lacks the amino-terminal L-arginine residue of angiotensin III, did not elicit an arteriolar response. When angiotensin II-(3-8) was topically applied subsequent to L-arginine, a 21.2 +/- 2.9% vasodilation was observed. L-Arginine itself induced only moderate vasodilation with a maximum of 4.0 +/- 0.9% at 10(-5) M L-arginine. The dilating response to angiotensin II-(3-8) after L-arginine was inhibited by methylene blue. It was not affected by amastatin. It is concluded that degradation products of angiotensin, rather than angiotensin II itself, induce endothelium-dependent dilation in rabbit brain arterioles without involvement of cyclooxygenase products.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Angiotensin degradation products mediate endothelium-dependent dilation of rabbit brain arterioles. 203 15

Decreased cardiac output and increased plasma thromboxane have been observed during aortic cross-clamping under general anesthesia. Amelioration of these changes has been reported by preoperative administration of cyclooxygenase inhibitors, but heterogeneity in patients' intravascular volume status has confounded analysis of the drugs' effects in previous studies. We studied hemodynamic conditions in 24 volume-loaded (pulmonary capillary wedge pressure greater than 10 mm Hg) patients undergoing abdominal aortic aneurysm repair under general plus epidural anesthesia, after preoperative double-blind administration of either ibuprofen 800 mg (n = 12) or placebo (n = 12). The hemodynamic response to aortic cross-clamping was similar in both groups. Pulse and mean arterial pressure remained unchanged; cardiac index decreased after aortic cross-clamping from 2.4 +/- 0.1 (mean +/- standard error of the mean [SEM]) to 2.1 +/- 0.1 1/min/m2 in the ibuprofen group and from 2.5 +/- 0.1 to 2.3 +/- 0.2 1/min/m2 in the placebo group (p less than 0.01 versus preclamp values in both groups, multivariate analysis of variance [MANOVA]), but improved after declamping. Both left and right ventricular stroke work indexes followed a similar pattern. Plasma 6-keto prostaglandin Fl alpha (6-k-PGF1 alpha) increased transiently from a baseline level of 304 +/- 44 to 2083 +/- 698 pg/ml plasma in mixed venous blood 30 minutes after incision in the placebo group (p less than 0.05), but no other significant change in plasma 6-keto prostaglandin Fl alpha or in thromboxane B2 occurred in either group at any other time.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effect of ibuprofen on cardiac performance during abdominal aortic cross-clamping. 203 9

Mesenteric traction during aortic surgery produces facial flushing, reduced mean arterial pressure (MAP), and systemic vascular resistance (SVR) with increased heart rate (HR) and cardiac index (CI). Elevated 6-keto-prostaglandin-F1 alpha (6-keto-PGF1 alpha) suggests prostacyclin is the mediator. To test this hypothesis, the cyclooxygenase inhibitor, ibuprofen (n = 14), or placebo (n = 13) was administered to patients electively scheduled for aortic reconstruction. The hemodynamic measurements and plasma concentrations of prostanoids between groups were compared immediately before (0), and 5, 10, 15, 30, and 45 min following mesenteric traction. Following mesenteric traction significant differences (P less than 0.05) were observed between the ibuprofen pretreatment and placebo group over time in SVR, MAP, HR, CI, 6-keto-PGF1 alpha, and thromboxane B2 (TXB2). Significant differences between groups at individual times were found in SVR, HR, CI, 6-keto-PGF1 alpha, and TXB2. In the placebo group flushing was accompanied by reduced SVR and MAP and increased HR and CI. The greatest effect was seen at 10 min and resolved over 30 min. Plasma concentration of 6-keto-PGF1 alpha increased from 159 +/- 103 (mean +/- SEM) pg/ml to a peak value of 3,765 +/- 803 at 10 min. A late increase in TXB2 occurred with a peak value of 1,970 +/- 891 (mean +/- SEM) pg/ml at 30 min. In the ibuprofen pretreated group no significant changes occurred in hemodynamic measurements or concentrations of prostanoids. The inhibition of 6-keto-PGF1 alpha and its associated hemodynamic changes in the treatment group, but not in the placebo group, confirms the hypothesis that prostacyclin is the mediator of the mesenteric traction response in abdominal aortic surgery.
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PMID:Ibuprofen pretreatment inhibits prostacyclin release during abdominal exploration in aortic surgery. 210 6

We have previously reported that epithelium-dependent inhibitory factors, both prostanoids and non-prostanoids, can be activated by electrical field stimulation (EFS) and direct nerve stimulation (DNS) in an in vitro nerve-muscle preparation of ferret trachea. In this study we set out to compare the release of the inhibitory prostanoids, PGE2 and PGI2, in preparations with intact and with removed epithelium. Ferret tracheae were mounted in organ baths and phasic contractions were induced by EFS and DNS. The bath concentrations of PGE2 and the PGI2-metabolite 6-keto-PGF1 alpha were measured using radioimmuno assays. The gradual decrease in contractile response to DNS, 2 Hz for 120 min, was 95 +/- 2% of baseline (mean +/- SEM) in preparations with intact epithelium compared with 29 +/- 8% in epithelium-denuded preparations (p less than 0.001). The bath-levels of PGE2 showed a slight but significant (p less than 0.01) increase in denuded preparations with a final bath-concentration at 120 min of 13 +/- 3 pg/ml. The release of PGE2 was more pronounced in preparations with intact epithelium which resulted in a final bath-concentrations of PGE2 of 84 +/- 38 pg/ml which was significantly higher compared with epithelium-denuded preparations and also compared with time-matched controls with the same pattern of contraction induced by DNS alone. The concentrations of 6-keto-PGF1 alpha showed a slight increase which was of comparable magnitude (ns) in intact and denuded preparations. In conclusion this study demonstrates that the cyclooxygenase-dependent component of the epithelium-dependent inhibition of the contractile response to cholinergic nerve stimulation in ferret trachea is mediated by PGE2 but not by PGI2.
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PMID:Epithelium-derived PGE2 inhibits the contractile response to cholinergic stimulation in isolated ferret trachea. 213 19

Allergen-stimulated release of a cyclooxygenase product (thromboxane [TX] A2) and a 5-lipoxygenase product (leukotriene [LT] E4) into the urine was measured in 10 atopic asthmatics undergoing allergen inhalation. Because indomethacin has been reported to increase allergic-stimulated 5-lipoxygenase product formation and to inhibit the late asthmatic response, we determined the effect of indomethacin (50 mg 3 times a day) or placebo on airway and biochemical responses to inhaled allergen in a randomized, blinded study. Urinary levels of the enzymatic metabolite of TXB2, 11-dehydro-TXB2, increased from 585 +/- 330 to 1,500 +/- 250 pg/mg creatinine (mean +/- SEM, p less than 0.05) 2 h after allergen. Urinary LTE4 increased from 190 +/- 37 to 1,100 +/- 400 (p less than 0.05) 2 h after challenge. The urinary levels of these eicosanoids were not elevated during the late response. Indomethacin significantly reduced urinary 11-dehydro-TXB2 levels without affecting the excretion of LTE4 or pulmonary function. Thus, we failed to obtain evidence for enhanced leukotriene formation during allergic stimulation in vivo in the presence of cyclooxygenase inhibition. Furthermore, we conclude that cyclooxygenase products are likely to play only a marginal role in allergic bronchoconstriction.
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PMID:Allergen-stimulated release of thromboxane A2 and leukotriene E4 in humans. Effect of indomethacin. 216 26

Exposure of human subjects to sufficiently high levels of ozone can result in reversible changes in lung function (restrictive in nature) and increases in nonspecific airway responsiveness. Several studies have implicated products of cyclooxygenase metabolism in the mediation of these changes. The purpose of this study was to determine if indomethacin (a cyclooxygenase inhibitor) would alter the changes in the ozone-induced increase in responsiveness to methacholine or the ozone-induced decrease in lung function. Thirteen male subjects underwent three randomly assigned 2-h exposure to 0.4 ppm ozone with alternating 15-min periods of rest and exercise on a cycle ergometer (30 L/min/m2, body surface area). For the 4 days before each of the exposures, the subjects received either indomethacin (150 mg/day) or placebo, or no modification. Of the 13 subjects, only seven had both detectable indomethacin serum levels on the indomethacin Study Day and a significant increase in bronchial responsiveness to methacholine on the No Medication Day. For this group of seven subjects, we found that indomethacin did not alter the ozone-induced increase in bronchial responsiveness to methacholine (decrease in PC100SRaw for the different study days: no medication, -78.4 +/- 5.3% [mean +/- SEM]; placebo, -48.9 +/- 12.2%; indomethacin, -64.5 +/- 6.3%; p greater than 0.2), although indomethacin did attenuate the ozone-induced decrease in lung function. The decrease in the FEV1 for the different study days was as follows: no medication, -20.7 +/- 5.0% (mean +/- SEM); placebo, -19.2 +/- 6.3%; indomethacin, -4.8 +/- 3.7% (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Indomethacin does not inhibit the ozone-induced increase in bronchial responsiveness in human subjects. 222 87

Evidence in vitro and in humans suggest that Mg2+ can alter systemic and renal vascular tone. However, the mechanism of these effects is not known. The role of vasodilator prostaglandin release and Ca2+ flux in Mg2+-induced changes in blood pressure and renal blood flow was studied in 10 normal subjects maintained on a fixed 80-mEq Na+ and K+ diet. Magnesium sulfate infused at 200 mg/hr for 3 hours reduced systolic and diastolic blood pressure within 1 hour (from 119 +/- 2 [SEM] to 109 +/- 4 mm Hg systolic; from 74 +/- 3 to 64 +/- 4 mm Hg diastolic; p less than 0.02). This hypotensive response was seen in all subjects and persisted for 3 hours. The pulse rate did not change, but renal blood flow (p-aminohippurate clearance) increased (from 902 +/- 78 to 1108 +/- 130 ml/min/1.73 m2; p less than 0.05). The Mg2+ infusion produced a significant increase in the excretion of the stable prostaglandin I2 (PGI2) metabolite 6-keto-PGF1 alpha (from 96 +/- 12 to 154 +/- 16 ng/g creatinine; p less than 0.01). In contrast, urinary PGE2 was not altered (328 +/- 75 vs 399 +/- 145 ng/g creatinine; p greater than 0.6). To evaluate the functional role of PGI2 release, the cyclooxygenase inhibitors indomethacin (75 mg) or ibuprofen (600 mg) were given before the Mg2+ infusion. Both cyclooxygenase blockers, given in doses that inhibited immunoreactive 6-keto-PGF1 alpha release, completely prevented the Mg2+-induced decline in blood pressure and increased renal blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Evidence that prostacyclin mediates the vascular action of magnesium in humans. 243 56

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