Disease relevance of C05961

• IFN-gamma did not alter the production of PGE2 in A549 cells (a human lung adenocarcinoma cell line) or 6-keto-PGF1alpha in human umbilical vein endothelial cells (HUVECs), although prostaglandin release and/or the expression of PGHS-2 RNA in these cell lines was upregulated by other proinflammatory cytokines [1].
• Treatment with an AT2R antagonist, PD123 319, normalizes the thrombosis time and nitrate and 6-keto-PGF1alpha [2].
• Similar changes in CSF 6 keto PGF1alpha concentration during hypoxia were also observed [3].
• 3. Endotoxaemia for 6 h caused hypotension, acute renal dysfunction, hepatocellular injury, pancreatic injury and an increase in the plasma levels of 6-keto-PGF1alpha (indicator of the induction of COX-2) and nitrite/nitrate (indicator of the induction of iNOS) [4].
• These events were concomitant with maintenance of a higher production of 6-keto-prostaglandin F1alpha The ability of CHF-1024 to improve postischemic ventricular dysfunction was correlated with a dose-dependent inhibition of the release of both norepinephrine (NE), from sympathetic nerve endings, and TNF-alpha from cardiac tissue [5].

High impact information on C05961

• Further experiments identified this secretagogue as 6-keto-PGF1alpha, a stable hydrolysis product of prostacyclin (PGI2) [6].
• Activated endothelial cells elicit paracrine induction of epithelial chloride secretion. 6-Keto-PGF1alpha is an epithelial secretagogue [6].
• In addition, these data reveal a novel action for the prostacyclin hydrolysis product 6-keto-PGF1alpha and provide a potential endothelial- epithelial crosstalk pathway in mucosal tissue [6].
• In in vitro studies, glyceryl trinitrate, sodium nitroprusside, and 3'-morpholinosydnonimine, at clinically attainable concentrations, increased cyclooxygenase activity in endothelial cells (EC), which resulted in a four- to sixfold release of 6-keto PGF1alpha [7].
• Release of 6-keto PGF1alpha by the NO donors increased the ability of these compounds to inhibit thrombin-induced human platelet aggregation by at least 10 times; this potentiation was inhibited by hemoglobin but not by MeB [7].

Chemical compound and disease context of C05961

• FR167653 had a different pharmacological profile from dexamethasone in the late phase of this model in that, unlike dexamethasone, it did not affect cyclooxygenase-2 expression in mesothelial cells, the 6-keto-prostaglandin F1alpha level in the exudate or hyperplasia of mesothelium [8].
• METHODS: Using a canine model of arterialized vein grafts, prostacyclin production (measured as 6-keto-PGF1a) was assessed in an ex vivo perfusion system from grafts exposed to thrombus for 10 days (group I) and 20 days (group II) [9].
• During pregnancy in both conditions measurements displayed uniform excretion of thromboxane B2 with progressively increased levels of 6-keto-prostaglandin F1alpha in chronic hypertension (R2 = 0.60, p < 0.005) [10].
• In both paired studies renal function was estimated by the clearance (cl.) method and the urinary concentrations of PGE2, 6-keto-PGF1alpha and TXB2 were estimated by RIA during sustained hypotonic polyuria (induced by oral water load) [11].
• However, patients with ovarian cancer excreted increased amounts of 6-keto-PGF1a (55.4 +/- 10.4 pmol/mmol creatinine, n = 11, P less than 0.05), although this bore no relation to tumour histology, clinical stage or the outcome of the patients [12].

Biological context of C05961

• RESULTS: In the analyses of 6-keto PGF1alpha, the level in the carotid arteries was significantly elevated 3 days after PGIS expression-vector transfection compared with that in the arteries after vehicle transfection [13].
• Prostacyclin release from rat isolated perfused hearts and from dog coronary circulation was studied by measuring immunoreactive 6-keto-PGF1 alpha (6-keto-PGF1a) in heart perfusate and in plasma obtained from the great cardiac vein respectively [14].
• Compared with control, perfusion with Px significantly increased perfusion pressure, vascular resistance, and the maternal and fetal secretion rates of lipid peroxides, thromboxane B2 (TXB2) and 6-keto prostaglandin F1alpha [15].
• In study 2, perfusing AA-2414 at a dose of 1 x 10(-5) mol/l completely inhibited Px-induced vasoconstriction and increases in lipid peroxide and TXB2 secretion rates, but only partially inhibited the increase in 6-keto prostaglandin F1alpha secretion [15].
• In shocked rats mercaptoethylguanidine prevented the increase in plasma nitrite/nitrate and 6-keto-prostaglandin F1alpha levels, ameliorated the decrease in mean arterial blood pressure, and inhibited the development of vascular hyporeactivity of the thoracic aorta ex vivo [16].

Anatomical context of C05961

• This was accompanied by a significant increase in the 6-keto-prostaglandin F1alpha content of the thoracic aorta and a marked increase in the cAMP content of the sciatic nerve [17].
• Neutrophil depletion preserved 6-keto PGF1a release after SK + R, whereas 6-keto PGF1a release in the NS-treated, SK + R group was significantly reduced (p < 0.05) [18].
• Superior mesenteric artery flow and splanchnic 6-keto PGF1a (metabolite of PGI2) release were measured [18].
• To investigate whether 20-HETE-induced relaxations were related to release of prostacyclin, we measured the release of 6-keto PGF1alpha, the stable metabolite of prostacyclin, from bovine coronary arteries [19].
• Aspirin treatment inhibited both pulmonary artery and platelet TXB2 production but had no effect on vessel 6-keto-prostaglandin F1alpha [20].

Associations of C05961 with other chemical compounds

• Additionally, increased receptors for chemotactic peptide (fMLPR), increased hydrogen peroxide release in response to phorbol myristic acetate stimulation, and the release of prostaglandins (PGE2 and 6-keto-PGF1a) follow exposure to lymphokine and cell line sources of myeloid colony-stimulating activity (CSA) [21].
• Similarly, PGF2alpha causes translocation of cytosolic phospholipase A2 and also results in a 7-fold increment in the formation of 6-keto-PGF1alpha, whereas 8,12-iso-iPF2alpha-III exerts no effect on this pathway [22].
• However, in acetylsalicylic acid-treated cells, after 6-h stimulation with IL-1alpha, newly synthesized Cox-2 produced less TXB2 than 6-keto-PGF1alpha compared to untreated cells [23].
• RESULTS: CSF concentrations of prostaglandin (PG) E2 were increased fivefold (p < 0.01) and 6-keto-PGF1alpha was decreased fourfold (p < 0.01) in probable AD patients [24].
• Incubation of ciliary body-iris microsomes with (1-14C)--8,11,14-eicosatrienoic acid produced PGF1alpha, PGD1, and PGE1 but no evidence of any thromboxane product or 6-keto-PGF1alpha [25].

Gene context of C05961

• Of the COX metabolites measured, PGE2 was the greatest > 6-keto PGF1a > TXB2 > PGF2a [26].
• The IL-6 blood levels and the ratio of TxB2/6 keto-PgF1alpha blood levels are increased during post-CABG lung injury [27].
• The behavior of plasma AVP, ANP, oxytocin, urinary 6-keto-PGF1alpha (a metabolite of prostacyclin) and urinary AQP-2 excretion were evaluated in all subjects [28].
• COX activity was measured by the production of 6-keto-PGF1alpha, PGE2, PGF2alpha and thromboxane B2 (TXB2) in the presence of exogenous arachidonic acids (10 microM for 10 min) using enzyme immunoassay (EIA) [29].
• In the presence of IL-1beta, PGE2, 15d-PGJ2, 6-keto PGF1alpha and PGF2alpha each enhanced COX-2 protein expression between 5- to 20-fold [30].

Analytical, diagnostic and therapeutic context of C05961

• In summary, these findings reveal a previously unappreciated 6-keto-PGF1alpha receptor on intestinal epithelia, the ligation of which results in activation of electrogenic Cl- secretion [6].
• Urinary excretion of 6-keto-prostaglandin F1alpha and thromboxane B2, the major metabolites of prostacyclin and of thromboxane A2, respectively, was measured by specific radioimmunoassays in five female patients with Bartter's syndrome and in five normal female controls [31].
• METHODS AND RESULTS: Thrombin receptor expression was assessed by Northern and Western blot analyses and functionally by measuring the release of 6-keto prostaglandin F1alpha [32].
• Analysis of eicosanoid synthesis in HMC by reversed-phase HPLC revealed that 6-keto-PGF1alpha, the spontaneous hydrolysis product of prostacyclin (PGI2), and prostaglandin E2 (PGE2) were the main eicosanoids produced [33].
• The single-step immunoassay for 6-keto-prostaglandin F1alpha reported here was developed using the bioluminescent protein aequorin as a label [34].

References