Biological conversion of 17-alpha-hydroperoxyprogesterone to 11-alpha, 17-alpha-dihydroxyprogesterone.
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Alcohols↗
Biomedical subjects
P Falardeau
Publications and source records attributed to P Falardeau.
Modulation of the contact hypersensitivity response by AE-941 (Neovastat), a novel antiangiogenic agent.
BACKGROUND: AE-941 (Neovastat) is an angiogenesis inhibitor noted to have antiinflammatory properties. OBJECTIVE: We tested Neovastat in a contact hypersensitivity (CHS) model to determine the mechanism of action of its antiinflammatory effects. METHODS: Neovastat was orally administered (200 mg/kg/day) during the sensitization and challenge phases of a murine CHS assay and inflammatory responses were measured. Subsequent assays were performed on mice treated with Neovastat or Cortisone (120 mg/kg/day, IP) and differential mRNA expression of several pro- and antiinflammatory cytokines was quantified using RT-PCR. RESULTS: Neovastat decreased inflammation by 39% when administered during sensitization but did not alter the CHS response when given during the challenge phase. Neovastat significantly induced IL-10 expression in skin and skin-draining lymph nodes (49% and 45%, respectively) and decreased IFNgamma expression in the lymph nodes (35%). CONCLUSION: Antiinflammatory effects of Neovastat observed in CHS could be linked to modulation of cytokines early in the sensitization phase.
Administration, Oral↗
Synthesis of prostaglandins and thromboxane B2 by cholesterol-fed rabbits.
Alterations in the synthesis of thromboxane A2 (TxA2) and prostacyclin have been implicated in the development of atherosclerosis. We measured the amounts of the degradation products of these substances, TxB2 and 6-oxo-prostaglandin F1 alpha (6-oxo-PGF1 alpha), respectively, as well as PGE2, that were synthesized by slices and the luminal surfaces of aortas from rabbits fed either a control diet or a diet supplemented with cholesterol and peanut oil. For these studies, we developed conditions that were designed to minimize the autoinactivation of cyclooxygenase during removal and preparation of the tissue. Pretreatment of aortas with a medium containing ibuprofen and EDTA resulted in an approximately twofold increase in 6-oxo-PGF1 alpha production upon subsequent incubation. Despite the increased lipid peroxidation associated with atherosclerotic lesions, we observed no changes in either aortic 6-oxo-PGF1 alpha production or in the levels of its major urinary metabolite, 2,3-dinor-6-oxo-PGF1 alpha, after as long as 15 weeks of dietary supplementation with cholesterol and peanut oil. Similarly, synthesis of PGE2 by aortic slices and the aortic lumen was the same in cholesterol-fed and control rabbits. In contrast to aortic 6-oxo-PGF1 alpha and PGE2 synthesis, there was a dramatic 10-fold increase in TxB2 released from slices of thoracic aorta after 15 weeks on the atherogenic diet. This was much greater than the approximately twofold increase in the synthesis of TxB2 by the luminal surface of the thoracic aorta, suggesting that the primary site of TxB2 synthesis in the aorta is in the inner part of the blood vessel.(ABSTRACT TRUNCATED AT 250 WORDS)
6-Ketoprostaglandin F1 alpha↗
In vivo production of prostaglandin I2 in Dahl salt-sensitive and salt-resistant rats.
Prostaglandin I2 (PGI2, prostacyclin), a potent vasodilator synthesized by the blood vessels, has been postulated to play a role in hypertension. The purpose of our study was to test this hypothesis by monitoring the in vivo production of PGI2 in Dahl salt-sensitive (S) and salt-resistant (R) rats under normal and high sodium intake. The 24-hour urinary excretion of two endogenous metabolites of PGI2, 2-,3-dinor-6-oxo-PGF1 alpha, an 2,3-dinor-13,14-dihydro-6,15-dioxo-PGF1 alpha was measured by combined gas chromatography-mass spectrometry (GC-MS) and used as an index of the total production of PGI2 by the animals. The pattern of urinary excretion of these two metabolites in the R and the S rats during the control period indicated that, under normal conditions, early in life the basal production of PGI2 was the same in both groups of rats. Following the chronic administration of a high sodium diet (8.1% sodium chloride, starting at 36 days of age), a significant and sustained increase in the urinary excretion of 2,3-dinor-6-oxo-PGF1 alpha was documented in the R rats (from 37 +/- 7 ng/24 hrs at age 35 days to 63 +/- 7, 52 +/- 4, and 56 +/- 10 ng/24 hrs at 50, 60, and 80 days, respectively), whereas the urinary levels of this metabolite decreased slightly in the S rats (from 41 +/- 7 ng/24 hrs at age 35 days to 25 +/- 5, 30 +/- 6, and 28 +/- 9 ng/24 hrs at 50, 60, and 80 days, respectively). During the same period, the R rats remained normotensive (103 +/- 5 mm Hg, systolic pressure) while the arterial pressure of the S rats increased gradually (to 142 +/- 8 and 180 +/- 19 mm Hg at ages 60 and 80 days, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
6-Ketoprostaglandin F1 alpha↗
Defective synthesis of vasodilator prostaglandins in the spontaneously hypertensive rat.
Results of in vitro studies performed in different laboratories have led to the hypothesis that in spontaneously hypertensive rats (SHR), the biosynthesis of the vasodilator prostaglandins (PG) I2 and E2 increases secondarily to the rise in the arterial pressure, as a protective mechanism for reducing the severity of hypertension. In this study, this hypothesis was tested in vivo in SHR and control Wistar-Kyoto (WKY) rats under normal and high sodium diets. The 24-hour urinary excretion of 2,3-dinor-6-oxo-PGF1 alpha, an endogenous metabolite of PGI2, was used as an index of the total production of PGI2 in the rats, whereas the urinary levels of PGE2 were used as an index of the renal production of this prostaglandin. Urinary levels of PGE2, obtained at 10 and 12 weeks of age, were always lower in SHR than in WKY rats and were not influenced by dietary sodium. In WKY and SHR on normal diets, the urinary levels of 2,3-dinor-6-oxo-PGF1 alpha did not differ significantly. However, the chronic administration of a high sodium diet (5.9% NaCl) was accompanied by a significant and sustained rise in the urinary excretion of 2,3-dinor-6-oxo-PGF1 alpha in the order of 30% to 50% in WKY but not in SHR, a finding similar to that in Dahl rats. These results point to the existence of an impaired capacity in SHR to synthesize vasodilator prostaglandins in vivo, contrary to the situation prevailing in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)
6-Ketoprostaglandin F1 alpha↗