| 2,3-Dinor-5,6-dihydro-15-F(2t)-isoprostane: a bioactive prostanoid metabolite. | |
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MedLine Citation:
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PMID: 11448840 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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15-F(2t)-isoprostane (15-F(2t)-IsoP), also termed 8-isoprostaglandin F(2alpha), is one of a series of prostanoids formed by free radical-mediated peroxidation of arachidonic acid and exerts potent biological actions such as vasoconstriction. We recently demonstrated that 15-F(2t)-IsoP is metabolized in humans to a major metabolite, 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP (15-F(2t)-IsoP-M). 15-F(2t)-IsoP-M can also potentially be formed as a product of free radical-induced oxidation of the low abundance fatty acid gamma-linolenic acid. We confirmed that 15-F(2t)-IsoP-M is generated during oxidation of gamma-linolenic acid and explored whether it may exhibit biological activity. 15-F(2t)-IsoP-M caused marked constriction of porcine surface retinal and intraparenchymal brain microvessels, comparable to that observed with 15-F(2t)-IsoP. These effects were associated with increased thromboxane A(2) (TXA(2)) formation and were virtually abolished by TXA(2)-synthase and -receptor inhibitors (CGS-12970 and L-670596). Vasoconstriction induced by either 15-F(2t)-IsoP or 15-F(2t)-IsoP-M on perfused ocular choroid was also abrogated by TXA(2)-synthase inhibition as well as by removal of endothelium. Similar to 15-F(2t)-IsoP, 15-F(2t)-IsoP-M evoked vasoconstriction and TXA(2) generation by activating Ca(2+) influx from nonvoltage-gated channels (SK&F96365 sensitive) in the retina and from both nonvoltage- and N-type voltage-gated Ca(2+) channels (omega-conotoxin MVIIA sensitive), respectively, in brain endothelial and astroglial cells; smooth muscle cells were unresponsive to both agents. Cross-desensitization experiments further suggest that 15-F(2t)-IsoP and 15-F(2t)-IsoP-M act on the same receptor mechanism. Findings reveal a novel concept by which a beta-oxidation metabolite of 15-F(2t)-IsoP that can also be formed by nonenzymatic oxidation of gamma-linolenic acid is equivalently bioactive to 15-F(2t)-IsoP and may prolong the vascular actions of F(2)-IsoPs. |
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Authors:
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X Hou; L J Roberts; D F Taber; J D Morrow; K Kanai; F Gobeil; M H Beauchamp; S G Bernier; G Lepage; D R Varma; S Chemtob |
Publication Detail:
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Type: In Vitro; Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: American journal of physiology. Regulatory, integrative and comparative physiology Volume: 281 ISSN: 0363-6119 ISO Abbreviation: Am. J. Physiol. Regul. Integr. Comp. Physiol. Publication Date: 2001 Aug |
Date Detail:
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Created Date: 2001-07-12 Completed Date: 2001-08-30 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 100901230 Medline TA: Am J Physiol Regul Integr Comp Physiol Country: United States |
Other Details:
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Languages: eng Pagination: R391-400 Citation Subset: IM |
Affiliation:
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Departments of Pediatrics and Pharmacology, Centre de Recherche de l'Hôpital Sainte-Justine, Université de Montréal, Montréal, Québec H3T 1C5, Canada. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
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pharmacology Animals Brain / blood supply* Calcium / metabolism Calcium Channel Blockers / pharmacology Carbazoles / pharmacology Dinoprost / analogs & derivatives, chemistry, metabolism, pharmacology* Endothelium, Vascular / drug effects, metabolism Enzyme Inhibitors / pharmacology F2-Isoprostanes Humans Microcirculation / drug effects, metabolism Prostaglandin Antagonists / pharmacology Pyridines / pharmacology Retinal Vessels / drug effects*, metabolism Swine Thromboxane A2 / antagonists & inhibitors, metabolism Vasoconstriction / drug effects* Vasoconstrictor Agents / chemistry, metabolism, pharmacology* gamma-Linolenic Acid / chemistry, metabolism |
| Chemical | |
Reg. No./Substance:
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0/2,3-dinor-5,6-dihydro-15-F-isoprostane; 0/Calcium Channel Blockers; 0/Carbazoles; 0/Enzyme Inhibitors; 0/F2-Isoprostanes; 0/Prostaglandin Antagonists; 0/Pyridines; 0/Vasoconstrictor Agents; 121083-05-4/L 670596; 27415-26-5/8-epi-prostaglandin F2alpha; 506-26-3/gamma-Linolenic Acid; 551-11-1/Dinoprost; 57576-52-0/Thromboxane A2; 7440-70-2/Calcium; 76898-47-0/15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 87627-28-9/3-methyl-2-(3-pyridyl)-1-indoleoctanoic acid |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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