2,3-Dinor-5,6-dihydro-15-F(2t)-isoprostane: a bioactive prostanoid metabolite.
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.
Hou
X
X
Departments of Pediatrics and Pharmacology, Centre de Recherche de l'Hôpital Sainte-Justine, Université de Montréal, Montréal, Québec H3T 1C5, Canada.
Roberts
L J
LJ
Taber
D F
DF
Morrow
J D
JD
Kanai
K
K
Gobeil
F
F
Beauchamp
M H
MH
Bernier
S G
SG
Lepage
G
G
Varma
D R
DR
Chemtob
S
S
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000098:blood supply*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D015237:Dinoprost / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D028441:F2-Isoprostanes; D006801:Humans; D066298:In Vitro Techniques; D008833:Microcirculation / Q000187:drug effects / Q000378:metabolism; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012171:Retinal Vessels / Q000187:drug effects* / Q000378:metabolism; D013552:Swine; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017965:gamma-Linolenic Acid / Q000737:chemistry / Q000378:metabolism
C433484:2,3-dinor-5,6-dihydro-15-F-isoprostane; D002121:Calcium Channel Blockers; D002227:Carbazoles; D004791:Enzyme Inhibitors; D028441:F2-Isoprostanes; D011448:Prostaglandin Antagonists; D011725:Pyridines; D014662:Vasoconstrictor Agents; C061299:L 670596; C075750:8-epi-prostaglandin F2alpha; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D017965:gamma-Linolenic Acid; C049113:3-methyl-2-(3-pyridyl)-1-indoleoctanoic acid; D015237:Dinoprost; D002118:Calcium