2,3-Dinor-5,6-dihydro-15-F(2t)-isoprostane: a bioactive prostanoid metabolite

Am J Physiol Regul Integr Comp Physiol. 2001 Aug;281(2):R391-400. doi: 10.1152/ajpregu.2001.281.2.R391.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / pharmacology
  • Animals
  • Brain / blood supply*
  • Calcium / metabolism
  • Calcium Channel Blockers / pharmacology
  • Carbazoles / pharmacology
  • Dinoprost / analogs & derivatives
  • Dinoprost / chemistry
  • Dinoprost / metabolism
  • Dinoprost / pharmacology*
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Enzyme Inhibitors / pharmacology
  • F2-Isoprostanes
  • Humans
  • In Vitro Techniques
  • Microcirculation / drug effects
  • Microcirculation / metabolism
  • Prostaglandin Antagonists / pharmacology
  • Pyridines / pharmacology
  • Retinal Vessels / drug effects*
  • Retinal Vessels / metabolism
  • Swine
  • Thromboxane A2 / antagonists & inhibitors
  • Thromboxane A2 / metabolism
  • Vasoconstriction / drug effects*
  • Vasoconstrictor Agents / chemistry
  • Vasoconstrictor Agents / metabolism
  • Vasoconstrictor Agents / pharmacology*
  • gamma-Linolenic Acid / chemistry
  • gamma-Linolenic Acid / metabolism


  • 2,3-dinor-5,6-dihydro-15-F-isoprostane
  • Calcium Channel Blockers
  • Carbazoles
  • Enzyme Inhibitors
  • F2-Isoprostanes
  • Prostaglandin Antagonists
  • Pyridines
  • Vasoconstrictor Agents
  • L 670596
  • 8-epi-prostaglandin F2alpha
  • Thromboxane A2
  • 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
  • gamma-Linolenic Acid
  • 3-methyl-2-(3-pyridyl)-1-indoleoctanoic acid
  • Dinoprost
  • Calcium