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2,3-Dinor-5,6-dihydro-15-F(2t)-isoprostane: a bioactive prostanoid metabolite
X Hou1, L J Roberts, D F Taber
1Departments of Pediatrics and Pharmacology, Centre de Recherche de l'Hôpital Sainte-Justine, Université de Montréal, Montréal, Québec H3T 1C5, Canada.
Summary
A newly identified metabolite of 15-F(2t)-isoprostane, 15-F(2t)-IsoP-M, exhibits potent vasoconstrictive effects comparable to the parent compound. This metabolite, also formed from gamma-linolenic acid, may prolong isoprostane-induced vascular actions.
Area of Science:
- Biochemistry
- Cardiovascular Physiology
- Oxidative Stress
Background:
- 15-F(2t)-isoprostane (15-F(2t)-IsoP) is a prostanoid formed by arachidonic acid peroxidation, known for vasoconstriction.
- A major human metabolite, 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP (15-F(2t)-IsoP-M), was recently identified.
- 15-F(2t)-IsoP-M can also arise from gamma-linolenic acid oxidation.
Purpose of the Study:
- To confirm the generation of 15-F(2t)-IsoP-M from gamma-linolenic acid.
- To investigate the biological activity of 15-F(2t)-IsoP-M, particularly its effect on microvessel constriction.
- To elucidate the mechanisms underlying 15-F(2t)-IsoP-M-induced vasoconstriction.
Main Methods:
- Oxidation of gamma-linolenic acid to generate 15-F(2t)-IsoP-M.
- Assessment of microvessel constriction in porcine retinal and brain tissues.
- Pharmacological inhibition of thromboxane A(2) (TXA(2)) synthase and receptors.
- Investigation of calcium ion (Ca(2+)) influx pathways using specific channel blockers.
- Cross-desensitization studies to compare receptor mechanisms.
Main Results:
- 15-F(2t)-IsoP-M induced significant vasoconstriction in retinal and brain microvessels, comparable to 15-F(2t)-IsoP.
- These effects were linked to increased TXA(2) formation and were inhibited by TXA(2)-related blockers.
- Vasoconstriction involved Ca(2+) influx through nonvoltage-gated channels in the retina and both nonvoltage- and N-type voltage-gated channels in brain.
- Cross-desensitization indicated that 15-F(2t)-IsoP and 15-F(2t)-IsoP-M act via the same receptor.
Conclusions:
- 15-F(2t)-IsoP-M is a bioactive metabolite with potent vasoconstrictive properties.
- Its formation from gamma-linolenic acid and its equivalent bioactivity to 15-F(2t)-IsoP suggest a significant role in vascular regulation.
- The findings reveal a novel mechanism by which isoprostane metabolites can prolong vascular actions.