title: Enhanced coronary vasoconstriction to oxidative stress product, 8-epi-prostaglandinF2 alpha, in experimental hypercholesterolemia.
abstract: OBJECTIVE
  The F2-isoprostanes are a family of novel prostaglandin isomers and a stable product of in vivo oxidative stress. 8-epi-prostaglandinF2 alpha, a member of this isoprostane family, is a vasoconstrictor and its local release may contribute to the abnormal vasomotor tone associated with hypercholesterolemia. We therefore aimed to outline the role of 8-epi-prostaglandinF2 alpha as a coronary vasoconstrictor in experimental hypercholesterolemia.
  
  
  RESULTS
  Pigs were randomized to two experimental groups (each n = 9): normal (N) and high cholesterol (HC) diet. To determine the vasoconstrictive effects of 8-epi-prostaglandinF2 alpha in vitro, doses from 10(-9) to 10(-5) M were used to constrict coronary epicardial rings. Plasma total and LDL cholesterol levels were significantly higher in the HC group compared with the N group (P < 0.005) as were plasma 8-epi-prostaglandinF2 alpha levels (P < 0.001). 8-epi-prostaglandinF2 alpha immunoreactivity was present in the vessel wall in both groups. Normal vessels with intact endothelium (n = 8 rings) contracted to 8-epi-prostaglandinF2 alpha (maximal contraction 15.5 +/- 8.74%). In the HC group, rings with intact endothelium had a greater contractile response to 8-epi-prostaglandinF2 alpha compared to normals (72.3 +/- 7.9%; n = 8; P < 0.0001). This was reversed by preincubation with NOR-3, a NO donor (maximal contraction 6.7 +/- 1.56%; n = 5; P < 0.0001). Enhanced contraction in normal vessels occurred with endothelial denudation (98.4 +/- 3.56%; n = 6; P < 0.0001) and with preincubation of the endothelium-intact rings with L-NMMA (N-monomethyl-L-arginine), an NO synthase inhibitor (85.5 +/- 10.3%, n = 6, P < 0.001). The enhanced contraction seen with hypercholesterolemia did not occur with other prostanoid vasoconstrictors.
  
  
  CONCLUSIONS
  Experimental hypercholesterolemia leads to a significant increase in 8-epi-prostaglandinF2 alpha levels in addition to enhanced 8-epi-prostaglandinF2 alpha-induced coronary vasoconstriction, in vitro. These findings support a role for the F2-isoprostanes in the regulation of coronary vasomotor tone in pathophysiologic states.
authors.affiliation: Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, MN 55905, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Wilson
authors.forename: P J
authors.initials: PJ
authors.lastname: Best
authors.forename: L O
authors.initials: LO
authors.lastname: Lerman
authors.forename: D R
authors.initials: DR
authors.lastname: Holmes
authors.forename: D M
authors.initials: DM
authors.lastname: Richardson
authors.forename: A
authors.initials: A
authors.lastname: Lerman
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001158:Arteries / Q000737:chemistry; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D003331:Coronary Vessels / Q000187:drug effects*; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000032:analysis / Q000494:pharmacology; D015232:Dinoprostone / Q000031:analogs & derivatives / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated; D005260:Female; D006834:Hydrazines / Q000494:pharmacology; D006937:Hypercholesterolemia / Q000378:metabolism*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009574:Nitro Compounds / Q000494:pharmacology; D018384:Oxidative Stress; D011897:Random Allocation; D013552:Swine; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D020030:Nitric Oxide Donors; D009574:Nitro Compounds; D014662:Vasoconstrictor Agents; C075750:8-epi-prostaglandin F2alpha; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C045749:SQ 29548; C061872:FK 409; D001120:Arginine; D002784:Cholesterol; D015237:Dinoprost; D019001:Nitric Oxide Synthase; D015232:Dinoprostone