© 1999 by European Society of Cardiology
Copyright © 1999, European Society of Cardiology
Enhanced coronary vasoconstriction to oxidative stress product, 8-epi-prostaglandinF2
, in experimental hypercholesterolemia
aDepartment of Internal Medicine, Division of Cardiovascular Diseases, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA
bDepartment of Internal Medicine, Division of Hypertension, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA
* Corresponding author. Tel.: +1-507-255-2446; fax: +1-507-255-2550 lerman.amir{at}mayo.edu
Objectives: The F2-isoprostanes are a family of novel prostaglandin isomers and a stable product of in vivo oxidative stress. 8-epi-prostaglandinF2
, 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 as a coronary vasoconstrictor in experimental hypercholesterolemia. Methods and 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 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 levels (P<0.001). 8-epi-prostaglandinF2 immunoreactivity was present in the vessel wall in both groups. Normal vessels with intact endothelium (n=8 rings) contracted to 8-epi-prostaglandinF2 (maximal contraction 15.5±8.74%). In the HC group, rings with intact endothelium had a greater contractile response to 8-epi-prostaglandinF2 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. Conclusion: Experimental hypercholesterolemia leads to a significant increase in 8-epi-prostaglandinF2 levels in addition to enhanced 8-epi-prostaglandinF2-induced coronary vasoconstriction, in vitro. These findings support a role for the F2-isoprostanes in the regulation of coronary vasomotor tone in pathophysiologic states.
KEYWORDS Coronary circulation; Cholesterol; Vasoconstriction/dilation; Prostaglandins; Free radicals; Nitric oxide
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