Enhanced coronary vasoconstriction to oxidative stress product, 8-epi-prostaglandinF(2 alpha), in experimental hypercholesterolemia

Objectives: The F-2-isoprostanes are a family of novel prostaglandin isomer s and a stable product of in vivo oxidative stress. 8-epi-prostaglandinF(2 alpha), a member of this isoprostane family, is a vasoconstrictor and its l ocal release may contribute to the abnormal vasomotor tone associated with hypercholesterolemia. We therefore aimed to outline the role of 8-epi-prost aglandinF(2 alpha) as a coronary vasoconstrictor in experimental hyperchole sterolemia. Methods and results: Pigs were randomized to two experimental g roups (each n=9): normal (N) and high cholesterol (HC) diet. To determine t he vasoconstrictive effects of 8-epi-prostaglandinF(2 alpha) in vitro, dose s 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 H C group compared with the N group (P<0.005) as were plasma 8-epi-prostaglan dinF(2 alpha) levels (P<0.001). 8-epi-prostaglandinF(2 alpha) immunoreactiv ity was present in the vessel wall in both groups. Normal vessels with inta ct endothelium (n=8 rings) contracted to 8-epi-prostaglandinF(2 alpha) (max imal contraction 15.5+/-8.74%). In the HC group, rings with intact endothel ium had a greater contractile response to 8-epi-prostaglandinF(2 alpha) com pared to normals (72.3+/-7.9%; n=8; P<0.0001). This was reversed by preincu bation with NOR-3, a NO donor (maximal contraction 6.7+/-1.56%; n=5; P<0.00 01). Enhanced contraction in normal vessels occurred with endothelial denud ation (98.4+/-3.56%; n=6; P<0.0001) and with preincubation of the endotheli um-intact rings with L-NMMA (N-monomethyl-L-arginine), an NO synthase inhib itor (85.5+/-10.3%, n=6, P<0.001), The enhanced contraction seen with hy pe rcholesterolemia did not occur with other prostanoid vasoconstrictors. Conc lusion: Experimental hypercholesterolemia leads to a significant increase i n 8-epi-prostaglandinF(2 alpha) levels in addition to enhanced 8-epi-prosta glandinF(2 alpha)-induced coronary vasoconstriction, in vitro. These findin gs support a role for the F-2-isoprostanes in the regulation of coronary va somotor tone in pathophysiologic states. (C) 1999 Elsevier Science B.V. All rights reserved.