CYCLOOXYGENASE-DEPENDENT VASOCONSTRICTOR ALTERS VASCULAR FUNCTION IN THE VITAMIN-E-DEPRIVED RAT

We tested the hypothesis that increased production of lipid peroxides, mediated by a dietary vitamin E deprivation, would alter the cyclooxy genase pathway of arachidonate metabolism, resulting in impaired endot helium-dependent vascular function. Mesenteric arteries from control ( n=12) and vitamin E-deprived (n=12) Sprague-Dawley rats were studied i n a myograph. Endothelium-dependent relaxations to methacholine were s imilar in the arteries from vitamin E-deprived rats compared with cont rol arteries (EC50, 0.057+/-0.006 versus 0.065+/-0.009 muM). However, in the arteries from the vitamin E-deprived rats, this response was po tentiated in the presence of a cyclooxygenase inhibitor (1 muM meclofe namate; EC50, 0.035+/-0.003 versus 0.057+/-0.006 muM; P<.05) or thromb oxane A2/prostaglandin H-2 receptor blocker (1 muM SQ 29548; EC50 0.02 9+/-0.002 versus 0.057+/-0.006 muM; P<.05) but had no effect on the ar teries from the control rats. Endothelium-independent relaxations to s odium nitroprusside were not effected by vitamin E deprivation. Arachi donic acid increased tension twofold more in the arteries from the vit amin E-deprived rats compared with the control rats (at 1 muM; 0.43+/- 0.05 versus 0.23+/-0.03 mN/mm; P<.05). The enhanced vasoconstriction w as blunted, and the group difference was eliminated by a cyclooxygenas e inhibitor (0.15+/-0.02 versus 0.43+/-0.05 mN/mm, P<.05) or a thrombo xane A2/Prostaglandin H-2 receptor blocker (0.17+/-0.04 versus 0.43+/- 0.05 mN/mm, P<.05). Prostaglandin endoperoxide synthase expression, de termined by Western immunoblotting on aortas from the same rats, was i ncreased in the vitamin E-deprived rats (3.14+/-0.8 versus 1.06+/-0.4 fmol/ng DNA, P<.05). In summary, mesenteric arteries from the vitamin E-deprived rats demonstrated altered endothelium-dependent responses t hat were in part due to a cyclooxygenase-dependent vasoconstrictor bin ding to the thromboxane A2/prostaglandin H-2 receptor. In the aorta, t here was an associative increase in the expression of prostaglandin en doperoxide synthase. We speculate that, in some vascular diseases, inc reased lipid peroxidation may influence endothelium-dependent vascular function by modulating the cyclooxygenase pathway of arachidonate met abolism.