IMPAIRMENT OF VASCULAR FUNCTION IS ASSOCIATED WITH AN AGE-RELATED INCREASE OF LIPID-PEROXIDATION IN RATS

We tested the hypothesis that an increase in endogenous lipid peroxida tion over time is associated with an impairment of endothelium-depende nt vascular function in resistance-sized mesenteric arteries that is d ue in part to alterations of arachidonate metabolism. Susceptibility t o red blood cell hemolysis and sera levels of malondialdehyde were inc reased (P < 0.05) from 20 wk (n = 12) to 40 wk (n = 12) in female Spra gue-Dawley rats. Arteries were studied in a myograph by examining the endothelial modification of phenylephrine vasoconstriction and the rel axation responses of the mesenteric arteries to methacholine. We obser ved the following. 1) An increase in sensitivity to al-adrenergic stim ulation occurred between 20 and 40 wk of age. Cyclooxygenase inhibitio n decreased the sensitivity to phenylephrine only in the arteries from the 40-wk-old rats, indicating that a cyclooxygenase-dependent vasoco nstrictor was modifying the phenylephrine response. 2) Nitric oxide sy nthase inhibition caused a greater increase in phenylephrine sensitivi ty in the arteries from the 20-wk-old rats than those from the 40-wk-o ld rats, indicating that nitric oxide modification of phenylephrine se nsitivity decreased with age. 3) Endothelium-independent relaxations w ere not affected between 20 and 40 wk of age. 4) At 40 wk, the sensiti vity to the methacholine-mediated relaxation response decreased withou t impairing the maximal relaxation response. This reduced sensitivity was removed with cyclooxygenase inhibition or thromboxane A(2)/prostag landin H-2 (PGH(2)) receptor blockade. 5) Aortas from the 40-wk-old ra ts had an increased expression of PGH synthase. Collectively, these ob servations indicate that, in the female rat, an increase in lipid pero xidation over time is associated with changes in endothelium-dependent vascular function that were due in part to a cyclooxygenase-dependent vasoconstrictor.