LDLS IMPAIR VASOMOTOR FUNCTION OF THE CORONARY MICROCIRCULATION - ROLE OF SUPEROXIDE ANIONS

Oxidized LDLs (Ox-LDLs) inhibit endothelium-dependent dilation of isol ated conduit arteries in a manner comparable to the impairment demonst rated in atherosclerotic vessels. However, it is not known whether the microvessels, which do not develop atherosclerotic lesions, are susce ptible to Ox-LDL. Since endothelial release of NO plays an important r ole in vasodilation and since its dysfunction associated with atherosc lerosis has been shown to extend into the coronary microcirculation, w e hypothesized that Ox-LDLs impair endothelium-dependent vasodilation of coronary arterioles by reducing the synthesis and/or release of NO. To test this hypothesis, porcine subepicardial vessels (50 to 100 mu m) were isolated, cannulated, and pressurized to 60 cm H2O without flo w for in vitro study. Isolated vessels developed basal lone and dilate d in a dose-dependent manner to the endothelium-dependent vasodilators serotonin, ATP, and ionomycin. These vasodilatory responses were inhi bited by the NO synthase inhibitor N-G-mono-methyl-L-arginine and were subsequently reversed by extraluminal administration of the NO precur sor L-arginine (3 mmoI/L), suggesting the involvement of NO in these v asomotor responses. Intraluminal incubation of the vessels with native LDL (N-LDL) or Ox-LDL (1 mg protein/mL) significantly attenuated dila tions to serotonin, ATP, and ionomycin. Ox-LDL produced more severe in hibition than did N-LDL, and the inhibitory effect was comparable to t hat of N-G-monomethyl-L-arginine. The inhibitory effects of N-LDL and Ox-LDL were reversed by exogenous L-arginine (3 mmol/L) and were preve nted by sodium dihydroxybenzene disulfonate (Tiron), a cell-permeable superoxide scavenger. In contrast, administration of the cell-impermea ble superoxide scavenger superoxide dismutase prevented the inhibitory effect of N-LDL but not of Ox-LDL. In addition, the inhibitory effect s of LDL were not restored by D-arginine or by removal of intraluminal LDL, Neither N-LDL nor Ox-LDL altered endothelium-independent vasodil ation to sodium nitroprusside. These results indicate that coronary ar terioles are susceptible to LDLs that specifically impair endothelium- dependent vasodilation by reducing NO synthesis. It is suggested that the initiation of superoxide anion production and the subsequent L-arg inine deficiency may be responsible for the detrimental effect of LDL.