NIP-261

To understand the direct involvement of hydroxyl radical (.OH) in the modification of functional reactivity in isolated rabbit lingual artery ring preparations, this study was undertaken to examine the effect of .OH generated from dihydroxy fumarate (DHF) plus Fe(3+)-ADP or from H2O2 plus FeSO4. When vasodilators (acetylcholine and nitroglycerin) were given after the .OH-generating system was removed from the organ chamber, the earlier .OH exposure produced an attenuation of the ring relaxation induced by acetylcholine but not that by nitroglycerin. Moreover, the earlier .OH exposure attenuated caffeine-induced contraction and depressed the phasic response, but potently enhanced the tonic response of norepinephrine-induced contraction. Both the enhanced tonic response of KCl-induced contraction produced by earlier .OH exposure and norepinephrine-induced contraction was inhibited by nisoldipine. These results are consistent with the view that .OH radicals can potentiate the voltage-dependent influx of Ca. It is also postulated that .OH may damage sarcoplasmic reticulum (SR) function in the smooth muscle cells, thus reducing Ca release from the SR (this may be reflected by the attenuation of the phasic response), and may selectively attenuate endothelium-dependent relaxation as opposed to endothelium-independent relaxation.

The anti-atherogenic effect of NIP-200 3,5-dimethyl-4,6-diphenyl-tetrahydro-2H-1,3,5-thiadiazine-2-thione ) was studied in experimental models of 1% cholesterol diet (HCD)-fed rabbits. Interference with growth of the animals did not occur in NIP-200-treated rabbits. NIP-200 had no effect on plasma total cholesterol (TC), triglyceride, free cholesterol and phospholipid during the entire experimental period. However, NIP-200 increased high density lipoprotein-cholesterol (HDL-C) at 1, 2, 4 and 6 weeks, although the average rate of increase was not statistically significant. Percentage surface areas of atherosclerotic lesions on the aorta in NIP-200-treated rabbits (26 +/- 6%) was significantly lower than those in HCD-fed rabbits (48 +/- 8%) (P less than 0.05). Histological studies indicated that NIP-200 prevented intimal thickening, proliferation of elastic fibers and fatty necrosis. Thus, NIP-200 prevented the progression of atherosclerosis without affecting the serum TC. The above results suggest that the improvement of lipoprotein metabolism on the arterial wall and the prevention of migration and proliferation of arterial smooth muscle cells may also be important factors in the progression of atherosclerosis.