alpha-(4-pyridyl-1-oxide)-n-tert-butylnitrone and tert-nitrosobutane

Abundant data suggest that the oxidative modification of low-density lipoprotein is mediated by lipid-derived free radicals and aldehydes derived from them. In this report we have addressed the site-specific aspects of low-density lipoprotein modification. To this end, both water-soluble and lipid-soluble spin traps (i.e., diamagnetic organic molecules containing nitroso or nitrone functional groups) were used. Radical adducts were detected by electron spin resonance-spin trapping technique. Biochemical indices of low-density lipoprotein modification were thiobarbituric acid reactive substances formation, electrophoretic mobility and macrophage-mediated uptake of oxidized low-density lipoprotein. Results from this study have shown that the lipophilic spin trap, alpha-phenyl-tert-butyl-N-nitrone, traps a primary low-density lipoprotein lipid-derived radical, while also inhibiting the total oxidative modification in a dose-dependent manner. The more hydrophilic analog, i.e., alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone, appeared to trap the secondary alkyl radicals and did not exert any inhibitory effect on oxidative modification of low-density lipoprotein. The lipophilic nitroso spin trap, 2-methyl-2-nitroso propane, which traps a lipid-derived radical, inhibited the low-density lipoprotein modification as did the water-soluble nitroso analog, 2-hydroxymethyl-2-nitroso propane. However, the water-soluble nitroso analog did not trap the lipid radical. The inhibitory effect of 2-hydroxymethyl-2-nitroso propane was tentatively attributed to trapping of aldehydes. It is conceivable that spin traps can inhibit the oxidative modification of low-density lipoprotein by trapping of the lipid radicals as well as trapping aldehydes formed from lipid peroxidation.

Topics: Animals; Apolipoproteins B; Cell Line; Cyclic N-Oxides; Electron Spin Resonance Spectroscopy; Free Radicals; Humans; Lipid Peroxidation; Lipoproteins, LDL; Macrophages; Models, Chemical; Nitrogen Oxides; Nitroso Compounds; Oxidation-Reduction; Pyridines; Rabbits; Spin Labels; Thiobarbituric Acid Reactive Substances

The objective of this study was to compare the effect of several structurally related nitrone and nitroso spin traps on the function of the isolated bicarbonate-buffer perfused rat heart model. Spin traps investigated were alpha-phenyl-tert-butyl N-nitrone (PBN), alpha-(4-pyridyl-1-oxide)-N-tert-butyl nitrone (POBN), 2-methyl-2-nitroso propane (MNP), 2-hydroxymethyl-2-nitroso propane (MNP/OH), nitrosobenzene (NB), dibromonitrosobenzene-sulfonic acid (DBNBS), and 5,5'-dimethyl-1-pyrroline-N-oxide (DMPO). During perfusion of hearts with increasing concentrations of spin traps, ventricular pressure, coronary flow rate, and heart rate were continuously recorded. The extent of contractile recovery was subsequently measured upon return to spin-trap free perfusion. The percentage of maximum increase in coronary flow with PBN, POBN, MNP, MNP-OH, NB, DBNBS, and DMPO were 11, 40, 45, 66, 28, 28, and 29%, respectively. Thus, all nitroso and nitrone spin traps studied acted as vasodilators. Over the dose range studied, POBN, MNP, MNP/OH, and DMPO did not exert any chronotropic effect. PBN, NB, and DBNBS exerted a negative chronotropic effect at higher concentrations. All spin traps studied, with the exception of DMPO, exerted a negative inotropic effect at the higher concentrations studied. We conclude that all spin traps examined acted as coronary vasodilators. Their negative chronotropic and inotropic effects were minimal in comparison and only manifest at the higher concentrations studied.

Topics: Aerobiosis; Animals; Benzenesulfonates; Cardiovascular Physiological Phenomena; Cardiovascular System; Coronary Circulation; Cyclic N-Oxides; Depression, Chemical; Heart Rate; Heart Ventricles; Mannitol; Nitrogen Oxides; Nitroso Compounds; Perfusion; Pressure; Pyridines; Rats; Rats, Sprague-Dawley; Spin Labels; Vasodilation; Ventricular Function