title: Enhanced endothelial adhesiveness in hypercholesterolemia is attenuated by L-arginine.
abstract: BACKGROUND
  We have shown that chronic administration of the nitric oxide (NO) precursor L-arginine normalizes NO-dependent vasodilation and markedly inhibits atherogenesis in a hypercholesterolemic rabbit model. We hypothesized that this antiatherogenic effect is due to modulation of endothelial adhesiveness by endothelium-derived NO.
  
  
  RESULTS
  New Zealand White rabbits were fed normal chow (Cont), a high-cholesterol diet (Chol), a high-cholesterol diet supplemented with L-arginine (Arg), or a normal diet supplemented with the NO synthase antagonist L-nitroarginine (L-NA) for 2 weeks. In additional studies, some animals receiving L-NA were also treated with hydralazine to normalize blood pressure. After 2 weeks, thoracic aortas were harvested, opened longitudinally, and placed in a culture dish with the endothelial surface exposed to medium containing WEHI 78/24 cells, a monocytoid cell line. After incubation with the monocytoid cells for 30 minutes on a rocking platform, the aortic segments were washed repeatedly to remove nonadherent cells and adherent cells counted by epifluorescent microscopy. Monocytoid cell binding to aortic endothelium was significantly increased in Chol (P < .001 versus Cont); binding was markedly reduced in arginine-fed hypercholesterolemic animals (P < .05, Arg versus Chol). Monocytoid cell binding to aortic endothelium was also significantly increased in L-NA (P < .05); hydralazine normalized blood pressure but did not reduce monocytoid cell binding. To confirm that alterations in NO activity modulate endothelial cell-monocyte interaction, the release of nitrogen oxides (NOx) by thoracic aortas was assessed by a chemiluminescent technique. The concentration of NOx in the conditioned medium from segments of Arg thoracic aortas was significantly greater than that from Cont aortas, whereas that from L-NA aortas was significantly less.
  
  
  CONCLUSIONS
  Hypercholesterolemia enhances the adhesiveness of aortic endothelium for monocytes; this effect is attenuated by dietary L-arginine. Conversely, inhibition of NO synthesis enhances monocyte binding. The results suggest that endothelium-derived NO plays an important role in regulating the endothelial adhesiveness for monocytes. Alterations in NO activity may play a critical role in atherogenesis.
authors.affiliation: Division of Cardiovascular Medicine, Stanford University School of Medicine, Calif. 94305.
authors.forename: P S
authors.initials: PS
authors.lastname: Tsao
authors.forename: L M
authors.initials: LM
authors.lastname: McEvoy
authors.forename: H
authors.initials: H
authors.lastname: Drexler
authors.forename: E C
authors.initials: EC
authors.lastname: Butcher
authors.forename: J P
authors.initials: JP
authors.lastname: Cooke
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D006937:Hypercholesterolemia / Q000473:pathology*; D008297:Male; D009000:Monocytes / Q000502:physiology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000502:physiology*; D019335:Nitroarginine; D011817:Rabbits; D013481:Superoxides / Q000378:metabolism
chemical_list: D002791:Cholesterol, Dietary; D013481:Superoxides; D019335:Nitroarginine; D009569:Nitric Oxide; D001120:Arginine