Endothelial dysfunction in atherosclerotic mice: improved relaxation by combined supplementation with L-arginine-tetrahydrobiopterin and enhanced vasoconstriction by endothelin


Department of Cardiology, Karolinska Hospital, S-171 76 Stockholm, Sweden. E-mail: john.pernow@ks.se


  • Mice lacking the apolipoprotein E and low density lipoprotein receptor genes (E°xLDLR°) develop atherosclerosis and endothelial dysfunction. The aim of this study was to characterize the roles of L-arginine and tetrahydrobiopterin (BH4) for endothelium-dependent relaxation and the changes in the vasoconstrictor response to endothelin-1 (ET-1) in thoracic aortic rings of E°xLDLR° mice.

  • Histological examination revealed severe atherosclerosis of the thoracic aorta of E°xLDLR° mice. Relaxations induced by acetylcholine (Ach), but not that to sodium nitroprusside, were significantly impaired in E°xLDLR° mice compared to control mice indicating attenuated endothelium-dependent relaxations.

  • Preincubation with the nitric oxide (NO) substrate L-arginine did not affect, whereas the co-factor for NO synthase, BH4, slightly improved the relaxations induced by Ach. Combined preincubation with L-arginine and BH4 induced a pronounced enhancement of Ach-induced relaxations in E°xLDLR° mice. The relaxations induced by Ach in E°xLDLR° mice in the presence of L-arginine and BH4 were not different from those observed in control mice.

  • Preincubation with superoxide dismutase did not affect Ach-induced relaxations in aorta from E°xLDLR° mice.

  • The contractile response to ET-1 was enhanced in E°xLDLR° mouse aorta. The contractions were abolished by the ETA receptor antagonist LU 135252. The ETB receptor agonist sarafotoxin 6c did not induce contractions or relaxations.

  • It is concluded that endothelial dysfunction of E°xLDLR° mouse aorta is reversed by combined administration of L-arginine and BH4. In addition, the ETA receptor-mediated vasoconstriction by ET-1 is enhanced in E°xLDLR° mice.

British Journal of Pharmacology (2000) 131, 1255–1261; doi:10.1038/sj.bjp.0703705