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

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Abstract
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