Background and Purpose—Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS). An elevation of plasma ADMA levels is associated with cardiovascular disease. ADMA is hydrolyzed by dimethylarginine dimethylaminohydrolases (DDAHs). The goal of this study was to determine whether overexpression of human DDAH-1 in transgenic (DDAH-1–Tg) mice inhibits the vascular effects of ADMA.

Methods—Using nontransgenic (non-Tg) and DDAH-1–Tg mice, we compared responses of the carotid artery and aorta (in vitro) and of the cerebral arterioles (in vivo) in the absence or presence of ADMA. DDAH-1 expression and plasma levels of ADMA were also measured.

Results—Western blotting indicated that vascular expression of DDAH-1 was increased markedly in DDAH-1–Tg mice. Plasma levels of ADMA were reduced by 50% in DDAH-1–Tg mice compared with non-Tg mice (0.19±0.02 vs 0.37±0.04 µmol/L, P<0.05). Contraction of the aorta to nitro-L-arginine methyl ester (an inhibitor of NOS), an index of basal production of NO, was increased in DDAH-1–Tg mice compared with controls (50±4% vs 34±4%, P<0.05). Relaxation of the carotid artery to acetylcholine (an endothelium-dependent agonist) was enhanced in DDAH-1–Tg animals compared with control mice (relaxation of 74±6% vs 59±5%, respectively, in response to 10 µmol/L acetylcholine, P<0.05). ADMA (100 µmol/L) impaired the vascular response to acetylcholine in both non-Tg and DDAH-1–Tg mice, but the relative difference between the 2 strains remained. Responses to the endothelium-independent NO donor nitroprusside were similar in all groups. In vivo, ADMA (10 µmol/L) reduced responses of the cerebral arterioles to acetylcholine by 70% in non-Tg mice (P<0.05), and this inhibitory effect was largely absent in DDAH-1–Tg mice.

Conclusions—These findings provide the first evidence that overexpression of DDAH-1 increases basal levels of vascular NO and protects against ADMA-induced endothelial dysfunction in the cerebral circulation.