Superoxide anion is generated selectively by endothelin‐1 in resistance vessels and enhances their contractility

Reactive oxygen spice (ROS) and endothelin‐1 (ET‐1) contribute to angiotensin‐induced hypertension. We used isolated mesenteric resistance arteries (MRAs) from EC‐SOD knockout (−/ −) mice (n=10) and EC‐SOD wild type (+/+) mice (n=10), as a model to investigate the hypothesis that microvascular ET‐1 and superoxide anion (O 2 .− ) interact to enhance contractility. Tension and O 2 .− were quantitated in real time in dihydroethidium (DHE)‐ loaded MRAs in a myograph equipped with a dual‐emission photon detection fluorescence system to measure ethidium (Eth):DHE ratio (E/D) as a direct readout of O 2 .− activity. Phenylephrine‐induced contractions were similar in MRAs from both groups and did not change E/D ratio. However, ET‐1 induced contractions were significantly increased in −/ − mice (100±3% vs 66±5%, p<0.01) and were accompanied by a selective increased in E/D ratio only in ECSOD−/− mice (3.7±0.5 vs 0.5±0.8, p<0.01). PEG‐SOD normalized augmented ET‐1 contraction (64 ± 4% vs 71 ± 3%; p=ns) and prevent an increase in E/D ratio in MRAs from −/− (0.6±0.5 vs 0.5 ±0.8, p=ns). In summary, ET‐1 generates microvascular O 2 .− that enhances its vasoconstrictive action. This is normally prevented by vascular metabolism of O 2 .− by EC‐SOD which therefore emerges as a major microvascular defense against ROS and vasoconstriction and a potential therapeutically target.