EDN1 and endothelial dysfunction: It has been established that the reduced relaxation response to ACh or SNP in SHR, due to endothelial dysfunction, is caused by oxidative stress [64,65], decreased production and bioavailability of NO [66,67,68], eNOS uncoupling [64,69], and hyper-responsiveness to contracting agents such as angiotensin II [70,71,72] and endothelin-1 [73].