The renal medulla has some of the highest levels of ET-1 and ET_B receptor expression in the body leading to speculation that the endothelin system regulates excretory function. Pharmacological or genetic disruption of ET_B receptors results in hypertension that is exacerbated by a high salt diet. The ET_A receptor generally is thought to oppose the actions of ET_B receptors by promoting renal vasoconstriction as well as inflammation and oxidative stress. We have recently used a method of direct intramedullary infusion of ET-related peptides to demonstrate a direct natriuretic action with the kidney. In male rats, we have observed that intramedullary infusion of the ET_B receptor agonist, sarafotoxin 6c (S6c), produces a dose-dependent natriuresis and diuresis that is independent of any changes in renal perfusion pressure and glomerular filtration rate, but is inhibited by inhibitors of NOS1 and a protein kinase G. In female rats, the natriuretic response to S6c is no different from males, but ET-1 produced a much larger natriuresis and diuresis compared to males. This response was blocked by an ET_A selective antagonist, and was clearly evident in female rats lacking a functional ET_B receptor. Intramedullary ET-1 infusion significantly decreases medullary blood flow in males, but not female rats. These studies clearly demonstrate a potential role for both ET_A and ET_B receptors in the natriuretic actions of ET-1 and may provide important clues for the development of edema in patients during chronic ET receptor blockade as well as a mechanism for reduced salt-dependent hypertension in pre-menopausal women.