We hypothesized that early life stress enhances endothelin (ET-1)-dependent acute stress responses in adulthood. We utilized a unique rat model, wildtype (WT) and ETB receptor-deficient spotting lethal (sl/sl) rats, as well as pharmacological blockade of ET receptors, in a model of early life stress, maternal separation (MS). MS was performed in male WT and sl/sl rats 3 h/day from day 2 to 14 of life. Acute air jet stress (AJS)-induced responses (elevation in blood pressure, plasma corticosterone, and plasma ET-1) were evaluated in adult MS rats compared with the nonhandled littermate (control) rats. MS significantly augmented the acute AJS-induced blood pressure response (area under the curve) in WT rats compared with control, while the AJS-induced pressor responses were similar in sl/sl MS and control rats. ET receptor blockade significantly blunted the AJS-induced pressor response in WT MS and control rats. Moreover, AJS-induced plasma corticosterone levels in control rats were sensitive to ET receptor blockade, yet, AJS did not alter plasma corticosterone levels in MS rats. MS significantly increased circulating ET-1 levels, and AJS-induced plasma ET-1 levels were similarly increased in control and MS rats. MS induced a significant downregulation in expression of ETA and ETB receptors in aortic tissue compared with control rats. These results indicate that early life stress reduced expression of ETA and ETB receptors, leading to alterations in the ET pathway, and an exaggerated acute stress-mediated pressor response in adulthood.early life stress; maternal separation; air jet stress; blood pressure; endothelin; corticosterone IN HUMANS, THERE IS A LARGE body of epidemiological evidence that early social experiences can promote phenotypic changes that persist in adult life (5,12,28). An adverse environment during early life increases the susceptibility to develop heart disease, as well as depression, drug abuse, obesity, and diabetes (21,24,32).Acute behavioral stress responses in adult life are influenced by early life maternal care in both humans (53) and rodents (36). Maternal separation is a widely used animal model of early life stress and chronic behavioral stress (20). Rat pups separated from their mothers daily for a prolonged period (up to 3 h) during the hyporesponsive period display abnormal anxiety-related behavior (41, 43), as well as increased acute behavioral and endocrine stress reactivity as adults (4,27,38,44).Individuals with increased susceptibility to stressors may also have an exacerbated rise in blood pressure (26). Acute stressors induce many physiological responses, and greater reactivity to stress or delayed poststress recovery predicts future cardiovascular disease risk (7), such as stroke (14), hypertension (37), and preclinical atherosclerosis (23,52). An acute stress-induced rise in blood pressure results from autonomic and neuroendocrine-mediated changes in cardiac contractility and peripheral vascular resistance (18). Particularly relevant to this study, acute stress is associa...