Ouabain is a cardiac glycoside produced in the adrenal glands and hypothalamus. It affects the function of all cells by binding to Na+/K+-ATPase. Several lines of evidence suggest that endogenous ouabain could be involved in the pathogenesis of essential (particularly, salt-sensitive) hypertension. However, information regarding the postulated hypertensive effect of the long-term administration of low-dose exogenous ouabain is inconsistent. This study was designed to help settle this controversy through the use of telemetric monitoring of arterial blood pressure and to elucidate the ouabain-induced alterations that could either promote or prevent hypertension. Ouabain (63 and 324 µg/kg/day) was administered subcutaneously to male Wistar rats. Radiotelemetry was used to monitor blood pressure, heart rate and measures of cardiovascular variability and baroreflex sensitivity. The continuous administration of ouabain for 3 months did not elevate arterial blood pressure. The low-frequency power of systolic pressure variability, urinary excretion of catecholamines, and cardiovascular response to restraint stress and a high-salt diet as well as the responsiveness to α1-adrenergic stimulation were all unaltered by ouabain administration, suggesting that the activity of the sympathetic nervous system was not increased. However, surrogate indices of cardiac vagal nerve activity based on heart rate variability were elevated. Molecular remodeling in mesenteric arteries that could support the development of hypertension (increased expression of the genes for the Na+/Ca2+ exchanger and Na+/K+-ATPase α2 isoform) was not evident. Instead, the plasma level of vasodilatory calcitonin gene-related peptide (CGRP) significantly rose from 55 (11, SD) in the control group to 89 (20, SD) pg/ml in the ouabain-treated rats (PTukey's = 18.10(-5)). These data show that long-term administration of exogenous ouabain does not necessarily cause hypertension in rodents. The augmented parasympathetic activity and elevated plasma level of CGRP could be linked to the missing hypertensive effect of ouabain administration.