The hemodynamic, hormonal, and renal excretory effects of intravenous bolus administration of synthetic murine leptin were examined in groups of anesthetized normotensive (Sprague-Dawley), hypertensive (spontaneously hypertensive), and both lean and obese Zucker rats. In the normotensive animals (n = 8) an intravenous bolus of 400 microgram/kg of leptin produced a significant six- to sevenfold elevation in sodium excretion compared with controls (n = 8). The onset of natriuresis was delayed for approximately 30-45 min. Mean arterial pressure (MAP), creatinine clearance, plasma renin activity (PRA), and plasma aldosterone concentration (PAC) remained unchanged. In contrast, the hypertensive rats were refractory to the natriuretic effects of leptin when infused either with 400 (n = 8) or 1,600 (n = 8) microgram/kg. Also in these animals MAP, creatinine clearance, PRA, and PAC were unmodified. Finally, whereas lean Zucker rats (n = 8) responded very similarly to the Sprague-Dawley animals, the natriuretic effect of the hormone was attenuated in the obese Zucker groups. At 400 microgram/kg (n = 8) no natriuresis was elicited, but at 1,600 microgram/kg (n = 8) a modest but significant two- to threefold increment in sodium excretion was observed in the obese rats. In both Zucker groups, MAP, creatinine clearance, PRA, and PAC were unchanged. Collectively, these results demonstrate a significant natriuretic effect of exogenous leptin in the normal rat and a blunted saluretic response in hypertension and obesity. It is suggested that leptin may be a potential salt-excretory factor in normal rats and may function pathophysiologically in obesity and hypertension.