periods of time, leptin produces increased sodium excretion and urine output with no changes in blood pressure in lean animals (Jackson and Li 1997; Villarreal et al 1998; Beltowski, Wojcicka, Gorny, et al 2002; Beltowski, Jochem, et al 2004). The increased natriuresis and fractional sodium excretion are not accompanied by substantial changes in glomerular filtration rate or the renin–aldosterone axis suggesting a decreased sodium tubular transport. Beltowski, Wojcicka, et al (2002) described a decreased sodium–potassium exchanger (Na/ K-ATPase) activity in the renal medulla following acute leptin administration. New evidence suggests that leptin stimulates systemic NO release which opposes the pressor and antinatriuretic effect of leptin-induced sympathetic activation (Beltowski, Wojcicka, Borkowska, et al 2002; Beltowski, Jochem, et al 2004). In this regard, Vecchione et al (2002) demonstrated that leptin stimulates NO production in endothelial cells and blood vessels. In other studies, leptin evoked a hypotensive effect when the sympathetic nervous system output was blocked pharmacologically, implying a likely leptin-mediated vasorelaxant effect (Fruhbeck 1999; Lembo et al 2000). It has been demonstrated that endogenously-produced NO inhibits renal sodium reabsorption in most of the tubule segments apparently through a decrease in the activity of both apical transporters and basolateral Na/K-ATPases (Ortiz and Garvin 2002). Likewise, Villarreal et al (2004) found that chronic inhibition of NO synthesis impairs the acute leptin-mediated natriuretic effect in normotensive lean rats. The kidney has been shown to express high amounts of leptin receptors (Serradeil-Le Gal et al 1997), yet it is not clear whether leptin evokes a direct effect on leptin receptors or indirectly via induction of NO release in renal tubules. Interestingly, the short-term leptin-induced natriuretic effect seen in lean animals was attenuated in obese rats and was even blunted in spontaneously hypertensive rats (SHR) (Villarreal et al 1998; Beltowski, Wojcicka, Gorny, et al 2002). This suggests a certain level of peripheral leptin resistance, probably as a result of several factors including renal receptor down-regulation induced by long-standing hyperleptinemia (Coatmellec-Taglioni et al 2003) and/or the presence of chronic antinatriuretic mechanisms, typical of these states, such as an enhanced RSNA and renin– angiotensin system (Villarreal et al 1998; Beltowski, Wojcicka, Gorny, et al 2002), which may have overcome leptin-mediated natriuresis. In agreement with this statement, Villarreal et al (2000) found that SHR after renal denervation Vascular Health and Risk Management 2006:2(2) Leptin and hypertension in obesity recovered the sodium excretory capacity in response to acute leptin administration. Chronic effects Conversely, long-term leptin administration increases both RSNA and blood pressure. Recent data indicate that chronic hyperleptinemia decreases natriuresis and urinary excretion of NO metabolites (NOx) (Beltowski, Jamroz-Wisniewska, et al 2004). In humans, a negative correlation between leptin and NOx was observed recently in obese hypertensive individuals (Golan et al 2002). Apparently, long-term hyperleptinemic states like obesity increase the level of systemic and intrarenal oxidative stress, leading to NO deficiency (Beltowski, Wojcicka, et al 2004). Leptin, chronically, would reduce natriuresis by up-regulation of the Na/K-ATPase pump, especially in the renal medulla, thereby promoting sodium retention (Beltowski, Jamroz- Wisniewska, et al 2004). This antinatriuretic response to chronic hyperleptinemia, could be either secondary to renal sympathetic activation (Echtenkamp and Dandridge 1989; Kirchheim et al 1989; Beach 1992) and/or deficiency of systemic and intrarenal NO production (Beltowski, Wojcicka, et al 2004). Chronic inhibition of NO synthesis in the renal medulla may reduce medullary blood flow by 30%, which is associated with sodium retention and high blood pressure (Mattson et al 1994). Supporting these observations, Bickel et al (2001) reported an increased number of different sodium tubular transporters in the kidney of obese rats. These animals exhibited a decreased natriuretic effect after a saline load when compared with their lean age mates. In addition, thiazide-sensitive Na/Cl cotransporters’ abundance has been shown to be associated with inhibition of NO synthesis. Clinical relevance Chronic hyperleptinemia, as mentioned, augments the blood pressure by means of different mechanisms in animal models. In humans, there have been several studies attempting to link leptin to hypertension (Figure 1). Serum leptin levels are elevated in obesity due to increase amount of adipose tissue which is the main source of the hormone and possibly secondary to some degree of central resistance to its action. A number of studies have found leptin to be positively correlated with systolic and diastolic blood pressure in both obese (Kunz et al 2000; Golan et al 2002; Itoh et al 2002; Al-Hazimi and Syiamic 2004; Canatan et al 2004a; Schutte et al 2005) and non-obese individuals (Uckaya et al 1999; Adamczak et al 2000; Takizawa et al 165