Pivotal role of nitric oxide in the control of blood pressure after leptin administration.

Abstract

Leptin administration has been shown to increase renal, adrenal, and lumbar sympathetic nerve activity. H o w e v e r, this generalized sympathoexcitatory activity is not always followed by an increase in arterial pressure. The present study tested the hypothesis that leptin induces a release of nitric oxide (NO) that opposes the pressor effect of sympathoexcitation. The effect of intravenous administration of leptin (10, 100, and 1,000 µg/kg body wt) or vehicle on blood pressure (BP), heart rate (HR), and serum nitrite/nitrate concentrations of anesthetized Wistar rats was examined. At 90 min after injection, the three leptin doses tested increased serum NO concentrations 20.5, 33.1, and 89.5%, respectively (P < 0.001 vs. baseline). The eff e c t of leptin on NO concentrations was significantly dosedependent on linear trend testing (P = 0.0001). In contrast, leptin did not change serum nitrite/nitrate concentrations of f a / f a rats. Leptin administration to Wistar rats under NO synthesis inhibition (N -n i t r o -Larginine methyl ester [L-NAME]) produced a statistically significant increase (P < 0.05) in both systolic BP and mean arterial pressure as well as in HR (P < 0.01). Injection of leptin into rats with pharmacologically induced ganglionic blockade (chlorisondamine) was followed by a decrease in BP and HR to values significantly lower (P < 0.01) than those observed with chlorisondamine treatment alone. The leptininduced hypotension observed in the setting of ganglionic blockade was blocked by L-NAME. These findings raise the possibility that the leptin-induced release of NO may contribute to the homeostasis of BP. D i a b e t e s 48: [903][904][905][906][907][908] 1999 O besity is associated with an increased incidence of hypertension and cardiovascular mortality (1-3). However, the mechanisms that link obesity with altered renal function and high blood pressure (BP) have not been fully elucidated. The adipocytederived hormone leptin has been suggested to be implicated in obesity-related hypertension (4). Intracerebroventricular as well as chronic intravenous administration of leptin have been shown to increase both mean arterial pressure (MAP) and heart rate (HR) (5-7). However, some studies have reported that MAP and HR were not changed by acute leptin infusion (7-9).Because leptin binding sites have been found in brain regions that are also important in cardiovascular control (10), there is reason to suspect that leptin may affect cardiovascular function through its effects on the central nervous system (CNS). This possibility is supported by the observation that leptin administration increases sympathetic nerve activity to kidneys, adrenals, and brown adipose tissue (BAT ) (5,8). However, leptin has also been shown to cause natriuresis and diuresis after bolus intravenous infusion (9). Thus, leptin may be influencing different regulatory pathways that have opposite effects on BP control. R e c e n t l y, it has been reported that the functional leptin receptor OB-Rb is expressed in endothelial c...

Leptin is favourably associated with vascular function in obese Caucasians, but not in obese Africans

“…Since leptin's positive [18][19][20] and negative 14,15 influences on vascular function has been reported, partial correlations were performed while adjusting for age to determine if leptin is associated with the obese African group's possible decreased vascular function, or the obese Caucasian group's possible normal or enhanced vascular function. By doing so, leptin failed to show any associations with the vascular profile in the obese African group.…”

“…Additionally, leptin correlated negatively with TPR and positively with C W , implicating leptin as a possible role player in the accommodating effect observed in the obese Caucasian group, but not in the obese African group. One may speculate that this accommodating effect could be the result of leptin's angiogenic 37,38 and/or vasodilatory [18][19][20] effect, which would lead to decreased TPR and increase C W .…”

“…Results in sodium retention and blood pressure elevation 19 Increases plasma angiotensin II, increasing vasoconstriction and blood pressure 19 (e) Leptin has depressor effects by causing vasodilation through nitric oxide dependent and independent mechanisms [18][19][20] What this study adds (a) This is the first study to compare the associations of chronically elevated leptin levels with cardiovascular function between obese African and Caucasian women (b) Chronically elevated leptin levels are favourably associated with vascular function in obese Caucasian women, but not in obese African women African women is supported by results from a recent publication, 21 which showed leptin to be independently associated with SBP and decreased C W in obese hypertensive African women. Since the SBP and DBP of both obese African and Caucasian groups were in the normotensive range, 39 the presence of prominent positive associations between leptin and vascular function in the obese Caucasians and the lack thereof in the obese Africans, could indicate that leptin predominantly exerts pathological influences on vascular function in obese African women, as determined previously in obese hypertensive African women.…”

“…Leptin has been shown, after acute administration, to cause vasodilation through nitric oxide dependent and independent mechanisms, decreasing TPR, increasing C W and decreasing blood pressure. [18][19][20] The above-mentioned studies determined that leptin has pressor and depressor effects that would result in decreased or increased vascular function and elevated or reduced blood pressure as serum leptin levels increase with increased adiposity. Associations of chronically elevated leptin levels with cardiovascular function in obese African women are limited 21 and comparisons of leptin's associations with cardiovascular function between Africans and Caucasians absent.…”

Cardiovascular consequences of obesity and targets for treatment

“…Unfortunately, obesity is associated with relative adiponection deficiency, which thus may contribute to impaired endothelial function. Leptin's effects are more complicated since some studies demonstrate it enhances sympathetic tone while increasing NO production, and others show it improves endothelial-and NO-independent vasodilation [33,34]. Other cytokines from adipocytes, IL-6, FAs, are thought to decrease NO production and so, contribute to impaired endothelial function.…”