Abstract 2461: Leptin Stimulates both Endothelin and Nitric Oxide Activity in the Human Forearm Circulation
Obesity is associated with increased plasma leptin concentrations that are an independent risk factor for cardiovascular disease. However, experimental studies have shown that leptin also has vasodilator effects mediated by nitric oxide (NO)-dependent mechanisms. Taken together, these observations raise the possibility that, in the human circulation, vasodilator actions of leptin to stimulate production of NO may be opposed by the release of other substances with vasculotoxic properties. To test this hypothesis, we determined hemodynamic responses to inhibition of endothelin (ET)-1 and NO activity, two endothelium-derived substances with opposing vasoactive effects, in the absence and the presence of hyperleptinemia in humans. Bioactivity of ET-1 and NO was assessed without leptin and during leptin infusion in the forearm circulation of lean healthy subjects (n=6) by use of a blocker of the ETA receptor subtype (BQ-123, 10 nmol/min for 60 min) and by NO synthesis inhibition (L-NMMA, 4 μmol/min for 15 min). In the absence of hyperleptinemia, ETA receptor blockade significantly increased forearm blood flow (23±7% at 60 min; P<0.001 vs. baseline). Intra-arterial leptin administration, at a dose (2 μg/min) aimed to achieve intravascular concentrations similar to those present in obesity, did not significantly modify unstimulated forearm blood flow (P=0.18). In the presence of hyperleptinemia, however, ET-1 receptor antagonism resulted in a vasodilator response (61±8%) significantly higher than in the absence of hyperleptinemia (P=0.005). Moreover, the vasoconstrictor response to NO inhibition by L-NMMA during ETA receptor blockade was significantly higher after leptin infusion (41±3%) than before (29±4%; P=0.015). Taken together, these findings suggest that, in the skeletal muscle microvascular bed, leptin stimulates both ET-1 and NO activity. Imbalance between the release of these two substances with opposing vascular actions may be involved in the pathophysiology of hypertension and atherosclerosis in leptin-resistant states associated with endothelial dysfunction, including obesity and type 2 diabetes.