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Inhibition of NO Synthesis Enhances Chronic Cardiovascular and Renal Actions of Leptin

Acute studies suggest that leptin has pressor and depressor actions, including stimulation of sympathetic activity as well as increased release of NO from the vascular endothelium. The goal of this study was to examine the role of NO in modulating the chronic blood pressure, heart rate, and renal responses to hyperleptinemia, comparable to that found in obesity-induced hypertension. Male Sprague-Dawley rats were implanted with arterial and venous catheters, and mean arterial pressure and heart rate were monitored continuously 24 h/d. After a 4-day control period, the rats were infused with isotonic saline vehicle (n=6) or NG-nitro-l-arginine methyl ester (L-NAME, 10 &mgr;g/kg per minute; n=9) to inhibit NO synthesis for 7 days. After 7 days of vehicle or L-NAME administration, leptin was infused intravenously for 7 days at a rate of 0.5 &mgr;g/kg per minute, followed by a leptin infusion at 1.0 &mgr;g/kg per minute for 7 days, along with vehicle or L-NAME. A 21-day infusion of L-NAME alone (n=6) served as a control for the L-NAME+leptin rats. Although the low dose of leptin alone did not significantly elevate arterial pressure, it raised the heart rate by 18±3 bpm. The higher leptin infusion rate raised arterial pressure from 96±3 to 104±3 mm Hg but did not increase the heart rate further. L-NAME+leptin increased arterial pressure by 40±6 mm Hg and heart rate by 79±19 bpm compared with pretreatment levels. In control L-NAME rats, mean arterial pressure increased by 31±4 mm Hg, whereas the heart rate was not altered significantly compared with pretreatment levels. Neither chronic leptin infusion alone nor L-NAME alone altered the glomerular filtration rate or renal plasma flow significantly, but L-NAME+leptin reduced glomerular filtration rate by 27±11% and renal plasma flow by 47±9%. These results indicate that impaired NO synthesis mildly enhances the chronic renal hemodynamic and hypertensive effects of leptin but markedly amplifies the tachycardia caused by hyperleptinemia.