Inhibition of NO synthesis enhances chronic cardiovascular and renal actions of leptin

Acute studies suggest that leptin has presser and depressor actions, includ ing stimulation of sympathetic activity as well as increased release of NO from the vascular endothelium. The goal of this study was to examine the ro le of NO in modulating the chronic blood pressure, heart rate, and renal re sponses to hyperleptinemia, comparable to that found in obesity-induced hyp ertension. Male Sprague-Dawley rats were implanted with arterial and venous catheters, and mean arterial pressure and heart rate were monitored contin uously 24 h/d. After a 4-day control period, the rats were infused with iso tonic saline vehicle (n=6) or N-G-nitro-L-arginine methyl ester (L-NAME, 10 mug/kg per minute; n=9) to inhibit NO synthesis for 7 days. After 7 days o f vehicle or L-NAME administration, leptin was infused intravenously for 7 days at a rate of 0.5 mug/kg per minute, followed by a leptin infusion at 1 .0 mug/kg per minute for 7 days, along with vehicle or L-NAR IE. A 21-day i nfusion of L-NAME alone (n=6) served as a control for the L-NAME+leptin rat s. Although the low dose of leptin alone did not significantly elevate arte rial pressure, it raised the heart rate by 18 +/-3 bpm. The higher leptin i nfusion rate raised arterial pressure from 96 +/-3 to 104 +/-3 mm Hg but di d not increase the heart rate further. L-NAME+leptin increased arterial pre ssure by 40 +/-6 mm Hg and heart rate by 79 +/- 19 bpm compared with pretre atment levels. In control L-NAME rats, mean arterial pressure increased by 31 +/-4 mm Hg, whereas the heart rate was not altered significantly compare d with pretreatment levels. Neither chronic leptin infusion alone nor L-NAM E alone altered the glomerular filtration rate or renal plasma flow signifi cantly, 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 ef fects of leptin but markedly amplifies the tachycardia caused by hyperlepti nemia.