Role of Nitric Oxide in Modulating the Chronic Cardiovascular and Renal Actions of Leptin

Abstract

64 Acute studies suggest that leptin has pressor and depressor actions, including stimulation of sympathetic activity as well as increased release of nitric oxide (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 hypertension. Male Sprague-Dawley rats were implanted with arterial and venous catheters and mean arterial pressure (MAP) and heart rate (HR) were monitored continuously 24h/d. After a 4 day control period, rats were treated with vehicle (n=6) or L-NAME (n=7) for 7 days. After 7 days of vehicle or L-NAME (10 μg/kg/min) treatment to inhibit NO synthesis, rats received a low rate (0.5 μg/kg/min) leptin infusion for 7 days followed by a moderate rate (1.0 μg/kg/min) leptin infusion 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 leptin+L-NAME rats. The low and moderate leptin infusions reduced food intake by 53±2%and 51±7%, respectively, but L-NAME did not alter the anorectic effect of leptin. Although the low dose of leptin alone did not significantly elevate MAP, it raised HR by 18±3 bpm. The moderate dose of leptin raised MAP from 96±3 to 104±3, but did not increase HR further. In rats pre-treated with L-NAME, the moderate dose of leptin raised MAP by 40±5 mmHg and HR by 73±17 bpm compared to pre-treatment levels. In control L-NAME rats, MAP increased by 31±4 mmHg, while HR was not altered significantly, compared to pre-treatment levels. Chronic leptin infusion alone did not alter glomerular filtration rate (GFR) or renal plasma flow (RPF). However, Leptin+L-NAME reduced GFR by 47±8% and RPF 58±7%; L-NAME alone decreased GFR by 36±11% and RPF 36±17%. Thus, NO does not appear to modulate the anorectic effect of leptin. However, impaired NO synthesis enhances the chronic renal hemodynamic and hypertensive effects of leptin, and greatly amplifies the tachycardia caused by hyperleptinemia, at levels comparable to those found in obesity hypertension.