Leptin is a peptide hormone produced by adipose tissue which acts centrally to decrease appetite and increase energy expenditure. Although leptin increases norepinephrine turnover in thermogenic tissues, the effects of leptin on directly measured sympathetic nerve activity to thermogenic and other tissues are not known. We examined the effects of intravenous leptin and vehicle on sympathetic nerve activity to brown adipose tissue, kidney, hindlimb, and adrenal gland in anesthetized Sprague-Dawley rats. Intravenous infusion of mouse leptin over 3 h (total dose 10-1,000 g/kg) increased plasma concentrations of immunoreactive murine leptin up to 50-fold. Leptin slowly increased sympathetic nerve activity to brown adipose tissue ( ϩ 286 Ϯ 64% at 1,000 g/kg; P ϭ 0.002). Surprisingly, leptin infusion also produced gradual increases in renal sympathetic nerve activity ( ϩ 228 Ϯ 63% at 1,000 g/kg; P ϭ 0.0008).The effect of leptin on sympathetic nerve activity was dose dependent, with a threshold dose of 100 g/kg. Leptin also increased sympathetic nerve activity to the hindlimb ( ϩ 287 Ϯ 60%) and adrenal gland (388 Ϯ 171%). Despite the increase in overall sympathetic nerve activity, leptin did not increase arterial pressure or heart rate. Leptin did not change plasma glucose and insulin concentrations. Infusion of vehicle did not alter sympathetic nerve activity. Obese Zucker rats, known to possess a mutation in the gene for the leptin receptor, were resistant to the sympathoexcitatory effects of leptin, despite higher achieved plasma leptin concentrations. These data demonstrate that leptin increases thermogenic sympathetic nerve activity and reveal an unexpected stimulatory effect of leptin on overall sympathetic nerve traffic. ( J. Clin. Invest. 1997. 100:270-278.)

Background —Patients with obstructive sleep apnea (OSA) experience repetitive episodic hypoxemia with consequent sympathetic activation and marked blood pressure surges, each of which may impair endothelial function. We tested the hypothesis that patients with OSA have impaired endothelium-dependent vasodilation, even in the absence of overt cardiovascular disease. Methods and Results —We studied 8 patients with OSA (age 44±4 years) and 9 obese control subjects (age 48±3 years). Patients with OSA were newly diagnosed, never treated for OSA, on no medications, and free of any other known diseases. All obese control subjects underwent complete overnight polysomnographic studies to exclude occult OSA. Resistance-vessel function was tested by use of forearm blood flow responses to intra-arterial infusions of acetylcholine (a vasodilator that stimulates endothelial release of nitric oxide), sodium nitroprusside (an exogenous nitric oxide donor), and verapamil (a calcium channel blocker). Conduit-vessel function was also evaluated by ultrasonography. Brachial artery diameter was measured under baseline conditions, during reactive hyperemia (with flow increase causing endothelium-dependent dilatation), and after sublingual administration of nitroglycerin (an endothelium-independent vasodilator). Patients with OSA had a blunted vasodilation in response to acetylcholine ( P <0.007), but responses to sodium nitroprusside and verapamil were not significantly different from those of control subjects. No significant difference in conduit-vessel dilation was evident between OSA patients and obese control subjects. Conclusions —Patients with OSA have an impairment of resistance-vessel endothelium-dependent vasodilation. This may be implicated in the pathogenesis of hypertension and heart failure in this condition.

Abstract-Leptin plays an important role in regulation of body weight through regulation of food intake and sympathetically mediated thermogenesis. The hypothalamic melanocortin system, via activation of the melanocortin-4 receptor (MC4-R), decreases appetite and weight, but its effects on sympathetic nerve activity (SNA) are unknown. In addition, it is not known whether sympathoactivation to leptin is mediated by the melanocortin system. We tested the interactions between these systems in regulation of brown adipose tissue (BAT) and renal and lumbar SNA in anesthetized Sprague-Dawley rats. Intracerebroventricular administration of the MC4-R agonist MT-II (200 to 600 pmol) produced a dose-dependent sympathoexcitation affecting BAT and renal and lumbar beds. This response was completely blocked by the MC4-R antagonist SHU9119 (30 pmol ICV). Administration of leptin (1000 g/kg IV) slowly increased BAT SNA (baseline, 41Ϯ6 spikes/s; 6 hours, 196Ϯ28 spikes/s; Pϭ0.001) and renal SNA (baseline, 116Ϯ16 spikes/s; 6 hours, 169Ϯ26 spikes/s; Pϭ0.014). Intracerebroventricular administration of SHU9119 did not inhibit leptin-induced BAT sympathoexcitation (baseline, 35Ϯ7 spikes/s; 6 hours, 158Ϯ34 spikes/s; Pϭ0.71 versus leptin alone). However, renal sympathoexcitation to leptin was completely blocked by SHU9119 (baseline, 142Ϯ17 spikes/s; 6 hours, 146Ϯ25 spikes/s; Pϭ0.007 versus leptin alone). This study demonstrates that the hypothalamic melanocortin system can act to increase sympathetic nerve traffic to thermogenic BAT and other tissues. Our data also suggest that leptin increases renal SNA through activation of hypothalamic melanocortin receptors. In contrast, sympathoactivation to thermogenic BAT by leptin appears to be independent of the melanocortin system. Key Words: autonomic nervous system Ⅲ renal nerves Ⅲ sympathetic nervous system Ⅲ brain Ⅲ obesity Ⅲ leptin R ecent studies of monogenic animal models of obesity have implicated several molecular mechanisms responsible for body weight control. These factors include leptin, 1 neuropeptide Y (NPY), 2,3 corticotrophin-releasing factor, 4 and the melanocortin system. 5,6 Abnormalities in these systems produce obesity through changes in appetite and food intake. In addition, leptin, neuropeptide Y, and corticotrophin-releasing factor have been shown to influence sympathetic nerve activity (SNA) to brown adipose tissue (BAT), thereby increasing thermogenesis. [7][8][9] In the neural melanocortin system that controls body weight, ␣-melanocyte-stimulating hormone (␣-MSH) derived from proopiomelanocortin (POMC) acts on melanocortin-4 receptors (MC4-Rs) to decrease appetite. 5,6 Obesity in humans has recently been linked to the POMC and MC4-R genes. 10 -12 Melanocortin agonists have been shown to inhibit appetite, but the effects of the melanocortin system on SNA to thermogenic and nonthermogenic tissues are not known. One purpose of this study was to examine the effects of the melanocortin-3 and melanocortin-4 receptor (MC3/4-R) agonist MT-II-Ac-Nle 4 -c[Asp 5 ,D-Phe 7 ,Lys ...

Background-Moderate elevations in plasma homocyst(e)ine concentrations are associated with atherosclerosis and hypertension. We tested the hypothesis that experimental perturbation of homocysteine levels produces resistance and conduit vessel endothelial dysfunction and that this occurs through increased oxidant stress. Methods and Results-Oral administration of L-methionine (100 mg/kg) was used to induce moderate hyperhomocyst(e)inemia (Ϸ25 mol/L) in healthy human subjects. Endothelial function of forearm resistance vessels was assessed by use of forearm vasodilatation to brachial artery administration of the endothelium-dependent dilator acetylcholine. Conduit vessel endothelial function was assessed with flow-mediated dilatation of the brachial artery. Forearm resistance vessel dilatation to acetylcholine was significantly impaired 7 hours after methionine (methionine, 477Ϯ82%; placebo, 673Ϯ110%; Pϭ0.016). Methionine did not alter vasodilatation to nitroprusside and verapamil. Flow-mediated dilatation was significantly impaired 8 hours after methionine loading (0.3Ϯ2.7%) compared with placebo (8.2Ϯ1.6%, Pϭ0.01). Oral administration of the antioxidant ascorbic acid (2 g) prevented methionine-induced endothelial dysfunction in both conduit and resistance vessels (Pϭ0.03). Conclusions-Experimentally increasing plasma homocyst(e)ine concentrations by methionine loading rapidly impairs both conduit and resistance vessel endothelial function in healthy humans. Endothelial dysfunction in conduit and resistance vessels may underlie the reported associations between homocysteine and atherosclerosis and hypertension.Increased oxidant stress appears to play a pathophysiological role in the deleterious endothelial effects of homocysteine.

Sleep apnea elicits increases in blood pressure and endothelin-1, with reductions in both after treatment. Vasoconstrictor and mitogenic effects of endothelin-1 may be implicated in increased cardiovascular risk in patients with obstructive sleep apnea.

Body weight is tightly regulated physiologically. The recent discovery of the peptide hormone leptin has permitted more detailed evaluation of the mechanisms responsible for control of body fat. Leptin is almost exclusively produced by adipose tissue and acts in the CNS through a specific receptor and multiple neuropeptide pathways to decrease appetite and increase energy expenditure. Leptin thus functions as the afferent component of a negative feedback mechanism to control adipose tissue mass. Increasing evidence suggests that leptin may have wider actions influencing autonomic, cardiovascular, and endocrine function. Intravenous leptin increases norepinephrine turnover and sympathetic nerve activity to thermogenic brown adipose tissue. Studies from our laboratory suggest that leptin also increases sympathetic nerve activity to kidney, hindlimb, and adrenal gland. However, systemic administration of leptin does not acutely increase arterial pressure or heart rate in anesthetized animals. Thus, longer-term exposure to hyperleptinemia may be necessary for full expression of the expected pressor effect of renal sympathoexcitation. Alternatively, leptin may have additional cardiovascular actions to oppose sympathetically mediated vasoconstriction. Leptin in high doses increases renal sodium and water excretion, apparently through a direct tubular action. In addition, leptin appears to increase systemic insulin sensitivity, even in the absence of weight loss. Although we are at an early stage of understanding, we speculate that abnormalities in the actions of leptin may have implications for the sympathetic, cardiovascular, and renal changes associated with obesity.

This study prompts three conclusions: (1) leptin-deficient ob/ob mice and agouti yellow obese mice have contrasting blood pressure responses to obesity, (2) obesity does not invariably increase arterial pressure in mice, and (3) the arterial pressure response to obesity may depend critically on the underlying genetic and neuroendocrine mechanisms.

The endothelin ETA/B receptor antagonist TAK-044 decreases peripheral vascular resistance and, to a lesser extent, blood pressure; increases circulating endothelin concentrations; and blocks forearm vasoconstriction to exogenous endothelin-1. These results suggest that endogenous generation of endothelin-1 plays a fundamental physiological role in maintenance of peripheral vascular tone and blood pressure. The vasodilator properties of endothelin receptor antagonists may prove valuable therapeutically.