Obesity may account for as much as 65% to 75% of human essential hypertension in most industrialized countries. Excess renal sodium reabsorption and a hypertensive shift of renal-pressure natriuresis play a key role in mediating obesity hypertension. Sympathetic activation contributes to obesity-induced sodium retention and hypertension because adrenergic blockade or renal denervation markedly attenuates these changes. Recent observations suggest that leptin and its multiple interactions with other neurochemical pathways in the hypothalamus may be a partial link between excess weight gain and increased sympathetic activity. Short-term administration of leptin into the cerebral ventricles increases renal sympathetic activity, and long-term intravenous leptin infusions in nonobese rodents at rates that raise plasma concentrations to the levels found in severe obesity increase arterial pressure and heart rate through adrenergic activation. Also, transgenic mice that overexpress leptin develop hypertension. Acute studies suggest that the renal sympathetic effects of leptin may depend on interactions with other neurochemical pathways in the hypothalamus, including melanocortin-4 receptors. However, it is unclear whether this pathway or others, such as neuropeptide Y, mediate the long-term effects of leptin on blood pressure. In addition, leptin has other actions, such as stimulation of nitric oxide formation and enhancement of insulin sensitivity, which may tend to reduce blood pressure in some conditions. Although the precise role of these complex interactions in human obesity has not been elucidated, this is an important area for further investigation, especially considering the current epidemic of obesity in most industrialized countries.

Abstract-This study was designed to determine the role of changes in adrenergic activity in mediating the chronic cardiovascular, renal, and metabolic actions of leptin. Male Sprague-Dawley rats were implanted with catheters for mean arterial pressure (MAP) and heart rate (HR) measurements and IV infusions of either vehicle (nϭ 7) or ␣-and ␤-adrenergic receptor antagonists, terazosin and propranolol (10 mg/kg/d; nϭ 8) throughout the study. After control measurements, murine leptin was infused IV (1.0 g/kg/min) for 7 days along with vehicle or adrenergic antagonists, followed by a 7-day recovery period. Leptin infusion significantly reduced food intake in control rats from 22.6Ϯ0.8 to 10.6Ϯ0.4 g/d and, in adrenergic blockade rats, from 22.6Ϯ0.8 to 13.2Ϯ0.8 g/d. Fasting plasma insulin decreased from 48Ϯ10 to 5Ϯ2 U/mL in control rats and from 51Ϯ9 to 9Ϯ2 U/mL in adrenergic blockade rats during leptin infusion. Leptin infusion did not significantly alter glomerular filtration rate in either group. MAP and HR increased by 6Ϯ1 mm Hg and 23Ϯ7 bpm after 7 days of leptin infusion in control rats. However, in adrenergic blockade rats, leptin infusion did not significantly alter MAP (Ϫ1Ϯ1 mm Hg) and decreased, rather than increased, HR (Ϫ23Ϯ8 bpm). These results indicate that leptin-induced increases in blood pressure and tachycardia are mediated by increased adrenergic activity and support the concept that leptin may be an important link between obesity, increased sympathetic activity, and hypertension. However, the chronic effects of leptin on insulin and glucose regulation do not appear to be altered by ␣-and ␤-adrenergic receptor blockade. Key Words: hypertension, obesity Ⅲ obesity Ⅲ nervous system, sympathetic Ⅲ kidney Ⅲ blood pressure.T he sympathetic nervous system appears to play a major role in mediating obesity-associated hypertension in experimental animals as well as in humans. 1,2 Pharmacologic blockade of the sympathetic nervous system or renal denervation markedly attenuates sodium retention and hypertension associated with a high-fat diet in experimental animals, 3,4 and pharmacologic blockade of adrenergic activity reduces blood pressure to a greater extent in obese than in lean hypertensive patients. 5 However, the mechanisms that link obesity and increased sympathetic activity are still poorly understood.Although the mechanisms that mediate sympathetic activation and hypertension in obesity have not been elucidated, recent studies suggest that hyperleptinemia is a possible candidate. Infusions of leptin, intravenous (IV) or intracerebroventricular (ICV), increased sympathetic activity in the kidneys, adrenals, and brown adipose tissue. 6,7 Chronic leptin infusions in rats, at rates that increased plasma concentrations to about 94 ng/mL, raised mean arterial pressure (MAP) and heart rate (HR) despite marked reductions in food intake. 8 Also, transgenic mice overexpressing leptin have higher blood pressures than control mice. 9 Finally, obese mice that are leptin deficient are not hypertensive and have sli...

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Despite considerable progress in understanding the pathophysiology of obesity, there are still no specific guidelines for the treatment of obesity hypertension other than weight reduction. Special considerations for obese hypertensive patients, in addition to controlling blood pressure, are correcting the metabolic abnormalities and protecting the kidneys from injury. This remains an important area for further research, especially in view of the current 'epidemic' of obesity in most industrialized countries.