Sympathoexcitation by Oxidative Stress in the Brain Mediates Arterial Pressure Elevation in Obesity-Induced Hypertension

Abstract

Background-Obesity is one of the major risk factors for cardiovascular disease and is often associated with increased oxidative stress and sympathoexcitation. We have already suggested that increased oxidative stress in the brain modulates the sympathetic regulation of arterial pressure in salt-sensitive hypertension, which is often associated with obesity. The present study was performed to determine whether oxidative stress could mediate central sympathoexcitation in the initial stage of obesity-induced hypertension. Methods and Results-Four-week-old male Sprague-Dawley rats were fed a high-fat (45% kcal as fat) or low-fat (10% kcal as fat) diet for 6 weeks. Fat loading elicited hypertension and sympathoexcitation, along with visceral obesity. In urethane-anesthetized and artificially ventilated rats, arterial pressure and renal sympathetic nerve activity decreased in a dose-dependent fashion when 53 or 105 mol/kg tempol, a membrane-permeable superoxide dismutase mimetic, was infused into the lateral cerebral ventricle. Central tempol reduced arterial pressure and renal sympathetic nerve activity to a significantly greater extent in high-fat diet-fed hypertensive rats than in low-fat diet-fed normotensive rats. Intracerebroventricular apocynin or diphenyleneiodonium, a reduced NADPH oxidase inhibitor, also elicited markedly greater reductions in arterial pressure and renal sympathetic nerve activity in the high-fat diet-fed rats. In addition, fat loading increased NADPH oxidase activity and NADPH oxidase subunit p22 phox , p47 phox , and gp91 phox mRNA expression in the hypothalamus. Key Words: brain Ⅲ hypertension Ⅲ obesity Ⅲ oxidative stress Ⅲ sympathetic nervous system M etabolic syndrome, a complex of highly debilitating disorders that consist of hypertension, diabetes mellitus, and dyslipidemia, is associated with the development of visceral obesity. 1 All of these features are risk factors for atherosclerosis; therefore, the metabolic syndrome results in a high incidence of cardiovascular events. Although hypertension is one of the major components of the metabolic syndrome, the mechanisms through which obesity contributes to hypertension have not been fully elucidated. Conclusions-In Clinical Perspective p 986Sympathetic activation is often associated with obesity. For example, studies using microneurography have consistently shown increased muscle sympathetic nerve activity in obese subjects. 2 Furthermore, muscle sympathetic nerve activity is closely associated with the level of abdominal visceral fat. 3 As expected, a number of studies indicated that sympathetic activation may be involved in obesity-induced hypertension. 4 In young, nondiabetic Japanese men, body mass index correlated with not only mean blood pressure but also pulse rate and plasma norepinephrine. 5 In an animal study, obese Zucker rats, which display hyperphagia-induced obesity caused by a mutation of the leptin receptor, have elevated sympathetic nerve activity and arterial pressure (AP). 6 Autonomic ganglionic blockade decreased m...

Sympathoexcitation by Brain Oxidative Stress Mediates Arterial Pressure Elevation in Salt-Induced Chronic Kidney Disease

“…We evaluated the responses of renal sympathetic nerve activity (RSNA) and arterial pressure to acute intracerebroventricular (ICV) administration of an antioxidant agent, Tempol, and the level of ROS in the hypothalamus. In our previous reports, [17][18][19] we showed the effects of acute ICV Tempol but did not show the effects of chronic ICV Tempol. Thus, our previous data only suggested a pathophysiological role of brain ROS but did not show the usefulness of central antioxidant treatment.…”

“…We have also shown that increased oxidative stress in the brain elevated arterial pressure, possibly through central sympathoexcitation, in a salt-sensitive hypertension model, Dahl salt-sensitive rats, 18 and in an obesity-induced hypertension model, high-fat diet-fed rats, 19 in both of which systemic ROS overproduction has been reported. 20,21 Similarly, increased oxidative stress has also been reported in CKD.…”

“…Mean arterial pressure (MAP) was recorded in the conscious state after waiting for 3 hours for recovery from anesthesia, as described previously. [17][18][19] After the baseline MAP measurement, the response of the MAP to a ganglionic blockade was examined by injecting IV 30 mg/kg of body weight of hexamethonium hydrochloride, to evaluate systemic sympathetic nerve activity. The maximal decrease in the MAP was considered as an index of sympathetic activity.…”

“…[17][18][19]34 The distal ends of real nerves were cut to measure their efferent discharge. For detailed methods about how to record RSNA, please see the online Data Supplement (available at http://hyper.ahajournals.org).…”

Artificial microRNA interference targeting AT1a receptors in paraventricular nucleus attenuates hypertension in rats

“…44 A depressor effect was induced by intravenous administration of hexamethonium hydrochloride (30 mg kg À1 ). The maximal decrease in the MAP was considered as an index of sympathetic activity.…”