Curves relating renal sympathetic nerve activity and mean arterial pressure were derived in conscious rabbits during ramp changes in mean arterial pressure, elicited by perivascular balloon inflation. The renal sympathetic nerve activity-mean arterial pressure relationship consisted of a high-gain sigmoidal region about resting, where renal sympathetic nerve activity rose or fell in response to moderate falls and rises of mean arterial pressure. With larger pressure rises, renal sympathetic nerve activity first fell to a lower plateau and then reversed at even higher mean arterial pressure. When mean arterial pressure was lowered below resting, renal sympathetic nerve activity rose to an upper plateau and then reversed abruptly toward resting at low mean arterial pressure. Both arterial and cardiac baroreceptors exerted substantial inhibitory influences on renal sympathetic nerve activity at all pressure levels. These effects appeared additive over the central high gain region of the curve, but beyond this region there were non-additive interactions. The latter were affected considerably by alfathesin anesthesia. In other experiments, we studied the effects of sustained alterations in resting mean arterial pressure induced by infusing nitroprusside and phenylephrine, which produced rapid resetting of the renal baroreflex. The latter could be accounted for, in part, by resetting of the threshold of the arterial baroreceptors and in part by contributions from other afferents, probably the cardiac receptors. During resetting associated with nitroprusside-induced falls in resting blood pressure, high-gain reflex adjustments in renal sympathetic nerve activity to moderate changes in mean arterial pressure were preserved, but during resetting associated with phenylephrine-induced rises in resting mean mean arterial pressure, the resting renal sympathetic nerve activity lay on the lower curve plateau, resulting in reduction in the apparent gain of the reflex renal sympathetic nerve activity response to moderate changes in mean arterial pressure.

Abstract-The activation of the sympathetic nervous system through the central actions of the adipokine leptin has been suggested as a major mechanism by which obesity contributes to the development of hypertension. However, direct evidence for elevated sympathetic activity in obesity has been limited to muscle. The present study examined the renal sympathetic nerve activity and cardiovascular effects of a high-fat diet (HFD), as well as the changes in the sensitivity to intracerebroventricular leptin. New Zealand white rabbits fed a 13.5% HFD for 4 weeks showed modest weight gain but a 2-to 3-fold greater accumulation of visceral fat compared with control rabbits. Mean arterial pressure, heart rate, and plasma norepinephrine concentration increased by 8%, 26%, and 87%, respectively (PϽ0.05), after 3 weeks of HFD. Renal sympathetic nerve activity was 48% higher (PϽ0.05) in HFD compared with control diet rabbits and was correlated to plasma leptin (rϭ0.87; PϽ0.01). Intracerebroventricular leptin administration (5 to 100 g) increased mean arterial pressure similarly in both groups, but renal sympathetic nerve activity increased more in HFD-fed rabbits. By contrast, intracerebroventricular leptin produced less neurons expressing c-Fos in HFD compared with control rabbits in regions important for appetite and sympathetic actions of leptin (arcuate: Ϫ54%, paraventricular: Ϫ69%, and dorsomedial hypothalamus: Ϫ65%). These results suggest that visceral fat accumulation through consumption of a HFD leads to marked sympathetic activation, which is related to increased responsiveness to central sympathoexcitatory effects of leptin. The paradoxical reduction in hypothalamic neuronal activation by leptin suggests a marked "selective leptin resistance" in these animals. (Hypertension. 2010;55:862-868.)Key Words: obesity-related hypertension Ⅲ sympathetic nervous system Ⅲ hypothalamus Ⅲ leptin Ⅲ leptin resistance Ⅲ New Zealand white rabbit O besity is associated with an elevated risk of cardiovascular morbidity and mortality with both clinical and animal studies reporting a strong association between body weight and blood pressure. 1 Several candidate mechanisms are implicated in the development of obesity-related hypertension and include hemodynamic alterations, endothelial dysfunction, impaired renal-pressure natriuresis, and activation of the renin-angiotensin and sympathetic nervous systems (SNS). 2-4 Converging lines of evidence from animals 5,6 and humans 7,8 indicate that obesity is characterized by a marked sympathetic activation. In humans, norepinephrine spillover and sympathetic nerve recording have established a greater sympathetic outflow to the kidneys and skeletal muscle vasculature in obese subjects, whereas cardiac sympathetic nerve activity is reduced. 7-9 Despite these observations, convincing direct evidence for elevated renal sympathetic nerve activity (RSNA) in obesity-related hypertension is lacking, and it is unknown whether SNS activation occurs early in the process or secondary to long-standing obesity...

Abstract-Hypertension and elevated sympathetic drive result from consumption of a high-calorie diet and deposition of abdominal fat, but the etiology and temporal characteristics are unknown. Rabbits instrumented for telemetric recording of arterial pressure and renal sympathetic nerve activity (RSNA) were fed a high-fat diet for 3 weeks then control diet for 1 week or control diet for 4 weeks. Baroreflexes and responses to air-jet stress and hypoxia were determined weekly. After 1 week of high-fat diet, caloric intake increased by 62%, accompanied by elevated body weight, blood glucose, plasma insulin, and leptin (8%, 14%, 134%, and 252%, respectively). Mean arterial pressure, heart rate, and RSNA also increased after 1 week (6%, 11%, and 57%, respectively). Whereas mean arterial pressure and body weight continued to rise over 3 weeks of high-fat diet, heart rate and RSNA did not change further. The RSNA baroreflex was attenuated from the first week of the diet. Excitatory responses to air-jet stress diminished over 3 weeks of high-fat diet, but responses to hypoxia were invariant. Resumption of a normal diet returned glucose, insulin, leptin, and heart rate to control levels, but body weight, mean arterial pressure, and RSNA remained elevated. In conclusion, elevated sympathetic drive and impaired baroreflex function, which occur within 1 week of consumption of a high-fat, high-calorie diet, appear integral to the rapid development of obesity-related hypertension. Increased plasma leptin and insulin may contribute to the initiation of hypertension but are not required for maintenance of mean arterial pressure, which likely lies in alterations in the response of neurons in the hypothalamus. Key Words: sympathetic nervous system Ⅲ obesity Ⅲ rabbits Ⅲ blood pressure Ⅲ heart rate O besity represents a significant risk for cardiovascular disease because of the relationship between excess body fat and hypertension. It is estimated that obesity contributes to hypertension in Ͼ60% of men and women entering the Framingham study.1 The mechanisms underlying this relationship are multifactorial, and for some time there was controversy as to whether the sympathetic nervous system was activated or inhibited in obesity-related hypertension. Bray 2 proposed that obesity was a result of low thermogenic activity secondary to low sympathetic activity, and certainly data from heart rate (HR) variability studies supported this hypothesis. Young and Landsberg 3 hypothesized that sympathetic outflow is increased in obesity to facilitate energy wastage by thermogenesis and to maintain body weight homeostasis, with elevated renal sympathetic activation and hypertension the sequelae. It is now clear that norepinephrine spillover to renal and skeletal muscle beds is increased in obese humans, 4 and microneurographic data indicate that skeletal muscle sympathetic nerve activity is greater in overweight humans, 5 consistent with the observation that sympathetic vasomotor activity in skeletal muscle is elevated in established obesity. 6,7 ...