Abstract P237: Dysregulation of Hypothalamic mTORC1, Sympathetic Nerve Activity and Vascular Reactivity in the Hypertensive Obese Prone Rats

Abstract

Neurogenic mechanisms play a major role in obesity-induced increase in sympathetic nerve activity (SNA) and arterial pressure, but the molecular pathways involved remain ill defined. Mechanistic target of rapamycin complex 1 (mTORC1) signaling in the hypothalamus has emerged as a critical molecular regulator of SNA, vascular function and arterial pressure. To analyze the status of hypothalamic mTORC1 signaling in obesity we compared the phosphorylated levels of ribosomal protein S6, a downstream effector of mTORC1, in the brain between obesity prone (OP) and obesity resistant (OR) rats. Body weight was elevated (P<0.05) in OP rats (763±22 g) relative to OR rats (575±19 g). OP rats also had higher fat mass. Interestingly, OP rats exhibited increased phospho-S6 in the mediobasal hypothalamus including the arcuate nucleus, but not in other nuclei such as the paraventricular nucleus, the supraoptic nucleus or the subfornical organ. Next, we assessed the hemodynamic and sympathetic parameters in OP and OR rats. Radiotelemetry systolic arterial pressure was greater in OP rats (133±1 mmHg) compared to OR rats (119±2 mmHg) at 8 weeks of age and remained elevated at 42 weeks of age. Ganglionic blockade with hexamethonium produced a dose-dependent decrease in arterial pressure in both the OP and OR rats, but the response was more pronounced (P<0.05) in OP rats. Direct SNA recording revealed elevated (P<0.05) renal and splanchnic SNA in OP rats (86±3 and 55±6 spikes/sec, respectively) compared to OR rats (48±2 and 22±4 spikes/sec). Using ultrasound Doppler, we found that OP rats have altered regional blood flows. Sodium nitroprusside-induced dilation was attenuated and phenylephrine-evoked constriction was potentiated in the hindquarters vasculature of OP rats relative to OR rats. However, there were no differences in the renal, mesenteric or abdominal aorta vascular beds. Acetylcholine (ACh)-mediated relaxation was impaired in isolated coronary arteries from OP rats (relaxation to 10 μM ACh: 41±8% in OP rats vs 67±10% in OR rats, P<0.05). These studies raise the possibility that overactivation of hypothalamic mTORC1 signaling contributes to the altered hemodynamic, sympathetic and vascular functions associated with the obesity prone phenotype.