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Objective:Hypertension affects one third of the population around the world and is a major contributor to cardiovascular disease. There is strong evidence that the main cause of hypertension is increases sympathetic nerve activity to specific organs. Plasma leptin levels correlate with blood pressure (BP) and renal sympathetic nerve activity (RSNA). The central effects of leptin are mediated primarily through the arcuate (ARC) nucleus of the hypothalamus. Both neuropeptide-Y (NPY) and alpha-melanocyte stimulating hormone (α-MSH) containing neurons ascend from the ARC and terminate in ventromedial hypothalamus (VMH) which are the key centres of energy homeostasis, hemodynamics and sympathetic tone to renal vasculature. It is possible that changes in the activity of key neurons may lead to increased sympathetic output in obesity, leading to hypertension. In the present study we assessed the contribution of α-MSH and NPY neurons in the VMH on diet-induced neurogenic hypertension.Design and Method:New Zealand White rabbits were instrumented with a VMH cannula and a renal sympathetic nerve electrode. BP was measured by means of an intra-arterial catheter. Rabbits were injected with α-MSH, SHU9119 (MC3/4R antagonist), NPY or leptin receptor antagonist into the VMH.Results:Following 3 weeks of a high fat diet (HFD, 13% fat), conscious rabbits had higher BP (+7.6 ± 0.5mmHg, P < 0.001) and RSNA (+4.6 ± 0.4 nu, P < 0.001) compared to control group (3.5% fat). α-MSH injection into the VMH increased BP (+7%) and RSNA (+35%) (P < 0.001) and SHU9119 injection showed reduction (P < 0.05) in BP (−7%) and RSNA (−23%) in HFD rabbits. Leptin antagonist or NPY injection showed dose dependent reduction in BP (−7%) and RSNA (-11%) (P < 0.05) when given to HFD rabbits.Conclusions:We conclude that the HFD feeding may induce pathway-specific changes in the VMH and VMH is the likely origin of leptin-mediated sympathoexcitation, α-MSH hypersensitivity and altered central responsiveness to NPY.

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