Glutamate receptors in the hypothalamic paraventricular

22 The sympathoexcitatory response to insulin is mediated by neurons in the arcuate 23 nucleus (ARC) and hypothalamic paraventricular nucleus (PVH). Previous studies have 24 reported that stimulation of ARC neurons increases sympathetic nerve activity (SNA) 25 and arterial blood pressure (ABP) through glutamate receptor activation in the PVH. 26 Therefore, the purpose of the present study was to determine whether glutamatergic 27 neurotransmission in the PVH contributes to insulin-induced sympathoexcitation. Male 28 Sprague-Dawley rats (275-400 g) were infused with isotonic saline or insulin 29 (3.75mU/kg/min) plus 50% dextrose to maintain euglycemia. IV infusion of insulin 30 significantly increased lumbar SNA without a significant change in mean ABP, renal 31 SNA, heart rate, or blood glucose. Bilateral PVH injection of the excitatory amino acid 32 antagonist kynurenic acid (KYN) lowered lumbar SNA and ABP of animals infused with 33 insulin. Similarly, a cocktail of the NMDA antagonist AP5 and non-NMDA antagonist 34 CNQX reduced lumbar SNA and mean ABP during infusion of insulin. In a final 35 experiment, bilateral PVH injection of AP5 only but not CNQX lowered lumbar SNA and 36 mean ABP of animals infused with insulin. The peak changes in lumbar SNA and mean 37 ABP of insulin-treated animals were not different between KYN, AP5 plus CNQX, or 38 AP5 alone. These drug treatments did not alter any variable in animals infused with 39 saline. Altogether, these findings suggest that glutamatergic NMDA neurotransmission 40 in the PVH contributes to insulin-induced sympathoexcitation. 41 42