Glutamate receptors in the hypothalamic paraventricular nucleus contribute to insulin-induced sympathoexcitation

Abstract

Stocker SD, Gordon KW. Glutamate receptors in the hypothalamic paraventricular nucleus contribute to insulin-induced sympathoexcitation. J Neurophysiol 113: 1302-1309, 2015. First published December 4, 2014 doi:10.1152/jn.00764.2014.-The sympathoexcitatory response to insulin is mediated by neurons in the arcuate nucleus (ARC) and hypothalamic paraventricular nucleus (PVH). Previous studies have reported that stimulation of ARC neurons increases sympathetic nerve activity (SNA) and arterial blood pressure (ABP) through glutamate receptor activation in the PVH. Therefore, the purpose of the present study was to determine whether glutamatergic neurotransmission in the PVH contributes to insulin-induced sympathoexcitation. Male Sprague-Dawley rats (275-400 g) were infused with isotonic saline or insulin (3.75 mU·kg Ϫ1 ·min Ϫ1 ) plus 50% dextrose to maintain euglycemia. Intravenous infusion of insulin significantly increased lumbar SNA without a significant change in mean ABP, renal SNA, heart rate, or blood glucose. Bilateral PVH injection of the excitatory amino acid antagonist kynurenic acid (KYN) lowered lumbar SNA and ABP of animals infused with insulin. Similarly, a cocktail of the NMDA antagonist DL-2-amino-5-phosphonopentanoic acid (AP5) and non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) reduced lumbar SNA and mean ABP during infusion of insulin. In a final experiment, bilateral PVH injection of AP5 only, but not CNQX, lowered lumbar SNA and mean ABP of animals infused with insulin. The peak changes in lumbar SNA and mean ABP of insulin-treated animals were not different between KYN, AP5 plus CNQX, or AP5 alone. These drug treatments did not alter any variable in animals infused with saline. Altogether, these findings suggest that glutamatergic NMDA neurotransmission in the PVH contributes to insulin-induced sympathoexcitation.hypothalamus; lumbar; sympathetic nerve activity; NMDA; blood pressure ACCUMULATING EVIDENCE INDICATES insulin acts within the hypothalamic arcuate nucleus (ARC) to activate downstream pathways including neurons of the hypothalamic paraventricular nucleus (PVH) and rostral ventrolateral medulla (RVLM) to increase sympathetic nerve activity (SNA) and alter baroreflex function (Bardgett et al.

Role of the Paraventricular Nucleus of the Hypothalamus in the Sympathoexcitatory Effects of Leptin

“…Indeed, we found that KYN also reduced the stimulatory effects of leptin on LSNA and baroreflex function, implicating a glutamatergic input to the PVN in the leptin responses. Nevertheless, like SHU9119, while our dose of KYN largely reversed the sympathoexcitatory effects of iv insulin, 34 it only partially reduced the effects of leptin. Moreover, the combined effects of SHU9119 and KYN did not produce a greater effect than either alone.…”

“…24, 42 Both α-MSH and glutamatergic inputs into the PVN are involved. 31, 34 Because insulin and leptin are often increased together, such as after a meal or in insulin resistant individuals, these parallel pathways may converge and amplify sympathoexcitatory effects. Moreover, because the effects of leptin 4 and insulin 31, 33, 43 to increase the activity of various sympathetic nerves are diverse, relative increases in leptin versus insulin may homeostatically and differentially engage increased sympathetic outflow to several organ beds.…”

Central Administration of Insulin and Leptin Together Enhance Renal Sympathetic Nerve Activity and Fos Production in the Arcuate Nucleus

“…We did not detect a statistically significant increase following insulin in those same regions. Although, the PVN and RVLM are believed to be involved in mediating the sympatho-excitatory effects of hyperinsulinemia, microinjections of insulin directly into those brain nuclei did not induce an increased sympathetic nerve activity suggesting there is no direct activation of insulin receptors in those brain nuclei (Bardgett et al, 2010; Ward et al, 2011; Stocker and Gordon, 2015). Since we found that insulin alone increased RSNA, it was perhaps, surprising that we did not detect an increase in Fos in those regions.…”

Cardiovascular Regulation by the Arcuate Nucleus of the Hypothalamus

“…Within the ARC, POMC and AgRP neurons are known to be equipped with the insulin receptor (63). These neurons may provide the melanocortinergic drive and/or glutamatergic neurotransmission to the paraventricular nucleus that have been implicated in mediating the sympathoexcitatory effects of insulin (64;65). …”