Insulin Activates a NMDA Pathway to the RVLM to Elevate Sympathetic Nerve Activity

Abstract

Hyperinsulinemia elevates lumbar sympathetic nerve activity (SNA) via activation of ionotropic glutamatergic receptors in the rostral ventrolateral medulla (RVLM). Therefore, the present study determined the contribution of NMDA vs non‐NMDA receptors. Male Sprague‐Dawley rats (250–300 g) were anesthetized with α‐chloralose and infused with insulin (3.75 mU/kg/min) and 50% dextrose (.25–.75 ml/hr) for 120 min. At 90 min, hyperinsulinemia significantly increased lumbar SNA (40±6%) with no change in arterial blood pressure (ABP, 0 min: 117±5 vs 90 min: 119±6 mmHg) or plasma glucose levels (0 min: 72±5 vs 90 min: 68±5 mg/dl). RVLM microinjection of the ionotropic glutamate receptor antagonist KYN significantly reduced lumbar SNA (−28±10%) and ABP (−8±2 mmHg, p<0.05). Similarly, RVLM microinjection of the NMDA receptor antagonist AP5 significantly attenuated lumbar SNA (−30±8%) and ABP (−5±3 mmHg, P<0.05). The decrease in lumbar SNA and ABP after injection of KYN vs AP5 was not statistically different. In contrast, microinjection of the non‐NMDA receptor antagonist NBQX into the RVLM had no significant effect on lumbar SNA (6±3%) or ABP (5±4 mmHg). In addition, direct microinjection of insulin into the RVLM did not significantly increase lumbar SNA or ABP. These findings indicate that hyperinsulinemia increases lumbar SNA through a glutamatergic NMDA projection to the RVLM.Supported by NIH HL090826, AHA 0630202N & 0815372D