Blockade Of Insulin Receptor Signaling In The Brain Impairs Arterial Baroreflex Function In Rats

The arterial baroreflex is a powerful neural negative feedback system for stabilizing blood pressure (BP) at rest and during physical activity. Brain insulin is involved not only in the regulation of glucose/lipid metabolism, but also in neural activity. Evidence suggests that changes in central insulin availability lead to alterations in arterial baroreflex function. However, the effects of blocking brain insulin receptor (IR) on arterial baroreflex function are not fully understood. As such, we hypothesized that the blockade of endogenous IR signaling in the brain acutely impairs arterial baroreflex function. PURPOSE: To determine the effects of intracerebroventricular (ICV) injection of an IR antagonist on open-loop baroreflex function in healthy male rats. METHODS: In anesthetized healthy male Sprague-Dawley rats (n = 21, body weight: 384 ± 20 g), the bilateral carotid sinus baroreceptors were isolated from the systemic circulation. Then, carotid sinus pressure (CSP) was increased stepwise from 60 to 180 mmHg to evaluate the static characteristics of the open-loop baroreflex. We measured BP and renal sympathetic nerve activity (RSNA) responses to stepwise CSP input before and 120 min after ICV injection of 1-μL IR antagonist (GSK1838705, 1 mM) or the same volume of artificial cerebrospinal fluid (aCSF, control solution). RESULTS: The maximum gain of the neural arc (the CSP-RSNA relationship) was significantly attenuated after ICV injection of GSK1838705 (before vs after: -2.16 ± 0.95 vs -1.16 ± 0.55, P < 0.01) but not after ICV injection of aCSF (before vs after: -2.38 ± 1.17 vs -2.39 ± 1.47, P = 0.97). The peripheral arc (the RSNA-BP relationship) did not significantly change after ICV injection of GSK1838705 or aCSF. Furthermore, ICV injection of GSK1838705, but not aCSF, significantly reduced the operating point of BP as estimated by the neural and peripheral arcs on a baroreflex equilibrium diagram (GSK1838705, before vs after: 130 ± 11 mmHg vs 116 ± 7 mmHg, P < 0.01; aCSF, before vs after: 128 ± 11 mmHg vs 124 ± 12 mmHg, P = 0.17). CONCLUSION: These findings suggest that blockade of endogenous insulin receptor signaling in the brain acutely reduces BP by impairing neural arc function in the open-loop baroreflex. NIH R01 HL-151632