Brain Insulin Receptor Antagonism Augments The Blood Pressure Response To Activation Of The Exercise Pressor Reflex

Abstract

Type 2 diabetes mellitus (T2DM) results in abnormal control of blood pressure (BP). However, the underlying mechanisms remain to be elucidated. The transport of insulin into the central nervous system is decreased in T2DM. The resultant central hypoinsulinemia reduces neuronal excitability. The nucleus tractus solitarius (NTS) is a key central integration site for incoming signals from peripheral sensory neurons including input from working skeletal muscle and arterial baroreceptors. Working skeletal muscle activates primary sensory fibers and evokes the exercise pressor reflex (EPR) to reflexively increase BP, a response modulated by the baroreflex. Central hypoinsulinemia in T2DM may influence how neurons in the NTS process this sensory information during exercise affecting BP responsiveness. PURPOSE: To determine whether acute antagonism of insulin receptors in the NTS alters EPR function in baro-intact and barodenervated rats. METHODS: L4 and L5 ventral roots were electrically stimulated in healthy decerebrated male Sprague-Dawley rats to evoke hindlimb muscle contraction and EPR activation in intact and sino-aortic barodenervated rats. Mean arterial pressure (MAP) responses to activation of the EPR were assessed before and 30 min following NTS microinjections of the insulin receptor antagonist, GSK1838705 (100uM), or vehicle, dimethyl sulfoxide (DMSO). RESULTS: In baro-intact rats, contraction-induced changes in MAP were significantly greater following GSK1838705 (Pre, 16 ± 10 mmHg vs. Post, 23 + 13 mmHg, n = 11, p < 0.01) but not DMSO (Pre, 15 ± 8 mmHg vs. Post, 15 + 8 mmHg, n = 9). In barodenervated rats, neither GSK1838705 (Pre, 27 ± 16 mmHg vs. Post, 28 ± 21 mmHg, n = 8) nor DMSO (Pre, 34 ± 17 mmHg vs. Post, 30 ± 27 mmHg, n = 9) affected the MAP response to contraction. CONCLUSIONS: The findings demonstrate that central insulin receptor antagonism augments the BP response to EPR activation, which is abolished by barodenervation. The findings also suggest that insulin in the NTS maintains the capacity to buffer EPR-mediated increases in BP via baroreflex-mediated mechanisms. Alterations in this buffering capacity due to the central hypoinsulinemia in T2DM could account, in part, for the exaggerated pressor response to exercise in this disease. Supported by NIH-NHLBI, Lawson & Rogers Lacy Research Fund.