Synaptic Mechanisms Regulating Sympathetic Drive

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The sympathetic drive emanating from the brain is increased in animal models of hypertension and in patients with hypertension. The paraventricular nucleus (PVN) of the hypothalamus is an important site for the control of sympathetic outflow through its projections to the sympathetically related sites in the brainstem and spinal cord. During the previous funding period, we have shown that augmented glutamatergic input contributes to increased excitability of PVN presympathetic neurons and elevated sympathetic vasomotor tone in an animal model of hypertension. However, little is known about the cellular and molecular mechanisms underlying the plasticity of glutamatergic input to the PVN and the sustained increase in sympathetic outflow in hypertension. Our preliminary data suggest that group I metabotropic glutamate receptors (mGluRs, including mGluR1 and mGluR5) in the PVN regulate glutamatergic input to PVN presympathetic neurons and are involved in the maintenance of elevated sympathetic outflow in spontaneously hypertensive rats. In this competitive renewal proposal, we will use spontaneously hypertensive rats as an animal model of essential hypertenSion to test the central hypotheSiS that mGluR1 and mGluR5 in the PVN contribute to the increase in sympathetic vasomotor tone in hypertension. The specific aims of this project are to determine (1) study the role of mGluR1 and mGluR5 in the PVN in elevated sympathetic vasomotor tone in hypertenSion and (2) determine the influence of hypertension on the functional role of mGluR1 and mGluR5 in the PVN in the control of sympathetic outflow. The important role of group I mGluRs in sustained increases in glutamatergic input and sympathetic outflow in hypertenSion has not been recognized previously. The proposed studies will provide substantial novel information about the mechanisms underlying glutamatergic synaptic plasticity and the persistent increase in sympathetic drive in hypertension. This new information also will be essential for our understanding of the role of the autonomic nervous system in the development of hypertension and for the design of more effective treatments for hypertension.