What is responsible for the elevated hypothalamic drive to sympathetic neurons in cardiovascular diseases?

      Accumulating evidence supports altered hypothalamic neuronal activity as a major factor contributing to increased sympathetic drive in major cardiovascular diseases, including hypertension and heart failure. Numerous precise underlying mechanisms have been distinctly proposed to contribute to hypothalamic-driven sympathetic activity. These include, among others, enhanced excitatory (glutamate, angiotensin II) and blunted inhibitory (GABA, nitric oxide) synaptic mechanisms, altered intrinsic ion channel function, as well as a pro-inflammatory glia microenvironment (gliosis, microglia cell activation). However, to what extent these seemingly disparate mechanisms are causally and functionally interrelated remains at present unknown. I will present a set of recent studies from our group in which we present a mechanistic functional link between Angiotensin II, glutamate and the potassium channel IA in the regulation of sympathetic-related neuronal activity in the hypothalamic paraventricular nucleus. Within this signaling pathway, we propose glial cells to function as key targets and intermediary cells mediating angiotensin II actions on hypothalamic sympathetic drive, both in healthy conditions and in cardiovascular disease states. We believe these studies will contribute to a more comprehensive understanding of how distinct, though functionally related cellular targets and signaling mechanisms contribute in an orchestrated manner to an enhanced sympathoexcitatory status in cardiovascular disease states.
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