Sympathetic hyperactivity in chronic heart failure: Role of glutamatergic mechanisms in the paraventricular nucleus

Increased sympathoexcitation is commonly observed in heart failure (HF). This study examined the role of neuronal activation, specifically excitatory glutamatergic mechanisms, of the paraventricular nucleus (PVN) on discharge of renal nerves in rats with HF. FosB immunohistochemistry revealed that PVN neurons are chronically activated in rats with HF. This increase in activation is likely due, in part, to enhanced glutamatergic mechanisms within the PVN in HF, demonstrated previously. Our second goal was to examine whether the mechanism by which exercise training (ExT) normalizes sympathetic outflow in HF is through normalization of PVN glutamatergic mechanisms. Three weeks of treadmill running normalized the potentiated increase in renal sympathetic nerve activity in response to NMDA microinjected into the PVN in rats with HF. This effect may result from normalization of the increased mRNA and protein expression of NMDA receptor subunit NR1 within the PVN by ExT in rats with HF. Since ExT normalized the elevated plasma angiotensin II (Ang II) in rats with HF, we speculated that ExT normalizes the elevated glutamatergic mechanisms within the PVN in rats with HF via normalization of plasma Ang II. For the final set of experiments, we hypothesized that chronic blockade of the Ang II type 1 receptor (AT1) with Losartan would normalize the glutamatergic mechanisms within the PVN in rats with HF in a manner similar to exercise training. Three weeks of peripheral Losartan administration, in the drinking water, normalized the potentiated increase in renal sympathetic nerve activity in response to NMDA microinjected into the PVN in rats with HF. Losartan treatment also normalized the elevated NR1 mRNA and protein expression within the PVN in rats with HF. These data demonstrate that chronic AT1 blockade normalizes the enhanced glutamatergic mechanisms within the PVN in HF. Collectively, these findings suggest that elevated plasma Ang II in HF contributes to the increased excitatory glutamatergic mechanisms within the PVN, which in turn increases activation of PVN neurons, increasing discharge of renal sympathetic nerves. Exercise training normalizes plasma Ang II in HF, leading to normalization of the PVN glutamatergic mechanisms, decreasing PVN neuronal activation, and normalizing renal sympathetic nerve activity.