Disruption in chloride homeostasis contributes to diminished GABAergic inhibition in the paraventricular nucleus and increased sympathetic vasomotor tone in hypertension

Although diminished GABAergic inhibition of presympathetic neurons in the paraventricular nucleus (PVN) plays an important role in increased sympathetic vasomotor tone in spontaneously hypertensive rats (SHR), an animal model of essential hypertension, the underlying mechanisms remain unclear. Using gramicidin‐perforated patch‐clamp recording in brain slices, we identified a depolarizing shift in GABA A reversal potential in spinally projecting PVN neurons in SHR. The derived intracellular Cl − concentration was significantly higher (11.51 ± 0.56 vs. 5.41 ± 0.51 mM) in SHR than in Wistar‐Kyoto (WKY) rats. Also, increased PVN neuronal activity by the GABA A antagonist was significantly less in SHR than in WKY. All these changes were normalized by blocking the Na‐K‐2Cl cotransporter NKCC1 but not the K‐Cl cotransporter KCC2. Furthermore, the NKCC1 protein level in the PVN was significantly higher in SHR than in WKY. Intracerebroventricular injection of an NKCC1 inhibitor potentiated the inhibition of blood pressure and lumbar sympathetic nerve activity by PVN‐microinjected muscimol in SHR. Our study provides novel evidence suggesting that upregulation of NKCC1 contributes to diminished GABAergic inhibition in the PVN and elevated sympathetic vasomotor tone in SHR. This new information improves our understanding of the pathogenesis of essential hypertension. Support: NIH HL77400 and AHA 10POST3430030