Chronic Stress Induces Persistent Hypertension and Increases NMDA Receptor Activity in the Paraventricular Nucleus in Borderline Hypertensive Rats

Abstract

Stress activates sympathetic outflow and promotes hypertension development in humans with genetic predisposition. The enhanced N‐methyl‐D‐aspartate receptor (NMDAR) activity in the hypothalamus paraventricular nucleus (PVN) plays a critical role in controlling sympathetic output in hypertension. However, it is unclear how chronic stress affects NMDAR activity in the PVN in borderline hypertensive rats (BHR). BHR are the F1 male offspring from crossing female spontaneously hypertensive rats with male Wistars Kyoto rats (WKY). Arterial blood pressure (ABP) was monitored in free moving rats by using radiotelemetry. Using a 6‐week chronic unpredictable stress protocol, we found that stressed WKY rats had increased ABP during chronic stress but ABP returned to the normal level within a few days after stress. However, the stressed BHR showed a greater increase in ABP during stress and the elevated ABP was sustained for at least 2 weeks after discontinuing stress. Furthermore, whole‐cell voltage clamp recording in brain slices showed that the amplitude of evoked‐NMDAR currents in spinally projecting PVN neurons was significantly higher in stressed BHR than in non‐stressed BHR controls. Inhibiting α2δ‐1 with gabapentin normalized the increased synaptic NMDAR activity of spinally projecting PVN neurons in stressed BHR. In addition, the expression level of GluN1 and α2δ‐1 in the PVN was significantly greater in stressed BHR than in stressed WKY or non‐stressed BHR. These results suggest that chronic stress induces persistent hypertension in BHR, which is associated with α2δ‐1‐mediated NMDAR hyperactivity in PVN presympathetic neurons.Support or Funding InformationAcknowledgmentsSupported by NIH grants HL131161 and HL142133.