Altered NMDA receptor-evoked intracellular Ca dynamics in magnocellular neurosecretory neurons of hypertensive rats.

KEY POINTS

NMDA receptor (NMDAR)-mediated Ca signalling plays a critical role in modulating hypothalamic neurosecretory function. However, whether an altered NMDAR-evoked changes in Ca (NMDAR-ΔCa ) signalling in magnocellular neurosecretory cells (MNCs) may contribute to neurohumoral activation during disease states is unknown. We show that activation of NMDARs evoked similar inward currents in MNCs of sham and renovascular hypertensive (RVH) rats. Despite this, a prolonged and larger NMDAR-ΔCa response was observed in the latter. The exacerbated NMDAR-ΔCa responses in MNCs of RVH rats affected both somatic and dendritic compartments. Inhibition of the endoplasmic reticulum sarcoendoplasmic reticulum calcium trasport ATPase (SERCA) pump prolonged NMDAR-ΔCa responses in sham rats, but not in RVH rats. Our study supports an altered spatiotemporal dynamic of NMDAR-ΔCa signalling in MNCs from RVH rats, partly due to blunted endoplasmic reticulum Ca buffering capacity.

ABSTRACT

A growing body of evidence supports an elevated NMDA receptor (NMDAR)-mediated glutamate excitatory function in the supraoptic nucleus and paraventricular nucleus of hypertensive rats that contributes to neurohumoral activation in this disease. However, the precise mechanisms underlying altered NMDAR signalling in hypertension remain to be elucidated. In this study, we performed simultaneous electrophysiology and fast confocal Ca imaging to determine whether altered NMDAR-mediated changes in intracellular Ca levels (NMDAR-ΔCa ) occurred in hypothalamic magnocellular neurosecretory cells (MNCs) in renovascular hypertensive (RVH) rats. We found that despite evoking a similar excitatory inward current, activation of NMDARs resulted in a larger and prolonged ΔCa in MNCs from RVH rats. Changes in NMDAR-ΔCa dynamics were observed both in somatic and dendritic compartments. Inhibition of the sarcoendoplasmic reticulum calcium trasport ATPase (SERCA) pump activity with thapsigargin prolonged NMDAR-ΔCa responses in MNCs of sham rats, but this effect was occluded in RVH rats, thus equalizing the magnitude and time course of the NMDA-ΔCa responses between the two experimental groups. Taken together, our results support (1) an exacerbated NMDAR-ΔCa response in somatodendritic compartments of MNCs of RVH rats, and (2) that a blunted ER Ca buffering capacity contributes to the altered NMDAR-ΔCa dynamics in this condition. Thus, altered spatiotemporal dynamics of the NMDAR-ΔCa response stands as an underlying mechanism contributing to neurohumoral activation in neurogenic hypertension.