Altered NMDA receptor-evoked intracellular Ca2+ dynamics in magnocellular neurosecretory neurons of hypertensive rats

Abstract

A growing body of evidence supports an elevated NMDA receptor-mediated glutamate excitatory function in the SON and PVN of hypertensive rats that contributes to neurohumoral activation in this disease. Still, the precise mechanisms underlying altered NMDAR signalling in hypertension remains to be elucidated. In this study, we performed simultaneous electrophysiology and fast confocal Ca²⁺ imaging to determine whether an altered NMDAR-mediated changes in intracellular Ca²⁺ levels (NMDAR-ΔCa²⁺) 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 ΔCa²⁺ in MNCs from RVH rats. Changes in NMDAR-ΔCa²⁺ dynamics were observed both in somatic and dendritic compartments. Inhibition of the ER SERCA pump activity with thapsigargin prolonged NMDAR-ΔCa²⁺ responses in MNCs of sham rats, but this effect was occluded in RVH rats, thus equalizing the magnitude and time course of the NMDA-ΔCa² responses between the two experimental groups. Taken together, our results support (1) an exacerbated NMDAR-ΔCa²⁺ response in somatodendritic compartments of MNCs of RVH rats, and (2) that a blunted ER Ca²⁺ buffering capacity contributes to the altered NMDAR-ΔCa²⁺ dynamics in this condition. Thus, an altered spatiotemporal dynamics of NMDAR-ΔCa²⁺ response stands as an underlying mechanisms contributing to neurohumoral activation in neurogenic hypertension.

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