GABAergic Excitation of Vasopressin Neurons

Abstract

Rationale: Increased arginine-vasopressin (AVP) secretion is a key physiological response to hyperosmotic stress and may be part of the mechanism by which high-salt diets induce or exacerbate hypertension. Objective: Using deoxycorticosterone acetate-salt hypertension model rats, we sought to test the hypothesis that changes in GABA A receptor–mediated inhibition in AVP-secreting magnocellular neurons contribute to the generation of Na + -dependent hypertension. Methods and Results: In vitro gramicidin-perforated recordings in the paraventricular and supraoptic nuclei revealed that the GABAergic inhibition in AVP-secreting neurons was converted into excitation in this model, because of the depolarization of GABA equilibrium potential. Meanwhile, in vivo extracellular recordings in the supraoptic nuclei showed that the GABAergic baroreflexive inhibition of magnocellular neurons was transformed to excitation, so that baroreceptor activation may increase AVP release. The depolarizing GABA equilibrium potential shift in AVP-secreting neurons occurred progressively over weeks of deoxycorticosterone acetate-salt treatment along with gradual increases in plasma AVP and blood pressure. Furthermore, the shift was associated with changes in chloride transporter expression and partially reversed by bumetanide (Na + -K + -2Cl – cotransporter inhibitor). Intracerebroventricular bumetanide administration during deoxycorticosterone acetate-salt treatment hindered the development of hypertension and rise in plasma AVP level. Muscimol (GABA A agonist) microinjection into the supraoptic nuclei in hypertensive rats increased blood pressure, which was prevented by previous intravenous V1a AVP antagonist injection. Conclusions: We conclude that the inhibitory-to-excitatory switch of GABA A receptor–mediated transmission in AVP neurons contributes to the generation of Na + -dependent hypertension by increasing AVP release. We speculate that normalizing the GABA equilibrium potential may have some utility in treating Na + -dependent hypertension.

High Salt Intake Increases Blood Pressure via BDNF-Mediated Downregulation of KCC2 and Impaired Baroreflex Inhibition of Vasopressin Neurons

“…In agreement with these observations, a previous study reported that the value of E GABA measured by perforated patch recording in VP MNCs in vitro lies below the threshold for action potential discharge (Kim et al, 2013). However, this result is contradicted by another study reporting that E GABA is depolarized in VP MNCs and that GABA excites these neurons in hypothalamic slices under control conditions (Haam et al, 2012).…”

“…However, a recent study has shown that rat MNCs display a collapse in the transmembrane chloride (Cl − ) gradient required for inhibitory GABA A R signaling after chronic salt loading (Kim et al, 2011). A similar effect can be induced by a high-salt diet in uni-nephrectomized rats treated with deoxycorticosterone acetate (DOCA), where a weakening of BR-mediated inhibition is also associated with a VP-dependent increase in BP (Kim et al, 2013). These observations indicate that plastic changes in the BR-mediated control of MNCs can allow these cells to participate in the regulation of BP.…”

Klotho Gene Deficiency Causes Salt-Sensitive Hypertension via Monocyte Chemotactic Protein-1/CC Chemokine Receptor 2–Mediated Inflammation

“…51 It was recently reported that g-aminobutyric acid-ergic excitation of vasopressin neurons in the supraoptic nucleus is a critical mechanism underlying sodium-dependent hypertension. 52 Therefore, additional study is warranted to assess if klotho deficiency promotes AVP synthesis and release in response to HS, which could contribute to the development of klotho deficiency-induced salt-dependent hypertension.…”

Cation-chloride cotransporters in neuronal development, plasticity and disease

“…However, the available data are not conclusive regarding the manner in which multimerization affects CCC functions 6,42,44 . CCCs are expressed in all organ systems and, in addition to being instrumental in neuronal signalling, they are involved in a range of physiological processes, including cell volume regulation (BOX 1), transepithelial ion transport, neuroendocrine signalling and blood pressure regulation 6,7,33,45–48 .…”

“…Strongly depolarizing GABAergic synaptic responses can be functionally excitatory, and they are termed ‘GABA PSPs’. Such responses are based on a high [Cl − ] i , and they are mainly seen in immature or diseased neurons 40,48,165–168 .…”