GABAergic Excitation of Vasopressin Neurons Possible Mechanism Underlying Sodium-Dependent Hypertension

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: Employing deoxycorticosterone acetate (DOCA)-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 (PVN) and supraoptic nuclei (SON) revealed that the GABAergic inhibition in AVP-secreting neurons was converted into excitation in this model, due to the depolarization of GABA equilibrium potential (E GABA ). Meanwhile, invivo extracellular recordings in the SON showed that the GABAergic baroreflexive inhibition of magnocellular neurons was transformed to excitation, so that baroreceptor activation may increase AVP release. The depolarizing E GABA shift in AVP-secreting neurons occurred progressively over weeks of DOCA-salt treatment along with gradual increases in plasma AVP and blood pressure. Further, the shift was associated with changes in chloride transporter expression and partially reversed by bumetanide (Na + -K + -2Cl- co-transporter inhibitor). Intracerebroventricular bumetanide administration during DOCA-salt treatment hindered the development of hypertension and rise in plasma AVP level. Muscimol (GABA A agonist) microinjection into the SON in hypertensive rats increased blood pressure, which was prevented by prior intravenous V1a AVP antagonist injection. Conclusions: We conclude that the inhibitory-to-excitatory switch of GABAA receptor-mediated transmission in AVP neurons contributes to the generation of Na + -dependent hypertension by increasing AVP release. We speculate that normalizing the E GABA may have some utility in treating Na + -dependent hypertension.