Oestrogen inhibits salt-dependent hypertension by suppressing GABAergic excitation in magnocellular AVP neurons

Abundant evidence indicates that oestrogen (E₂) plays a protective role against hypertension. Yet, the mechanism underlying the antihypertensive effect of E₂ is poorly understood. In this study, we sought to determine the mechanism through which E₂ inhibits salt-dependent hypertension.

To this end, we performed a series of in vivo and in vitro experiments employing a rat model of hypertension that is produced by deoxycorticosterone acetate (DOCA)-salt treatment after uninephrectomy. We found that E₂ prevented DOCA-salt treatment from inducing hypertension, raising plasma arginine-vasopressin (AVP) level, enhancing the depressor effect of the V1a receptor antagonist (Phenylac¹,D-Tyr(Et)²,Lys⁶,Arg⁸,des-Gly⁹)-vasopressin, and converting GABAergic inhibition to excitation in hypothalamic magnocellular AVP neurons. Moreover, we obtained results indicating that the E₂ modulation of the activity and/or expression of NKCC1 (Cl⁻ importer) and KCC2 (Cl⁻ extruder) underpins the effect of E₂ on the transition of GABAergic transmission in AVP neurons. Lastly, we discovered that, in DOCA-salt-treated hypertensive ovariectomized rats, CLP290 (prodrug of the KCC2 activator CLP257, intraperitoneal injections) lowered blood pressure, and plasma AVP level and hyperpolarized GABA equilibrium potential to prevent GABAergic excitation from emerging in the AVP neurons of these animals.

Based on these results, we conclude that E₂ inhibits salt-dependent hypertension by suppressing GABAergic excitation to decrease the hormonal output of AVP neurons.