Endogenous angiotensin II facilitates GABAergic neurotransmission afferent to the Na⁺-responsive neurons of the rat median preoptic nucleus

Abstract

Henry M, Grob M, Mouginot D. Endogenous angiotensin II facilitates GABAergic neurotransmission afferent to the Na ϩ -responsive neurons of the rat median preoptic nucleus. Am J Physiol Regul Integr Comp Physiol 297: R783-R792, 2009. First published July 8, 2009 doi:10.1152/ajpregu.00226.2009.-The median preoptic nucleus (MnPO) is densely innervated by efferent projections from the subfornical organ (SFO) and, therefore, is an important relay for the peripheral chemosensory and humoral information (osmolality and serum levels ANG II). In this context, controlling the excitability of MnPO neuronal populations is a major determinant of body fluid homeostasis and cardiovascular regulation. Using a brain slice preparation and patch-clamp recordings, our study sought to determine whether endogenous ANG II modulates the strength of the SFOderived GABAergic inputs to the MnPO. Our results showed that the amplitude of the inhibitory postsynaptic currents (IPSCs) were progressively reduced by 44 Ϯ 2.3% by (Sar 1 , Ile 8 )-ANG II, a competitive ANG type 1 receptor (AT1R) antagonist. Similarly, losartan, a nonpeptidergic AT1R antagonist decreased the IPSC amplitude by 40.4 Ϯ 5.6%. The facilitating effect of endogenous ANG II on the GABAergic input to the MnPO was not attributed to a change in GABA release probability and was mimicked by exogenous ANG II, which potentiated the amplitude of the muscimol-activated GABAA/ Cl Ϫ current by 53.1 Ϯ 11.4%. These results demonstrate a postsynaptic locus of action of ANG II. Further analysis reveals that ANG II did not affect the reversal potential of the synaptic inhibitory response, thus privileging a cross talk between postsynaptic AT 1 and GABAA receptors. Interestingly, facilitation of GABAergic neurotransmission by endogenous ANG II was specific to neurons responding to changes in the ambient Na ϩ level. This finding, combined with the ANG II-mediated depolarization of non-Na ϩ -responsive neurons reveals the dual actions of ANG II to modulate the excitability of MnPO neurons. hydromineral homeostasis; sodium homeostasis; neuropeptides; hypothalamus THE MEDIAN PREOPTIC NUCLEUS (MnPO) is the midline structure of the lamina terminalis and a pivotal brain site for the hydromineral and cardiovascular homeostasis (for detailed reviews, see Refs. 18 and 30). Chemical lesions of the MnPO produce deficits in both osmotically-and angiotensin II (ANG II) -stimulated water intake and vasopressin secretion (7,13,27) and increase need-free sodium intake (12). Similar lesions impaired cardiovascular reflex activity (28) and blocked pressor responses elicited by sodium hyperosmolality or intracerebroventricular injection of ANG II (5, 17, 44).In the context of a functional hypothalamic neuronal network, the MnPO is considered an integrator of chemosensory (osmolality) and humoral (ANG II) signals relevant to hydromineral and cardiovascular homeostasis. Changes in plasma osmolality have been shown to alter the spiking activity of MnPO neurons (1, 29, 37, 38), and our laboratory discovered tha...

AT1 receptor blockade in the central nucleus of the amygdala attenuates the effects of muscimol on sodium and water intake

“…The present results show that blockade of CeA AT1 receptors by injections of losartan into the CeA reverses hypertonic NaCl and water intake reduced by the activation of CeA GABA A receptors with muscimol injected into the CeA in WD-PR or in FURO rats. Thus, it appears that ANG II may act on postsynaptic AT1 receptors in the CeA to enhance the effects of GABAergic activation on CeA neurons via a mechanism similar to that described in the MnPO (Henry et al, 2009). Taken together, these results suggest that interactions of angiotensinergic and GABAergic mechanisms in the CeA are important to restrict sodium intake.…”

“…Xing et al, 2009). For example, ANG II acting on post-synaptic AT1 receptors increases IPSCs in sodium-sensitive neurons in the MnPO (Henry et al, 2009). The present results show that blockade of CeA AT1 receptors by injections of losartan into the CeA reverses hypertonic NaCl and water intake reduced by the activation of CeA GABA A receptors with muscimol injected into the CeA in WD-PR or in FURO rats.…”

“…The CeA contains AT1 receptors (Thunhorst and Fitts, 1994;McKinley et al, 1996) and has been proposed as a possible site of interaction between ANG II and mineralocorticoids to stimulate sodium appetite (Galaverna et al, 1992;McKinley et al, 2003). Previous studies using whole-cell voltage-clamp techniques have suggested that ANG II acting on AT1 receptors may modulate GABAergic synaptic transmission and produce opposite effects, depending on whether pre-or post-synaptic AT1 receptors are activated (Li et al, 2003;Li and Pan, 2005;Henry et al, 2009;Xing et al, 2009). The pharmacological activation of pre-synaptic AT1 receptors reduces GABA release and decreases the amplitude of evoked GABAergic inhibitory post-synaptic currents (IPSCs), which can be blocked by the AT1 receptor antagonist losartan, but not by the AT2 receptor antagonist PD123319 (Li et al, 2003;Li and Pan, 2005;Xing et al, 2009).…”

“…The pharmacological activation of pre-synaptic AT1 receptors reduces GABA release and decreases the amplitude of evoked GABAergic inhibitory post-synaptic currents (IPSCs), which can be blocked by the AT1 receptor antagonist losartan, but not by the AT2 receptor antagonist PD123319 (Li et al, 2003;Li and Pan, 2005;Xing et al, 2009). In contrast, endogenous ANG II acting on post-synaptic AT1 receptors increases IPSCs in sodiumsensitive neurons in the MnPO, revealing a post-synaptic action of endogenous ANG II, which facilitates the effects of the GABAergic input to the MnPO (Henry et al, 2009). In addition, ANG II failed to excite PVN neurons in the presence of bicuculline and had no effect on excitatory post synaptic currents in the PVN neurons or in the dorsolateral periaqueductal gray (Li et al, 2003;Li and Pan, 2005;Xing et al, 2009).…”

“…Considering the effects of the activation of GABA A receptors in the CeA on hypertonic NaCl and water intake (Kang et al, 2004;Wang et al, 2012), and the already-reported role of AT1 receptor activation in the modulation of GABAergic mechanisms (Li et al, 2003;Li and Pan, 2005;Henry et al, 2009;Xing et al, 2009), in the present study we investigated the effects of previous injection of the specific AT1 receptor antagonist, losartan, into the CeA on water and hypertonic NaCl intake reduced by muscimol injections into the CeA in water deprivation-partial rehydration (WD-PR) or FURO-treated rats.…”