Abstract P109: Activation Of Hypothalamic Glutamate Receptors Is Required For Angiotensin II-elicited Hypertensive Response Sensitization (HTRS) In Rats

Abstract

Hypertension is associated with sympathetic nervous system activation, which involves interactions between the renin-angiotensin system and glutamatergic mechanisms in the hypothalamic paraventricular nucleus (PVN). Using the Induction-Delay-Expression (IND-DEL-EXP) experimental paradigm, our previous studies demonstrated that administration of a subpressor dose of angiotensin (ANG) II (10 ng/kg/min) during IND sensitizes subsequent ANG II (120 ng/kg/min)-elicited hypertension during EXP. Systemic or intracerebroventricular administration of glutamatergic NMDA-R antagonists (MK801 and AP5) during the IND period abolishes the IND of ANG II-elicited hypertensive response sensitization (HTRS). In the present study, we investigated further the role of hypothalamic glutamate and glutamate receptors (GluRs) in ANG II-elicited HTRS. First, PVN neurons to be studied in vitro were back-labelled by a tracer injected into the rostral ventrolateral medulla (RVLM). After sufficient time for retrograde transport, the rats were treated with a subpressor dose of ANG II sufficient to induce HTRS. In PVN brain slices studied following DEL, basal firing activities of PVN-RVLM projecting neurons did not differ between rats treated with saline and rats treated with a subpressor dose of ANG II. However, bath application of ANG II (2.0 μM) induced a significant increase in the firing rate of PVN-RVLM neurons in rats treated with ANG II during IND as compared to saline treated controls. This enhanced excitatory effect of ANG II on PVN-RVLM neurons was blocked by an NMDAR antagonist, AP5 (50 μM). Pre-treatment with the subpressor dose of ANG II during IND also significantly increased evoked NMDAR- excitatory postsynaptic currents in PVN-RVLM neurons. In functional studies, we found that bilateral PVN microinjections of glutamate (100 nm, 100 nl) during IND produced HTRS whereas PVN vehicle injections did not (Δ50.8±3.2 vs Δ20.8±6.5 mmHg). Taken together, our findings indicate that GluR activation in the PVN is sufficient and necessary for the IND of ANG II-elicited HTRS. The results indicate that a sustained increase in excitability of PVN-RVLM projecting neurons is likely to play an important role in maintaining the CNS state that produces HTRS.