Prostaglandin E2 (PGE2) type‐1 receptors (EP1R) mediate the voltage‐gated calcium currents and superoxide production induced by Angiotensin II (AngII) in subfornical organ (SFO) neurons

Abstract

The SFO is a critical brain region for the cardiovascular effects of systemic administration of slow pressor doses of AngII. AngII signaling in neurons depends on superoxide (O2−.) and modulation of Ca2+ channels. Cyclooxygenase (COX)‐derived PGE2 and EP1R are involved in AngII‐induced slow pressor hypertension (Peterson et al, Hypertension, 2008, 52:E128), but it is unknown whether AngII signaling in the SFO requires PGE2 or EP1R. We tested the hypothesis that EP1R play a role in AngII‐induced O2−. production and Ca2+ currents in SFO neurons. In whole‐cell patch‐clamp recordings in dissociated mouse SFO neurons, AngII (100nM) increased nifedipine‐sensitive Ca2+ currents (ICa) (+29±5%; p<0.01; n=8). The increase was blocked by the EP1R antagonist SC51089 (10 μM) or the COX1 inhibitor SC560 (10 μM), but not by the COX2 inhibitor NS398 (10 μM; p>0.05; n=4). PGE2 (100nM) also increased ICa (+36±4%; p<0.01; n=6), an effect blocked by SC51089 (n=4). In addition, AngII or PGE2 failed to increase ICa in SFO neurons lacking the CaV1.3 L‐type channel. O2−. production in SFO neurons, assessed using dihydroethidium, was increased (p<0.05) by AngII (+152±55%; n=14) or PGE2 (+126±57%; n=14), an effect blocked by SC51089 (n=15). Our results suggest that AngII signaling in SFO neurons depends on COX1‐derived PGE2 and EP1R, and provide the cellular bases for the prominent role that EP1R play in AngII slow pressor hypertension (supported by HL18974)