Modulation of net outward current in cultured neurons by angiotensin II: involvement of AT1 and AT2 receptors.

In this study we have used whole-cell, voltage-clamp procedures to determine the effects of angiotensin II (AII) on net outward current (I_no) in neurons co-cultured from the hypothalamus and brainstem of 1-day-old rats. I_no is the sum of all inward and outward membrane currents (minus Na⁺, which is blocked by tetrodotoxin) which occur during the repolarization phase of the action potential. We have determined that AII elicits two separate effects on I_no in cultured neurons. AII caused a reversible and concentration (0.1 nM–10 μM)-dependent increase in I_no. This effect is inhibited by the AT₂ receptor-selective antagonists, PD123177 and PD123319 (both 100 nM), but not by the AT₁-selective receptor blocker, DuP753 (Losartan; 100 nM), and so it is mediated by AT₂ receptors. In a smaller number of neurons AII induced a reversible and concentration (0.01 nM–10 μM)-dependent decrease in I_no that was blocked by Losartan (100 nM) but not by PD123177 (100 nM). Thus the decrease in I_no is mediated by AT₁ receptors. Additionally, some neurons displayed both AT₁- and AT₂ receptor-mediated effects on I_no. Our results demonstrate two distinct actions of AII on membrane ionic currents in cultured neurons, effects that are mediated by different AII receptor subtypes.