MODULATION OF NET OUTWARD CURRENT IN CULTURED NEURONS BY ANGIOTENSIN-II - INVOLVEMENT OF AT(1)-RECEPTOR AND AT(2)-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-mu-M)-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-mu-M)-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.