Angiotensin II inhibits GABAergic synaptic transmission in dorsolateral periaqueductal gray neurons

Abstract

The purpose of this study was to determine the role of angiotensin II (Ang II) in modulating inhibitory and excitatory synaptic inputs to the dorsolateral periaqueductal gray (dl-PAG). The whole cell voltage-clamp recording was performed to examine inhibitory and excitatory postsynaptic currents (IPSCs and EPSCs) of the dl-PAG neurons. Ang II, at the concentration of 2 µM, decreased the frequency of miniature IPSCs from 0.83 ± 0.02 to 0.45 ± 0.03 Hz (P < 0.05) in 10 tested neurons. This did not significantly affect the amplitude and decay time constant. The effect of Ang II on miniature IPSCs was blocked by the prior application of Ang II AT1 receptor antagonist losartan, but not by AT2 receptor antagonist PD123319. Additionally, Ang II decreased the amplitude of evoked IPSCs from 148 ± 15 to 89 ± 7 pA (P < 0.05), and increased the paired-pulse ratio from 96 ± 5% to 125 ± 7% (P < 0.05) in eight tested neurons. In contrast, Ang II had no distinct effects on the EPSCs. Our data suggest that Ang II inhibits GABAergic synaptic inputs to the dl-PAG through activation of presynaptic AT1 receptors. KeywordsAngiotensin II; Synaptic transmission; GABA; Midbrain PAG Angiotensin II (Ang II) plays an important role in the control of balance of hydromineral and fluid volume, as well as sympathetic nerve activity [5,26]. Also, Ang II can regulate arterial blood pressure in the development and maintenance of hypertension [6,30]. Ang II receptor subtypes, called AT1 and AT2, are engaged in action of Ang II [12].The prior studies have revealed the presence of both AT1 and AT2 throughout the rat brain [13,16]. In particular, AT1 receptors are present within the midbrain periaqueductal gray (PAG) area [16]. Ang II injected into the PAG of rats increases arterial blood pressure [11]. Ang II was likely injected into the lateral or dorsolateral PAG according to the coordinates presented in this previous study. The blockade of AT1 receptors but not AT2 attenuates the increase in blood pressure induced by injection of Ang II [11]. Thus AT1 receptors are likely to play a role in modulating blood pressure in regions of the PAG. However, the underlying mechanisms by which Ang II affects synaptic signaling to the PAG neurons have not specifically been studied. In this study we used an in vitro whole cell recording technique in [18,35]. The solution was adjusted to pH 7.25 with 1 M of KOH and osmolarity of 280-300 mOsm. The slice was placed in a recording chamber (Warner Instruments, Hamden, CT) and fixed with a grid of parallel nylon threads supported by a U-shaped stainless steel weight. The aCSF saturated with 95% O 2 -5% CO 2 was perfused into the chamber at 3.0 ml/ min. The temperature of the perfusion solution was maintained at 34 °C by an in-line solution heater with a temperature controller (Model TC-324; Warner Instruments). Whole cell recordings from the dl-PAG neurons were performed visually using differential interference contrast (DIC) optics on an upright microscope (BX50WI, Olympus, Tokyo, Japan). The tissue image wa...

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