NTS adenosine A_2a receptors inhibit the cardiopulmonary chemoreflex control of regional sympathetic outputs via a GABAergic mechanism

Abstract

Adenosine is a powerful central neuromodulator acting via opposing A1 (inhibitor) and A2a (activator) receptors. However, in the nucleus of the solitary tract (NTS), both adenosine receptor subtypes attenuate cardiopulmonary chemoreflex (CCR) sympathoinhibition of renal, adrenal, and lumbar sympathetic nerve activity and attenuate reflex decreases in arterial pressure and heart rate. Adenosine A1 receptors inhibit glutamatergic transmission in the CCR pathway, whereas adenosine A2a receptors most likely facilitate release of an unknown inhibitory neurotransmitter, which, in turn, inhibits the CCR. We hypothesized that adenosine A2a receptors inhibit the CCR via facilitation of GABA release in the NTS. In urethane-chloralose-anesthetized rats (n = 51), we compared regional sympathetic responses evoked by stimulation of the CCR with right atrial injections of the 5-HT3 receptor agonist phenylbiguanide (1-8 μg/kg) before and after selective stimulation of NTS adenosine A2a receptors [microinjections into the NTS of CGS-21680 (20 pmol/50 nl)] preceded by blockade of GABAA or GABAB receptors in the NTS [bicuculline (10 pmol/100 nl) or SCH-50911 (1 nmol/100 nl)]. Blockade of GABAA receptors virtually abolished adenosine A2a receptor-mediated inhibition of the CCR. GABAB receptors had much weaker but significant effects. These effects were similar for the different sympathetic outputs. We conclude that stimulation of NTS adenosine A2a receptors inhibits CCR-evoked hemodynamic and regional sympathetic reflex responses via a GABA-ergic mechanism.

Colocalization of A2abut not A1adenosine receptors with GABA-ergic neurons in cardiopulmonary chemoreflex network in the caudal nucleus of the solitary tract

“…; Minic et al. ). The major finding of the study is colocalization of A 2a , but not A 1 adenosine receptors with GABA synthesizing neurons in the NTS.…”

“…In contrast, adenosine A 2a receptors inhibit CCR network via facilitation of neurotransmitter release from GABA‐ergic neurons in the NTS (Minic et al. ).…”

“…A 1 receptors most likely inhibit glutamate release in the CCR network (Ichinose et al 2012). Our recent studies indicated that adenosine A 2a receptors inhibit CCR transmission in the NTS (Minic et al 2014b) and this inhibition occurs via a GABA-ergic mechanism (Minic et al 2015). A 2a adenosine mediated inhibition is markedly attenuated, that is, the CCR responses are restored following GABA-ergic blockade in the NTS.…”

“…2014b) and this inhibition occurs via a GABA‐ergic mechanism (Minic et al. ). A 2a adenosine mediated inhibition is markedly attenuated, that is, the CCR responses are restored following GABA‐ergic blockade in the NTS.…”

Purinergic Signaling in the Cardiovascular System

“…A 2A receptors in the nucleus tractus solitarii (NTS) mediate the inhibition of the cardiopulmonary chemoreflex control of sympathetic outputs via a GABAergic mechanism. 44 Reflex regulation of the cardiovascular system seems, in part, dependent on ATP release and activation of P2X receptors; these mechanisms exist both in the periphery and in the NTS. Within the carotid body, the transduction of hypoxia to afferent discharge depends, in part, on ATP release and activation of P2 receptors.…”