Nucleus tractus solitarii A2a adenosine receptors inhibit cardiopulmonary chemoreflex control of sympathetic outputs

Abstract

Previously we have shown that stimulation of inhibitory A1 adenosine receptors located in the nucleus tractus solitarii (NTS) attenuates cardiopulmonary chemoreflex (CCR) evoked inhibition of renal, adrenal and lumbar sympathetic nerve activity and reflex decreases in arterial pressure and heart rate. Activation of facilitatory A2a adenosine receptors, which dominate over A1 receptors in the NTS, contrastingly alters baseline activity of regional sympathetic outputs: it decreases renal, increases adrenal and does not change lumbar nerve activity. Considering that NTS A2a receptors may facilitate release of inhibitory transmitters we hypothesized that A2a receptors will act in concert with A1 receptors differentially inhibiting regional sympathetic CCR responses (adrenal>lumbar>renal). In urethane/chloralose anesthetized rats (n=38) we compared regional sympathetic responses evoked by stimulation of the CCR with right atrial injections of serotonin 5HT3 receptor agonist, phenylbiguanide, (1–8 µg/kg) before and after selective stimulation, blockade or combined blockade and stimulation of NTS A2a adenosine receptors (microinjections into the NTS of CGS-21680 0.2–20 pmol/50 nl, ZM-241385 40 pmol/100 nl or ZM-241385+CGS-21680, respectively). We found that stimulation of A2a adenosine receptors uniformly inhibited the regional sympathetic and hemodynamic reflex responses and this effect was abolished by the selective blockade of NTS A2a receptors. This indicates that A2a receptor triggered inhibition of CCR responses and the contrasting shifts in baseline sympathetic activity are mediated via different mechanisms. These data implicate that stimulation of NTS A2a receptors triggers unknown inhibitory mechanism(s) which in turn inhibit transmission in the CCR pathway when adenosine is released into the NTS during severe hypotension.

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. 2014b). Adenosine is released into the NTS during life‐threatening situations such as ischemia, hypoxia, and severe hemorrhage (Winn 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.…”

“…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. ).…”

“…Adenosine is a powerful modulator of cardiovascular reflexes including the arterial baroreflex and cardiopulmonary chemoreflex (CCR) which are primarily integrated in the nucleus of the solitary tract (NTS) (Mosqueda-Garcia et al 1989;Abdel-Rahman and Tao 1996;Spyer and Thomas 2000;Scislo et al 2001Scislo et al , 2008Scislo and O'Leary 2005;Ichinose et al 2009Ichinose et al , 2012Minic et al 2014b). Adenosine is released into the NTS during life-threatening situations such as ischemia, hypoxia, and severe hemorrhage (Winn et al 1979;Van Wylen et al 1986;Phillis et al 1987;Yan et al 1995;Scislo and O'Leary 2006;Minic et al 2014a).…”

Regadenoson for myocardial perfusion imaging: Is it safe?

“…Activation of peripheral A2A causes increased release of adrenergic neurotransmitters, 23 whereas activation of nucleus tractus solitarii A2A is reported to inhibit regional sympathetic and hemodynamic reflex responses. 24 In laboratory animals and in humans, regadenoson decreases systolic and diastolic blood pressures and causes an increase in heart rate. 8,23,25,26 Thus, the drop in blood pressure is usually countered by direct sympathoexcitation and an autonomically mediated elevation in heart rate that increases cardiac output and maintains adequate perfusion of vital organs.…”