A₁Adenosine Receptors Modulate Respiratory Activity of the Neonatal Mouse Via the cAMP-Mediated Signaling Pathway

Abstract

The effects of adenosine and its analogs on the function of the respiratory center were studied in the spontaneously active rhythmic slice of neonatal and juvenile mice (4-14 days old). Whole cell, spontaneous postsynaptic currents (sPSCs) and single channel KATP currents were recorded in inspiratory neurons of the pre-Bötzinger complex. Adenosine (50-600 microM) inhibited the respiratory rhythm. This was accompanied by increase in the activity of KATP channels in cell-attached patches. The A1 adenosine receptor agonist, 2-chloro-N6-cyclopentyladenosine (CCPA, 0.3-2 microM), inhibited the respiratory rhythm, sPSCs, and enhanced activity of KATP channels. The A1 adenosine receptor antagonist, 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX, 1-3 microM), showed opposite effects and occluded the CCPA actions. Agents specific for A2 adenosine receptors (CGS 21860 and NECA, both applied at 1-10 microM) were without effect. Elevation of intracellular cAMP concentration ([cAMP]i) by 8-Br-cAMP (200-500 microM), forskolin (0.5-2 microM), or isobutylmethylxantine (IBMX, 30-90 microM) reinforced the rhythm, whereas NaF (100-800 microM) depressed it. The open probability of single KATP channels in cell-attached patches decreased after application of forskolin and increased in the presence of NaF. [cAMP]i elevation reversed the effects of A1 receptors both on the respiratory rhythm and KATP channels. A1 receptors and [cAMP]i modified the hypoxic respiratory response. In the presence of A1 agonists the duration of hypoxic augmentation shortened, and depression of the respiratory rhythm occurred earlier. Elevation of [cAMP]i prolonged augmentation and delayed the development of the depression. We conclude that A1 adenosine receptors modulate the respiratory rhythm via inhibition of intracellular cAMP production and concomitant activation of KATP channels.

P2Y1Receptor Modulation of the Pre-Bötzinger Complex Inspiratory Rhythm Generating NetworkIn Vitro

“…In respiratory networks, adenosine is clinically significant because it depresses ventilation (Herlenius et al, 1997;Herlenius and Lagercrantz, 1999;Mironov et al, 1999), and is implicated in the hypoxia-induced depression of ventilation (Yan et al, 1995) and apnea in newborns (Runold et al, 1989;Lopes et al, 1994). Our observation that the post-ATP decrease in frequency depends on ATP breakdown suggests that effects of ATP on rhythm will be determined by an interaction between P2 and P1 receptors.…”

Tripartite Purinergic Modulation of Central Respiratory Networks during Perinatal Development: The Influence of ATP, Ectonucleotidases, and ATP Metabolites

“…Its effects, however, are confounded by possible actions at excitatory A 2a receptors, and developmental studies have yielded inconsistent results (Yamamoto et al, 1994;Kawai et al, 1995;Herlenius and Lagercrantz, 1999;Mironov et al, 1999;Brockhaus and Ballanyi, 2000;Wang et al, 2005;Mayer et al, 2006).…”

“…The ontogeny of this effect is also uncertain. Reports suggest that the inhibition is limited to embryonic stages with only weak effects in adults (Yamamoto et al, 1994;Herlenius and Lagercrantz, 1999) or that it extends from embryonic to neonatal (Kawai et al, 1995;Wang et al, 2005) or juvenile (Mironov et al, 1999) stages.…”

Protective role of neuronal KATP channels in brain hypoxia

“…However, the SK1-mediated current is blocked by anoxia while the BK current is not changed (Kulik et al, 2002). For some neuronal systems, it appears that accumulation of interstitial adenosine due to anoxic degradation of ATP acts via A1 receptors on K + channels, possibly including KATP channels, to exert a protective role by suppressing electrical activity (Pek-Scott and Lutz, 1998;Mironov et al, 1999;Mironov and Richter, 2000). However, in dorsal vagal neurons, adenosine does not mimic the hyperpolarising effect of anoxia while the anoxic hyperpolarisation is not blocked by the A1 receptor antagonist DPCPX .…”

“…Hypoxia-anoxia elevates adenosine levels in the VRG of adult cats in vivo and in the rostral brainstem of fetal sheep (Koos et al, 1994). The rostral brainstem has a high density of A1 adenosine receptors (Bissonnette and Reddington, 1991) that are possibly involved in central respiratory inhibition in vitro and in vivo (Herlenius and Lagercrantz, 1999;Mironov et al, 1999). Furthermore, the adenosine receptor antagonist theophylline blocks, at least partly, the depressant response to oxygen deprivation in vivo (Darnall, 1985).…”