Adenosinergic modulation of respiratory neurones in the neonatal rat brainstem in vitro

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Abstract
1. The mechanism underlying adenosinergic modulation of respiration was examined in vitro by applying the whole-cell patch-clamp technique to different types of respiration-related neurones located in the rostral ventrolateral medulla of neonatal rats (0-4 days old). 2. The adenosine A1-receptor agonist (R)-N6-(2-phenylisopropyl)-adenosine (R-PIA, 10 microM; n = 31) increased the burst distance of rhythmic C4 inspiratory discharges and decreased the duration of inspiratory discharges (control: 8.00 +/- 2.49 s and 918 +/- 273 ms; R-PIA: 12.10 +/- 5.60 s and 726 +/- 215 ms). 3. Expiratory neurones demonstrated a reversible decrease in input resistance (Rin), a depression of action potential discharges and a hyperpolarization of the membrane potential (Vm) during application of R-PIA (1-10 microM). Similar responses of Rin and Vm to R-PIA were evident after synaptic activity had been blocked by 0.5 microM tetrodotoxin (TTX). 4. Some of the biphasic expiratory (biphasic E) neurones, but none of the inspiratory neurones, demonstrated changes in Rin or Vm during R-PIA application. With TTX present, R-PIA did not alter Vm or Rin in biphasic expiratory or inspiratory neurones. 5. Furthermore, R-PIA decreased the spontaneous postsynaptic activities of all neurones examined. The effects of R-PIA on respiratory activity, Rin and Vm could be reversed by the A1-receptor antagonist 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX; 200 nM). 6. Our data suggest that the modulation of respiratory output induced by adenosinergic agents can be explained by (1) a general decrease in synaptic transmission between medullary respiration-related neurones mediated by presynaptic A1-receptors, and (2) an inactivation, via membrane hyperpolarization, of medullary expiratory neurones mediated by postsynaptic A1-receptors. Furthermore, our data demonstrate that inactivation of expiratory neurones does not abolish the respiratory rhythmic activity, but only modulates respiratory rhythm in vitro.

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