Sl. Mironov et al., A(1) adenosine receptors modulate respiratory activity of the neonatal mouse via the cAMP-mediated signaling pathway, J NEUROPHYS, 81(1), 1999, pp. 247-255
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 cu
rrents (sPSCs) and single channel K-ATP currents were recorded in inspirato
ry neurons of the pre-Botzinger complex. Adenosine (50-600 mu M) inhibited
the respiratory rhythm. This was accompanied by increase in the activity of
K-ATP channels in cell-attached patches. The A(1) adenosine receptor agoni
st, 2-chloro-N-6-cyclopentyladenosine (CCPA, 0.3-2 mu M), inhibited the res
piratory rhythm, sPSCs, and enhanced activity of K-ATP channels. The A(1) a
denosine receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 1-
3 mu M), showed opposite effects and occluded the CCPA actions. Agents spec
ific for A(2) adenosine receptors (CGS 21860 and NECA, both applied at 1-10
mu M) were without effect. Elevation of intracellular cAMP concentration (
[cAMP]i) by 8-Br-cAMP (200-500 mu M), forskolin (0.5-2 mu M), or isobutylme
thylxantine (IBMX, 30-90 mu M) reinforced the rhythm, whereas NaF (100-800
mu M) depressed it. The open probability of single K-ATP channels in cell-a
ttached patches decreased after application of forskolin and increased in t
he presence of NaF. [cAMP](i) elevation reversed the effects of A(1) recept
ors both on the respiratory rhythm and K-ATP channels. A(1) receptors and [
cAMP](i) modified the hypoxic respiratory response. In the presence of A(1)
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 tha
t A(1) adenosine receptors modulate the respiratory rhythm via inhibition o
f intracellular cAMP production and concomitant activation of K-ATP channel
s.