Abstract
1. PD 81,723 has been shown to enhance binding of adenosine to A1
receptors by stabilizing G protein-receptor coupling ('allosteric
enhancement'). Evidence has been provided that in the perfused hearts
and isolated atria PD 81,723 causes a sensitization to adenosine
via this mechanism. 2. We have studied the effect of PD 81,723 in
guinea-pig isolated atrial myocytes by use of whole-cell measurement
of the muscarinic K+ current (IK(ACh)) activated by different Gi-coupled
receptors (A1, M2, sphingolipid). PD 81,273 caused inhibition of
IK(ACh) (IC50 approximately 5 microM) activated by either of the
three receptors. Receptor-independent IK(ACh) in cells loaded with
GTP-gamma-S and background IK(ACh), which contributes to the resting
conductance of atrial myocytes, were equally sensitive to PD 81,723.
At no combination of concentrations of adenosine and PD 81,723 could
an enhancing effect be detected. 3. The compound was active from
the outside only. Loading of the cells with PD 81,723 (50 microM)
via the patch pipette did not affect either IK(ACh) or its sensitivity
to adenosine. We suggest that PD 81,723 acts as an inhibitor of inward
rectifying K+ channels; this is supported by the finding that ventricular
I(K1), which shares a large degree of homology with the proteins
(GIRK1/GIRK4) forming IK(ACh) but is not G protein-gated, was also
blocked by this compound. 4. It is concluded that the functional
effects of PD 81,723 described in the literature are not mediated
by the A1 adenosine receptor-Gi-IK(ACh) pathway.
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