Inhibition of muscarinic K+current in guinea‐pig atrial myocytes by PD 81,723, an allosteric enhancer of adenosine binding to A1receptors

PD 81,723 has been shown to enhance binding of adenosine to A1receptors 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.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≃5μm) activated by either of the three receptors. Receptor‐independent IK(ACh)in cells loaded with GTP‐γ‐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.The compound was active from the outside only. Loading of the cells with PD 81,723 (50μm) 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 IK1, 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.It is concluded that the functional effects of PD 81,723 described in the literature are not mediated by the A1adenosine receptor‐Gi‐IK(ACh)pathway.