INHIBITION OF MUSCARINIC K-PIG ATRIAL MYOCYTES BY PD-81,723, AN ALLOSTERIC ENHANCER OF ADENOSINE BINDING TO A(1) RECEPTORS( CURRENT IN GUINEA)

1 PD 81,723 has been shown to enhance binding of adenosine to A(1) rec eptors by stabilizing G protein-receptor coupling ('allosteric enhance ment'). Evidence has been provided that in the perfused hearts and iso lated atria PD 81,723 causes a sensitization to adenosine via this mec hanism. 2 We have studied the effect of PD 81,723 in guinea-pig isolat ed atrial myocytes by use of whole-cell measurement of the muscarinic K+ current (I-K(ACh)) activated by different G(i)-coupled receptors (A (1), M-2, sphingolipid). PD 81,273 caused inhibition of I-K(ACh) (IC(5 0)similar or equal to 5 mu M) activated by either of the three recepto rs. Receptor-independent I-K(ACh) in cells loaded with GTP-gamma-S and background I-K(ACh), which contributes to the resting conductance of atrial myocytes, were equally sensitive to PD 81,723. At no combinatio n of concentrations of adenosine and PD 81,723 could an enhancing effe ct be detected. 3 The compound was active from the outside only. Loadi ng of the cells with PD 81,723 (50 mu M) via the patch pipette did not affect either I-K(ACh) or its sensitivity to adenosine. We suggest th at PD 81,723 acts as an inhibitor of inward rectifying K+ channels; th is is supported by the finding that ventricular I-K1, which shares a l arge degree of homology with the proteins (GIRK1/GIRK4) forming I-K(AC h) 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 th e literature are not mediated by the A(1) adenosine receptor-G(i)-I-K( ACh) pathway.