Non-receptor-mediated activation of IK(ATP) and inhibition of IK(ACh) by diadenosine polyphosphates in guinea-pig atrial myocytes

1. The effects of diadenosine polyphosphates (AP(n)A, where n = 4-6) were studied on beating frequency of perfused guinea-pig hearts and on muscarinic K+ current (I-K(ACh)) and ATP-regulated K+ current (I-K(ATP)) in atrial myocytes from guinea-pig hearts using whole-cell voltage clamp. 2. Bradycardia induced by AP,A in perfused hearts was completely inhibited by 8-cyclopentyl-1,3-dipropylxanthine (CPX, 20 mu M), a selective antagonist at A, adenosine receptors, and was augmented by dipyridamole (Dipy), an inhibitor of cellular adenosine (Ado) uptake. 3. Whereas exposure of atrial myocytes to Ado (100 mu M) within about 1 s induced a significant whole-cell I-K(ACh). AP(n)A up to 1 mM applied for some tens of seconds failed to activate I-K(ACh). If present for periods > 2 min, AP(n)A caused inhibition of agonist-evoked I-K(ACh) and activation of a weakly inward rectifying K+ current, which was identified as I-K(ATP) by its sensitivity to glibenclamide and its current-voltage curve. 4. The actions of extracellular AP(n)A on I-K(ACh) and I-K(ATP) were mimicked by intracellular loading of compounds via the patch clamp pipette and by intracellular loading of AMP. 5. The results from isolated myocytes exclude AP(n)A acting as A(1) agonists. It is suggested that myocytes can take up AP(n)A, which are degraded to BMP. In the presence of ATP, AMP is converted to ADP, a physiological activator of ATP-regulated K+ channels, by adenylate kinase. A similar mechanism resulting in a reduction of the [GTP]/[GDP] ratio might be responsible for inhibition of I-K(ACh). 6. In the perfused heart and other multicellular cardiac preparations the actions of AP,A are mediated by Ado via A, receptors. It is suggested that AP,A in multicellular cardiac tissue are hydrolysed by an ectohydrolase to yield AMP which is converted to Ado by ectonucleotidases.