NON-RECEPTOR-MEDIATED ACTIVATION OF I-K(ATP) AND INHIBITION OF I-K(ACH) BY DIADENOSINE POLYPHOSPHATES IN GUINEA-PIG ATRIAL MYOCYTES

1. The effects of diadenosine polyphosphates (AP(n)A, where n = 4-6) w ere 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 completel y inhibited by 8-cyclopentyl-1,3-dipropylxanthine (CPX, 20 mu M), a se lective antagonist at A, adenosine receptors, and was augmented by dip yridamole (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 p eriods > 2 min, AP(n)A caused inhibition of agonist-evoked I-K(ACh) an d activation of a weakly inward rectifying K+ current, which was ident ified 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 p atch 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 acti vator of ATP-regulated K+ channels, by adenylate kinase. A similar mec hanism resulting in a reduction of the [GTP]/[GDP] ratio might be resp onsible for inhibition of I-K(ACh). 6. In the perfused heart and other multicellular cardiac preparations the actions of AP,A are mediated b y Ado via A, receptors. It is suggested that AP,A in multicellular car diac tissue are hydrolysed by an ectohydrolase to yield AMP which is c onverted to Ado by ectonucleotidases.