1. The effects of diadenosine
polyphosphates (APnA, where n = 4-6) were studied on beating frequency of perfused guinea-pig hearts and on
muscarinic K+ current (IK(ACh)) and
ATP-regulated K+ current (IK(
ATP)) in atrial myocytes from guinea-pig hearts using whole-cell voltage clamp. 2.
Bradycardia induced by APnA in perfused hearts was completely inhibited by 8-cyclopentyl-
1,3-dipropylxanthine (CPX, 20 microM), a selective antagonist at A1
adenosine receptors, and was augmented by
dipyridamole (Dipy), an inhibitor of cellular
adenosine (
Ado) uptake. 3. Whereas exposure of atrial myocytes to
Ado (100 microM) within about 1 s induced a significant whole-cell IK(ACh), APnA up to 1 mM applied for some
tens of seconds failed to activate IK(ACh). If present for periods > 2 min, APnA caused inhibition of agonist-evoked IK(ACh) and activation of a weakly inward rectifying K+ current, which was identified as IK(
ATP) by its sensitivity to
glibenclamide and its current-voltage curve. 4. The actions of extracellular APnA on IK(ACh) and IK(
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 APnA acting as A1 agonists. It is suggested that myocytes can take up APnA, which are degraded to
AMP. 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 IK(ACh). 6. In the perfused heart and other multicellular cardiac preparations the actions of APnA are mediated by
Ado via A1 receptors. It is suggested that APnA in multicellular cardiac tissue are hydrolysed by an ectohydrolase to yield
AMP which is converted to
Ado by ectonucleotidases.