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

Bodo Brandts, Annette Brandts, Marie-Cécile Wellner-Kienitz, Walter Zidek *, Hartmut Schlüter * and Lutz Pott

1. The effects of diadenosine polyphosphates (AP_nA, 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_nA in perfused hearts was completely inhibited by 8-cyclopentyl- 1,3-dipropylxanthine (CPX, 20 µM), 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 µM) within about 1 s induced a significant whole-cell I_K(ACh), AP_nA up to 1 mM applied for some tens of seconds failed to activate I_K(ACh). If present for periods > 2 min, AP_nA 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_nA 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_nA acting as A₁ agonists. It is suggested that myocytes can take up AP_nA, 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 I_K(ACh).

6. In the perfused heart and other multicellular cardiac preparations the actions of AP_nA are mediated by Ado via A₁ receptors. It is suggested that AP_nA in multicellular cardiac tissue are hydrolysed by an ectohydrolase to yield AMP which is converted to Ado by ectonucleotidases.

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