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

Abstract
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.
AuthorsB Brandts, A Brandts, M C Wellner-Kienitz, W Zidek, H Schluter, L Pott
JournalThe Journal of physiology (J Physiol) Vol. 512 ( Pt 2) Pg. 407-20 (Oct 15 1998) ISSN: 0022-3751 [Print] England
PMID9763631 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Adenine Nucleotides
  • Potassium Channels
  • Adenosine Triphosphate
  • Acetylcholine
Topics
  • Acetylcholine (physiology)
  • Adenine Nucleotides (pharmacology)
  • Adenosine Triphosphate (physiology)
  • Animals
  • Chromatography, High Pressure Liquid
  • Electric Stimulation
  • Electrophysiology
  • Guinea Pigs
  • Heart Atria (cytology, metabolism)
  • In Vitro Techniques
  • Membrane Potentials (physiology)
  • Myocardium (cytology, metabolism)
  • Patch-Clamp Techniques
  • Potassium Channels (drug effects, metabolism)

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