Cardiac ATP-sensitive K+ channel: a target for diadenosine 5',5''-P1,P5-pentaphosphate.
In numerous studies the intracellular mononucleotide-dependent gating of ATP-sensitive K+ (KATP) channels has been demonstrated. However, it is not known whether dinucleotide polyphosphates, a family of endogenous compounds structurally-related to ATP, could also modulate this ion conductance. Therefore, in the present study we assessed the direct effect of diadenosine 5',5''-P1,P5-pentaphosphate (Ap5A) on cardiac KATP channel activity using the inside-out configuration of the patch-clamp technique. Addition of Ap5A (50 microM) to the internal side of membrane patches, excised from guinea-pig ventricular cells, strongly inhibited KATP channel activity. The estimated NPO (where N is the number of channels in the patch and PO the open probability of each channel) was 4.16 +/- 0.50 in the absence and 0.85 +/- 0.30 in the presence of Ap5A (50 microM). This effect of Ap5A was partially reversible, and the NP0 was 2.26 +/- 0.60 after washout of Ap5A. Exposure of KATP channels to increasing concentrations of Ap5A revealed that the Ap5A-induced inhibition is concentration-dependent with the half-maximal effective concentration of 16 microM (Hill coefficient: 1.6). On the basis of these results, we conclude that Ap5A is a potent antagonist of the KATP channel activity. This represents a previously unrecognized property of Ap5A, as well as the discovery of a potentially novel endogenous ligand of myocardial KATP channels.
Jovanovic
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Division of Cardiovascular Diseases, Mayo Clinic, Mayo Foundation, Rochester, MN 55905, USA.
Alekseev
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AE
Terzic
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D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D015226:Dinucleoside Phosphates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D015226:Dinucleoside Phosphates; D015221:Potassium Channels; D014662:Vasoconstrictor Agents; C012275:P(1),P(5)-di(adenosine-5'-)pentaphosphate; D000255:Adenosine Triphosphate