Inhibition of muscarinic potassium current by the class III antiarrhythmic drug RP58866 in guinea-pig atrial myocytes.
RP58866 is a potent antiarrhythmic drug that maintains its antiarrhythmic properties during ischemia. Since interstitial concentrations of adenosine increase during ischemia, we examined the properties of the drug with respect to the muscarinic K+ current (IK(ACh)), with a main emphasis on the adenosine (Ado)-induced current (IK(Ado)). Using different Gi-coupled receptors (M2, A1, sphingolipid), we studied the effect of RP58866 in isolated guinea-pig atrial myocytes by the whole-cell voltage clamp technique. Application of 50 microM RP58866 resulted in complete inhibition of the muscarinic K+ current. Inhibition was observed during activation of IK(ACh) by each of the three receptors. IC50 was approximately 2.0 microM. GTP-gamma-S induced IK(ACh) was reduced by RP58866. The drug was active from the outside only, and its intracellular application via the patch pipet had no inhibitory effect. Despite the structural homologies between inward rectifying K+ channels, the adenosine triphosphate-sensitive K+ current (IK(ATP)) was not inhibited by the compound. It is concluded that muscarinic K+ current is inhibited by RP58866, an inhibition not limited to IK1, Ito, and IKr. High interstitial adenosine concentrations during ischemia are expected to increase the participation of IK(Ado) on repolarization. RP58866-induced inhibition of IK(Ado) would, therefore, be of particular relevance during ischemia. The high sensitivity of IK(Ado) to RP58866 may partially explain the unique properties of the drug toward arrhythmias developing in the ischemic myocardium.
Brandts
B
B
Department of Cardiology and Angiology, Ruhr-University Bochum, Hoelkeskampring 40, 44625 Herne, Germany. Bodo.Brandts@Ruhr-Uni-Bochum.de
Van Bracht
M
M
Tüttelmann
F
F
Allessie
M A
MA
Trappe
H J
HJ
D000109:Acetylcholine / Q000494:pharmacology; D000241:Adenosine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002839:Chromans / Q000494:pharmacology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006168:Guinea Pigs; D006325:Heart Atria / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism*; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D002839:Chromans; D018727:Muscarinic Antagonists; D010880:Piperidines; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; C005356:sphingosine phosphorylcholine; D010767:Phosphorylcholine; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000255:Adenosine Triphosphate; C063899:terikalant; D000241:Adenosine; D000109:Acetylcholine; D013110:Sphingosine; D011188:Potassium