Propranolol inhibits IK(Ado) by competitive A1-receptor interaction.
OBJECTIVE
Betablocking agents are known to exert anti-arrhythmic effects in ischemic myocardium due to blockade of myocardial beta-1-receptors. Since adenosine (Ado) induced muscarinic potassium current (IK(Ado)) and ATP sensitive potassium current (IK(ATP)) are discussed to be activated during ischemia we studied the effect of propranolol on IK(Ado) and IK(ATP).


RESULTS
The effect of propranolol on muscarinic potassium current and IK(ATP) was studied in isolated rat atrial myocytes by means of the whole-cell voltage clamp tech- nique. Propranolol (50 microM) completely inhibited IK(Ado). IC50 was 7 microM. Inhibition of acetylcholine induced current (IK(ACh)) and GTP-gamma-S induced muscarinic potassium current was less potent (IC50 29 microM and 31 microM respectively). Propranolol was active from the outside only. Intracellular application did not significantly affect muscarinic potassium current. (+)-propranolol, an isomer without beta-blocking properties, was as effective as (+/-)-propranolol. The inwardly rectifying potassium current IK(ATP) showed minor sensitivity to the compound (10% current reduction, propranolol 50 microM).


CONCLUSIONS
Propranolol inhibits IK(Ado). Inhibition is not due to beta-receptor blockade. Predominantly an interaction with A1-receptors seems to be involved. The observations in part might explain the anti-arrhythmic properties of the drug in ischemic/fibrillating myocardium based on the prolongation of refractoriness.
Brandts
B
B
Medizinische Klinik II, Schwerpunkte Kardiologie und Angiologie, Ruhr-Universität Bochum, Hölkeskampring 40, 44625 Herne, Germany. bodo.brandts@rub.de
Dirkmann
D
D
Borchard
R
R
Wickenbrock
I
I
Van Bracht
M
M
Prull
M W
MW
Trappe
H-J
HJ
D000109:Acetylcholine / Q000494:pharmacology*; D000241:Adenosine / Q000037:antagonists & inhibitors*; D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000187:drug effects; D006325:Heart Atria / Q000166:cytology / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors*; D011433:Propranolol / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D043682:Receptor, Adenosine A1 / Q000187:drug effects*; D011976:Receptors, Muscarinic / Q000187:drug effects*
D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D043682:Receptor, Adenosine A1; D011976:Receptors, Muscarinic; D000255:Adenosine Triphosphate; D011433:Propranolol; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D000241:Adenosine; D000109:Acetylcholine