Anti-cholinergic effects of quinidine, disopyramide, and procainamide in isolated atrial myocytes: mediation by different molecular mechanisms.
Effects of quinidine, disopyramide, and procainamide on the acetylcholine (ACh)-induced K+ channel current were examined in single atrial cells, using the tight-seal, whole-cell clamp technique. The pipette solution contained guanosine-5'-triphosphate (GTP) or guanosine-5'-O-(3-thiotriphosphate) (GTP-gamma S, a nonhydrolysable GTP analogue). In GTP-loaded cells, not only ACh but also adenosine induced a specific K+ channel current via GTP-binding proteins (G) by activating muscarinic ACh or adenosine receptors. Quinidine and disopyramide depressed the ACh-induced K+ current quite effectively. Procainamide had a weak inhibitory effect. Quinidine also depressed adenosine-induced K+ current, while the effect of disopyramide on adenosine-induced current was much smaller than that on ACh-induced current. In GTP-gamma S-loaded cells, the K+ channel was uncoupled from the receptors and was activated irreversibly, probably due to direct activation of G proteins by GTP-gamma S. Quinidine depressed the GTP-gamma S-induced K+ current just as in the cases of ACh- and adenosine-induced currents of GTP-loaded cells. Disopyramide had only a weak inhibitory effect and procainamide showed no effect. From these results, it is strongly suggested that the major mechanisms underlying the anti-cholinergic effects of quinidine, disopyramide, and procainamide are different; quinidine may inhibit the muscarinic K+ channel itself and/or G proteins, while disopyramide and high doses of procainamide may mainly block functions of muscarinic ACh receptors in atrial myocytes.
Nakajima
T
T
2nd Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Kurachi
Y
Y
Ito
H
H
Takikawa
R
R
Sugimoto
T
T
D000818:Animals; D001696:Biomechanical Phenomena; D004206:Disopyramide / Q000494:pharmacology*; D006160:Guanosine Triphosphate / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D009206:Myocardium / Q000166:cytology; D010276:Parasympatholytics / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects; D011342:Procainamide / Q000494:pharmacology*; D011802:Quinidine / Q000494:pharmacology*; D011976:Receptors, Muscarinic / Q000502:physiology; D011983:Receptors, Purinergic / Q000502:physiology
D010276:Parasympatholytics; D015221:Potassium Channels; D011976:Receptors, Muscarinic; D011983:Receptors, Purinergic; D006160:Guanosine Triphosphate; D004206:Disopyramide; D011802:Quinidine; D011342:Procainamide