Anti-cholinergic effect of verapamil on the muscarinic acetylcholine receptor-gated K+ channel in isolated guinea-pig atrial myocytes.
Effects of verapamil on the acetylcholine (ACh)-induced K+ 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 non-hydrolysable GTP analogue). In GTP-loaded cells, ACh induced a specific K+ current, which is known to be mediated by pertussis toxin-sensitive GTP-binding (G) proteins. Verapamil (0.1-100 microM) depressed the ACh-induced K+ current in a concentration-dependent fashion. In GTP-gamma S-loaded cells, the K+ current remained persistently after wash-out of ACh, probably due to irreversible activation of G proteins by GTP-gamma S. Verapamil (0.1-100 microM) also depressed the intracellular GTP-gamma S-induced K+ current. However, the magnitude of verapamil-depression of the K+ current in GTP-gamma S-loaded cells was significantly smaller than that in GTP-loaded cells at concentrations between 1 and 10 microM of the drug. From these results, it is suggested that verapamil may block not only the function of muscarinic ACh receptors but also of G proteins and/or the K+ channel itself and thereby depress the ACh-induced K+ current in isolated atrial myocytes.
Ito
H
H
2nd Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Takikawa
R
R
Kurachi
Y
Y
Sugimoto
T
T
D000109:Acetylcholine / Q000037:antagonists & inhibitors; D000818:Animals; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D006160:Guanosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D010276:Parasympatholytics; D015221:Potassium Channels / Q000187:drug effects*; D011950:Receptors, Cholinergic / Q000187:drug effects*; D011976:Receptors, Muscarinic / Q000187:drug effects*; D013873:Thionucleotides / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology*
D010276:Parasympatholytics; D015221:Potassium Channels; D011950:Receptors, Cholinergic; D011976:Receptors, Muscarinic; D013873:Thionucleotides; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D006160:Guanosine Triphosphate; D014700:Verapamil; D000109:Acetylcholine