title: Mechanisms of the anticholinergic effect of SUN 1165 in comparison with flecainide, disopyramide and quinidine in single atrial myocytes isolated from guinea-pig.
abstract: 1. The mechanism of the anticholinergic effect of SUN 1165 on the acetylcholine (ACh)-induced K+ current (IK.ACh) was examined and compared with those of flecainide, disopyramide and quinidine in single atrial myocytes, in a whole-cell configuration by use of the concentration-jump technique. This technique combines an intracellular perfusion and a rapid exchange of external solution surrounding the voltage-clamped single myocyte within 2 ms. 2. In the cells loaded with guanosine-5'-triphosphate (GTP), 100 microM, the muscarinic ACh response, (IK.ACh), was mediated by GTP-binding proteins. The concentrations of the test drugs that produced a half-maximal inhibition of ACh (1 microM)-induced IK.ACh (IC50) were 29 microM for SUN 1165, 3.6 microM for flecainide, 1.7 microM for disopyramide, and 1.6 microM for quinidine. The blockade of IK.ACh by SUN 1165 and its recovery from the inhibition occurred within a few seconds. Disopyramide had a similar rapid action, while the effects of flecainide and quinidine occurred much more slowly within a few tens of seconds. 3. In cells loaded with 100 microM guanosine-5'-O-(3-thiotriphosphate) (GTP gamma S, a nonhydrolysable GTP analogue), the K+ channel was uncoupled from the muscarinic receptors and activated irreversibly due to direct activation of GTP-binding proteins by GTP gamma S. SUN 1165 and disopyramide had a weak inhibitory effect (IC50 greater than 100 microM for both), while flecainide and quinidine depressed the GTP gamma S-induced K+ current with similar potencies to the cases of ACh-induced currents; IC50 was 5.3 microM for flecainide and 4.4 microM for quinidine. 4 These results suggest that the mechanisms underlying the anticholinergic effects of these antiarrhythmic drugs are different; disopyramide and high concentrations of SUN 1165 mainly block muscarinic ACh receptors in atrial myocytes, while flecainide and quinidine inhibit the K+ channel itself and/or GTP-binding proteins.
authors.affiliation: Laboratory of Molecular Pharmacology, Suntory Institute for Biomedical Research, Osaka, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Inomata
authors.forename: T
authors.initials: T
authors.lastname: Ishihara
authors.forename: N
authors.initials: N
authors.lastname: Akaike
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004206:Disopyramide / Q000494:pharmacology; D005424:Flecainide / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006160:Guanosine Triphosphate / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D008012:Lidocaine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D010276:Parasympatholytics / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects; D011802:Quinidine / Q000494:pharmacology; D011950:Receptors, Cholinergic / Q000187:drug effects / Q000502:physiology
chemical_list: D000889:Anti-Arrhythmia Agents; D010276:Parasympatholytics; D015221:Potassium Channels; D011950:Receptors, Cholinergic; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D006160:Guanosine Triphosphate; D008012:Lidocaine; C042288:pilsicainide; D019204:GTP-Binding Proteins; D004206:Disopyramide; D011802:Quinidine; D005424:Flecainide; D000109:Acetylcholine