PMID- 1810589
OWN - NLM
STAT- MEDLINE
DCOM- 19920603
LR  - 20190510
IS  - 0007-1188 (Print)
IS  - 0007-1188 (Linking)
VI  - 104
IP  - 4
DP  - 1991 Dec
TI  - Mechanisms of the anticholinergic effect of SUN 1165 in comparison with 
      flecainide, disopyramide and quinidine in single atrial myocytes isolated from 
      guinea-pig.
PG  - 1007-11
AB  - 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.
FAU - Inomata, N
AU  - Inomata N
AD  - Laboratory of Molecular Pharmacology, Suntory Institute for Biomedical Research, 
      Osaka, Japan.
FAU - Ishihara, T
AU  - Ishihara T
FAU - Akaike, N
AU  - Akaike N
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (Anti-Arrhythmia Agents)
RN  - 0 (Parasympatholytics)
RN  - 0 (Potassium Channels)
RN  - 0 (Receptors, Cholinergic)
RN  - 37589-80-3 (Guanosine 5'-O-(3-Thiotriphosphate))
RN  - 86-01-1 (Guanosine Triphosphate)
RN  - 98PI200987 (Lidocaine)
RN  - AV0X7V6CSE (pilsicainide)
RN  - EC 3.6.1.- (GTP-Binding Proteins)
RN  - GFO928U8MQ (Disopyramide)
RN  - ITX08688JL (Quinidine)
RN  - K94FTS1806 (Flecainide)
RN  - N9YNS0M02X (Acetylcholine)
SB  - IM
MH  - Acetylcholine/pharmacology
MH  - Animals
MH  - Anti-Arrhythmia Agents/*pharmacology
MH  - Disopyramide/pharmacology
MH  - Flecainide/pharmacology
MH  - GTP-Binding Proteins/metabolism
MH  - Guanosine 5'-O-(3-Thiotriphosphate)/antagonists & inhibitors/pharmacology
MH  - Guanosine Triphosphate/pharmacology
MH  - Guinea Pigs
MH  - Heart/*drug effects
MH  - In Vitro Techniques
MH  - Lidocaine/*analogs & derivatives/pharmacology
MH  - Male
MH  - Myocardium/cytology/metabolism
MH  - Parasympatholytics/*pharmacology
MH  - Potassium Channels/drug effects
MH  - Quinidine/pharmacology
MH  - Receptors, Cholinergic/drug effects/physiology
PMC - PMC1908839
EDAT- 1991/12/01 00:00
MHDA- 1991/12/01 00:01
PMCR- 1992/12/01
CRDT- 1991/12/01 00:00
PHST- 1991/12/01 00:00 [pubmed]
PHST- 1991/12/01 00:01 [medline]
PHST- 1991/12/01 00:00 [entrez]
PHST- 1992/12/01 00:00 [pmc-release]
AID - 10.1111/j.1476-5381.1991.tb12541.x [doi]
PST - ppublish
SO  - Br J Pharmacol. 1991 Dec;104(4):1007-11. doi: 10.1111/j.1476-5381.1991.tb12541.x.