A model study of time- and voltage-dependent effects of class I antiarrhythmic drugs in guinea-pig papillary muscles as related to external potassium concentration.
1. A piecewise exponential three-state model previously introduced by the authors in 5.4 mmol/l was intended to apply to states with different [K+]o and with a different drug. Using the conventional microelectrode technique the effects of 20 mumol/l mexiletine (MEX), 5 mumol/l aprindine (APR), 20 mumol/l quinidine (QUI), 5 mumol/l flecainide (FLE), 5 mumol/l E-0747 (dl-6-chloro-2,2'-dimethyl-1'-[3-(4-hydroxypiperizino)propyl]spiro [chroman-4,4'-imidazolidine]-2',5'-dione hydrochloride and 100 mumol/l QX-222, a quaternary derivative of lidocaine, on action potentials (APs) in guinea-pig papillary muscles were studied. Specific objects of the study were (1) steady state Vmax values at various frequencies (all drugs), (2) the recovery process of Vmax in premature responses (MEX) and (3) Vmax changes during a train of stimulation at 1 Hz after a rest period (all other drugs) in 2.7 and 10 mmol/l [K+]o. Further, those of APR alone and APR plus 1 mmol/l nicorandil (NIC), which shortened action potential durations (APDs) specifically, were investigated on the above items (1) and (3) in 5.4 mmol/l [K+]o. 2. All the drugs reduced the Vmax of APs frequency-dependently and, except QX-222, more markedly in 10 mmol/l [K+]o than in 2.7 mmol/l [K+]o at 1 Hz. 3. The rate constants estimated from the model fitting characterized MEX and APR and the other drugs as predominantly inactivated and activated channel blockers, respectively. The calculated rate of onset of block, lambda T, does not differ much between the three [K+]o levels. lambda T shows that APR belongs to class Ia rather than class Ib.(ABSTRACT TRUNCATED AT 250 WORDS)
Hamamoto
T
T
Second Department of Internal Medicine, School of Medicine, Yamaguchi University, Japan.
Kojima
M
M
Matsuzaki
M
M
Kusukawa
R
R
Ban
T
T
D000200:Action Potentials / Q000187:drug effects; D000465:Algorithms; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004558:Electric Stimulation; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008839:Microelectrodes; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D011188:Potassium / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors
D000889:Anti-Arrhythmia Agents; D011188:Potassium