Modelling of frequency-dependent effects of lignocaine homologues on the maximum upstroke velocity of action potentials in guinea-pig papillary muscles.
1. The effects of 14 lignocaine homologues on the maximum upstroke velocity (Vmax) of the action potentials (AP) were studied in guinea-pig papillary muscles. These drugs possess one, two or three methyl groups in different positions: an ortho-chloro, -carbomethoxy or -ethyl group instead of an ortho-methyl group; or an N-butyl group instead of an N-diethyl group in lignocaine molecules. 2. At 50-100 mumol/L, six drugs possessing two ortho substituents (but not the other eight) reduced Vmax more prominently at 2-4 Hz than at 1 Hz, and slowed the time courses of recovery of the premature responses. None of the drugs affected resting potential. 3. Besides the two-state piecewise exponential model (models I and II) frequently used, a time-dependent and time-independent, two-state model (model III) was formulated and applied to these experimental data. The above two groups were effectively distinguished by the difference of the estimated association and dissociation rate constants (model II) and equilibrium constants for phasic state (model III) and for resting (model II) or tonic (model III) states. 4. The equilibrium constants for resting or tonic state correlated well with log P (where P = the n-octanol: water partition coefficients), but correlated better with an indicator variable that denotes the existence of two ortho substituents, suggesting the importance of the contribution of steric factors to the activity.
Hamamoto
T
T
Department of Pharmacology, School of Medicine, Yamaguchi University, Ube, Japan.
Ichiyama
M
M
Takahashi
Y
Y
Ban
T
T
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects; D066298:In Vitro Techniques; D007700:Kinetics; D008012:Lidocaine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D008433:Mathematics; D008954:Models, Biological; D008970:Molecular Weight; D010210:Papillary Muscles / Q000187:drug effects*; D015222:Sodium Channels / Q000187:drug effects
D015222:Sodium Channels; D008012:Lidocaine