The effects of bucumolol (BUC), nadolol (NAD) and nifenalol (NIF) on contractile forces and on action potentials (APs) were investigated in isolated guinea pig atrial and papillary muscles, respectively. Log 1/ED40 values for the negative inotropic effects of these drugs were 0.097, 10 and 0.74 mmol/l in this order. BUC (50 mumol/l), NAD (0.5 mmol/l) and NIF (0.2 mmol/l) produced about 60, 20 and 20% reduction of Vmax at 1 Hz. The frequency-dependent reductions at these and higher concentrations were greatest for BUC, intermediate for NAD and least for NIF. These potencies at certain frequencies were, as a whole, consistent with log P-potency relationship established in our previous papers (Harada et al. 1981; Ban et al. 1985). The reductions of Vmax in APs in response to premature stimuli during basic stimuli at the rate of 0.25 or 0.027 Hz decayed exponentially during diastolic intervals (DI). The time constants of these decay process (tau) estimated by linear and nonlinear regression analyses and by eye were 12.2-9.6 s for BUC (50-100 mumol/l) and 2.9-4.8 s for NAD (1-2 mmol/l) and 57-87 ms for NIF (0.2-1 mmol/l). In terms of the molecular weight (MW)-log tau relationship (Ban et al. 1985), these tau values are within the 95% fiducial limit for BUC and NAD and deviated from the lower fiducial limit for NIF. The frequency-dependent reductions of Vmax by these drugs were explained in terms of a function of tau and the intercept Ao. Based on the study made by Cohen et al.(ABSTRACT TRUNCATED AT 250 WORDS)

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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.

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