Effects of bucumolol, nadolol and nifenalol on maximum upstroke velocity of action potential in guinea pig papillary muscles

Summary

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 μmol/l), NAD (0.5 mmol/l) and NIF (0.2 mmol/l) produced about 60,20 and 20% reduction of V _max 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 V _max 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 processes (τ) estimated by linear and nonlinear regression analyses and by eye were 12.2–9.6 s for BUC (50–100 μmol/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 τ relationship (Ban et al. 1985), these τ 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 V _max by these drugs were explained in terms of a function of τ and the intercept A_o. Based on the study mady by Cohen et al. (1984) we estimated the distortion of the time course of recovery of V _max from that of sodium channel availability in the presence of drugs. Our computation shows that the relative change of the τ estimated at the same level of the zero-intercept does, but that of the τ estimated at different levels does not, reflext exactly that of the time constants of the recovery of sodium channel availability.