Effects of para-substituted beta-adrenoceptor blocking agents and methyl-substituted phenoxypropanolamine derivatives on maximum upstroke velocity of action potential in guinea-pig papillary muscles

Summary The effects of atenolol (2–5 mmol/l), sotalol (1–2 mmol/l) and pamatolol (0.1–1 mmol/l), together with N-tertiary butyl phenoxypropanolamines with o-methyl (D-2T: 50–100 mol/l) m-methyl (D-3T: 50–100 mol/l) and p-methyl (D-4T:100–200 mol/l) group as well as with o,p-methyl groups (D-24T) (50–100 mol/l) on action potentials (APs) were investigated in isolated guinea-pig papillary muscles. All the drugs in these concentrations produced a concentration-dependent reduction of the maximum upstroke velocity (V_max). The reduction ofV_max in premature APs induced by stimuli interpolated between the basic driving rate of 0.25, 0.1 or 0.027 Hz decayed exponentially during diastolic intervals. The time constants of these decay processes for atenolol, pamatolol and sotalol ranged between 260–541 ms, those for D-3T and D-4T between 655–1,166 ms, and D-2T and D-24T between 1,565–1,931 ms. A drug which provided larger values caused the reduction ofV_max in a wider range of the frequency. With respect to the aryloxypropanolamine derivatives so far studied (Sada and Ban 1980, 1981 a, b; Sada et al. 1983) fairly good correlations were found as follows: between logn-octanol/water partition coefficient (logP) and ED₂₀ at 0.25 Hz, ED₃₀ at 1 and 4 Hz for 11–14 compounds; between logP and resting block, between molecular weight and A_o^c i.e. the value extrapolated to the time of APD₉₀ of the conditioning response relative to the predrugV_max value which may represent a fraction of channels blocked per AP for 100 mol/l of 20–22 compounds. With respect to 8 compounds with methyl substituents in the benzene ring or amine part the ortho methyl group makes a major contribution to increase the resting block and to increase log values.