Effects of various structurally related beta-adrenoceptor blocking agents on maximum upstroke velocity of action potential in guinea-pig papillary muscles

Summary The effects of indenolol (7.0–100 mol/l), befunolol (15.3–250 mol/l), metoprolol (58.4–1000 mol/l), Kö707 (7.3–100 mol/l), D-25 (3.7–100 mol/l) and Kö1313 (73.9–1000 mol/l) on action potentials were investigated in isolated guinea-pig papillary muscles. All these aryloxyisopropylaminopropanol derivatives produced a concentration-dependent reduction of _max at a basic rate of 1 Hz. The reduction was less prominent when interstimulus intervals were prolonged. The time course of recovery of _max during diastole was studied by assessing _max in premature responses at 0.25, 0.1 and 0.027 Hz and in responses after interrupting driving stimuli of 1 Hz. The recovery process was approximated by a single exponential function. The results, together with those reported previously (Sada and Ban 1980, 1981), revealed: (1) a significant correlation between potencies of these derivatives for depression of _max at 0.027, 0.25, 1 and 5 Hz and their log n-octanol/water partition coefficients (log P); (2) The time constants of recovery were relatively concentration independent and correlated significantly with the molecular weights. The results suggest that the potency of these drugs for the depression of _max was mainly determined by log P, being modified secondarily by the time constants of recovery which are intimately associated with the molecular weights.