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

The effects of indenolol (7.0–100 μmol/l), befunolol (15.3–250 μmol/l), metoprolol (58.4–1000 μmol/l), Kö707 (7.3–100 μmol/l), D-25 (3.7–100 μmol/l) and Kö1313 (73.9–1000 μmol/l) on action potentials were investigated in isolated guinea-pig papillary muscles. All these aryloxyisopropylaminopropanol derivatives produced a concentration-dependent reduction of \(\dot V\) _max at a basic rate of 1 Hz. The reduction was less prominent when interstimulus intervals were prolonged. The time course of recovery of \(\dot V\) _max during diastole was studied by assessing \(\dot V\) _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 \(\dot V\) _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 \(\dot V\) _max was mainly determined by log P, being modified secondarily by the time constants of recovery which are intimately associated with the molecular weights.