Effects of D-600 and its optical isomers on force of contraction in cat papillary muscles and guinea-pig auricles

Abstract

1 (--)-D-600 and (+)-D-600 exerted concentration-dependent negative inotropic effects in papillary muscles from cats, the potency of (--)-D-600 being about 100 times greater than that of (+)-D-600. The action was more pronounced at high than at low frequencies of stimulation. Time to peak force, relaxation time and therefore also total duration of contraction were not significantly affected by the drugs. 2 The negative inotropic effects of both drugs were not reversible after washing in drug-free solution for 60 min at all concentrations tested. 3 The same negative inotropic effects were seen in guinea-pig left auricles with the racemic mixture of both isomers. 4 Uptake measurements of D-600-[nitrile-14C] in isolated left auricles of guinea-pigs showed the drug to be accumulated in the myocardial tissue; tissue-medium ratios from 1.25 to 6.0 were found at exposure times from 1 to 100 minutes. Preparations which were loaded first with D-600-[nitrile-14C] for 100 min and then washed in drug-free solution for different times lost up to about 80% of the initial radioactivity, whereas the depression of force of contraction was not reversible. 5 The results show that there are marked quantitative differences between the actions of (--)-D-600 and (+)-D-600 on isometric force of contraction in cat papillary muscles. Although the time course of the uptake of D-600-[nitrile-14C] and the development of the negative inotropy in guinea-pit left auricles were reasonably well related, the magnitude of the negative inotropy does not seem to be dependent on the total tissue concentration once the negative inotropic effect has been fully developed.