Electrophysiological Studies of Some Semisynthetic Cardiac Glycoside Derivatives in Isolated Papillary Muscle of the Guinea-pig

The effects of digitoxin, 3 alpha-methyl-digitoxigenin-3 beta-monoglucoside (3 alpha-MDM), 3 alpha-methyl-digitoxigenin (3 alpha-MD), proscillaridin, 4, 5-methylene-procillaridin (4, 5-MP), and 3 beta-hydroxy-4, 5-methylene-A, B-trans-scillarenin (3 beta-HMTS) on force of contraction and on the transmembrane action potentials were examined in isolated papillary muscles of guinea-pigs. All derivatives exhibited the typical cardiac glycoside effects: i.e. they increased the force of contraction and shortened the action potential duration at 20% (plateau phase) and 90% of repolarization. With digitoxin, 3 beta-HMTS and 4, 5-MP a transient prolongation in action potential duration was observed at the lower concentrations. The action potential amplitude and the resting membrane potential were reduced consistently only with the higher concentrations used. The onset of the positive inotropic effects of 3 alpha-MDM, 3 alpha-MD and 3 beta-HMTS was more rapid than that of digitoxin and proscillaridin. The increment in contractile force reached a maximum well before the full shortening effect on the action potential duration had developed. The shortening of the action potential is thought to be responsible for the biphasic nature of the positive inotropic effect. With 3 alpha-MD and 3 alpha-MDM even toxic effects, e.g. increase in baseline tension, were completely reversible after washing in drug-free solution. The dose-response curves for the positive inotropism can only be compared reliably once the equilibrium of drug action has been established. This steady state is probably reflected by the development of the full shortening in action potential duration.