ABSTRACT
The effects of 10(-7) and 10(-6) M digitoxin, and some of its metabolites, digitoxigenin-bis-digitoxoside, digitoxigenin-mono-digitoxoside and digitoxigenin on the transmembrane potential and contractile characteristics of guinea-pig right ventricle strips were studied to define the role of the sugar side-chain in these cleavage products of digitoxin. Digitoxin and digitoxigenin produced their maximum inotropic responses, without induction of arrhythmias, at about 30 min. However, the bis and mono compounds produced arrhythmias within 12 min, so the inotropy recorded may not be the maximum response. Digitoxin with 3 sugar residues and the bis compound with 2 sugar residues produced a prolongation in the action potenital duration. In contrast, the mono compound with one sugar residue and the digitoxigenin with no sugar residue produced a shortening of the action potential duration. There may be a relationship between the number of sugar moieties and the action potential duration; digitoxin and its bis derivative increased the action potential duration and mono- and digitoxigenin decreased the action potential duration. There also appeared to be an unusual relationship between the number of sugar moieties and induction of arrhythmias; arrhythmogenicity occurred at the doses employed with only the bis- and mono-digitoxoside. Finally, there appeared to be no simple relationship between chemical structure and inotropic potency.
Subject(s)
Digitoxin/analogs & derivatives , Digitoxin/pharmacology , Membrane Potentials/drug effects , Myocardial Contraction/drug effects , Action Potentials/drug effects , Animals , Digitoxigenin/pharmacology , Guinea Pigs , In Vitro Techniques , Male , Structure-Activity Relationship , Time FactorsSubject(s)
Heart Ventricles/drug effects , Membrane Potentials/drug effects , Ouabain/pharmacology , Phenytoin/pharmacology , Action Potentials/drug effects , Animals , Arrhythmias, Cardiac/chemically induced , Dose-Response Relationship, Drug , Electric Stimulation , Guinea Pigs , Heart Rate/drug effects , In Vitro Techniques , Male , Microelectrodes , Ouabain/antagonists & inhibitors , Time FactorsSubject(s)
Androstenols/pharmacology , Anti-Arrhythmia Agents/pharmacology , Heart Conduction System/drug effects , Action Potentials/drug effects , Animals , Drug Interactions , Guinea Pigs , Heart Ventricles/innervation , In Vitro Techniques , Ketosteroids/pharmacology , Male , Ouabain/antagonists & inhibitors , Ouabain/pharmacology , Propionates/pharmacologySubject(s)
Heart/drug effects , Membrane Potentials/drug effects , Thioridazine/pharmacology , Action Potentials/drug effects , Animals , Arrhythmias, Cardiac/chemically induced , Electric Stimulation , Electrophysiology , Guinea Pigs , Heart/physiology , Heart Atria/drug effects , Heart Ventricles/drug effects , In Vitro Techniques , Male , Microelectrodes , Muscle Contraction/drug effects , Norepinephrine/antagonists & inhibitors , Norepinephrine/pharmacology , Thioridazine/administration & dosageABSTRACT
A model is developed for predicting the interval-strength relationship in mammalian atrium. The postulates underlying the model relate the intracellular and transmembrane calcium fluxes to changes in contractility. The predictions of the model agree qualitatively with the behavior of atrium for the following patterns of stimulation: (a) constant interval between stimuli, (b) a rest, or period with no stimuli, after the attainment of a steady-state force level, (c) a sudden change in the interval between stimuli, and (d) paired pulse stimulation. The effects of varying several parameters of the model on both the contraction staircases, after a rested-state contraction, and the steady-state interval-strength relationship are examined. Additional considerations are made: (a) estimates are made of the tissue calcium content available for contraction; (b) the physical meaning of the rested-state contraction is discussed; and (c) estimates are made of the proportionality constant between the maximum value of the contractile tension and the amount of calcium released before a contraction.
