Concentration-response curves of positive inotropic agents before and after ouabain pretreatment

Current therapy for congestive heart failure (diuretics, digitalis, vasodilators) may be insufficient. Addition of a second positive inotropic substance to digitalised patients has been previously shown to increase cardiac index and decrease vascular resistance. To test the hypothesis that the positive inotropy of ouabain can be increased by other inotropic agents, the following studies were performed. Firstly, concentration-response curves of positive inotropic agents (ouabain, dobutamine, dopamine, orciprenaline, phenylephrine, theophylline, amrinone, sulmazole and histamine) were measured in contracting left atria and papillary muscles from cat and guinea pig hearts. The maximal increase in force of contraction was similar for all compounds except histamine and phenylephrine which gave decreased effects in guinea pig heart muscle. Secondly, these positive inotropic agents were added to the contracting heart muscles after maximal inotropy without toxicity of a ouabain concentration which gave more than 90% of the maximal increase in force of contraction. In guinea pig left atria, dobutamine was the only compound to give a significant, although transient, increase in force of contraction above the maximal ouabain response. Theophylline (2 X 10(-4) mol X litre-1, EC25) produced significant decreases in force of contraction. In papillary muscles, low concentrations of all positive inotropic compounds, except amrinone, significantly increased force of contraction after a submaximal ouabain concentration. However, the maximal increase in force of contraction after combined addition of ouabain and a second inotropic agent was not different from the maximal increase with ouabain, dobutamine or dopamine alone. Addition of higher concentrations of the second inotropic agents after ouabain pretreatment led to a markedly increased incidence of toxicity with only transient positive inotropic effects. These results indicate that any haemodynamic improvement observed in adequately digitalised patients after combined positive inotropic therapy is unlikely to result from directly additive inotropic effects but is probably a result of other cardiovascular effects such as vasodilatation.