Historical perspectives on inotropic agents

Although early experiments in animals and humans suggested that digitalis glycosides increased cardiac output only in the failing heart, later studies showed that these cardiotonic agents increase intraventricular systolic pressure and decrease relaxation time in the normal animal. The controversy concerning the peripheral vascular or direct cardiac effects of digitalis was finally resolved when new methods were applied to the study of the effects of this drug on intraventricular pressures and cardiac contractile force. Other positive inotropic agents, such as the adrenergic agonists, have also been tested for the treatment of heart failure. However, during long-term oral or intravenous therapy, the effectiveness of these drugs appears to diminish. Clinical studies of glucagon, a polypeptide with positive inotropic and chronotropic effects, have revealed its potential for causing side effects and its reduced activity in patients with chronic heart failure. With the discovery of several new types of inotropic agents, i.e., the bipyridines and the imidazole and benzimidazole derivatives, interest in revising our therapeutic approach to congestive heart failure has increased. This review discusses recent developments in this area.