Ouabain improves cardiac function in vivo in rats with heart failure after chronic but not acute treatment

Abstract

Rats are generally believed to be insensitive for cardiac glycosides. However, like in humans, the hemodynamic effects may be related to the pathophysiological condition. Since the hemodynamic effects of cardiac glycosides have never been investigated in rats with heart failure, the aim of the present experiments was to investigate the role of the pathophysiological condition in the rat. Therefore, hemodynamic and cardiac effects of ouabain were investigated both in normal rats and rats with heart failure due to myocardial infarction (MI). Since the effects of ouabain may also depend on the treatment scheme, rats were treated either for a short-term period or a long-term period. Three weeks after sham surgery or ligation of the left coronary artery (MI), Wistar rats were treated for two weeks with ouabain (14.4mg/kg.d s.c.), either continuously (osmotic minipumps) or intermittently (once daily). A separate group of rats was treated for 45–60min (1–100μg/kg·min ouabain; i.v. infusion 5 weeks after MI). Hemodynamic measurements were performed at rest and after volume loading in conscious rats, chronically instrumented with an electromagnetic flow probe and catheters. Induction of MI resulted in a significant increase in total peripheral resistance (TPR), and a significant decrease in basal and maximal cardiac output following volume loading (basal CO: sham, 92±5; MI, 74±5ml/min; maximal CO: sham, 152±4; MI, 105±7ml/min; n=7–11). Chronic intermittent ouabain treatment further increased TPR in MI rats. In contrast, continuous ouabain treatment normalized TPR in rats. Only in continuously treated MI rats, basal and maximal CO improved significantly (basal: 83±4; maximal: 134±7ml/min; n=7). Acute treatment dose-dependently worsened the hemodynamic conditions of MI rats, since TPR and MAP increased and CO and stroke volume decreased significantly. These experiments demonstrate that ouabain can improve cardiac function in rats, although only in MI rats and strongly depending on the delivery regimen. Thus, in contrast to the general belief, the presently used rat model is suitable for investigation of cardiac glycosides in heart failure. The preferential improvement of cardiac function in MI rats continuously treated with ouabain may depend upon changes in Na⁺,K⁺-ATPase or altered neurohumoral conditions due to MI and chronic treatment.