Abstract 3017: Na+-H+ Exchange Inhibition by Cariporide Enhances Cardiac Positive Inotropic and Lusitropic Responses to Dobutamine in Heart Failure: Assessment by Pressure-Volume Analysis
Background. Inability of failing hearts to respond to positive inotropic agents such as dobutamine (DOB) represents a major clinical problem. We have shown previously that in addition to intracellular acidosis, various signaling pathways such as endothelin-1 and angiotensin II also activate cardiac Na+-H+ exchange (NHE). In congestive heart failure (HF), increased stimulation of NHE decreases myocardial calcium sensitivity. We hypothesized that blocking NHE with cariporide (CAR), a NHE-1-selective inhibitor, may improve β-adrenergic inotropic responsiveness in HF and enhance left ventricle (LV) positive inotropic and lusitropic responses of DOB.
Methods. We compared the effect of clinically relevant doses of CAR (3.5 μg/kg, iv) on LV functional performance and LV contractile response to DOB (6 μg/kg/min, iv, 10 min) in 5 instrumented, conscious dogs after pacing-induced HF. LV contractile performance was measured by pressure (P)-volume (V) analysis. Animals received DOB first. After stopping DOB for 30 minutes, both DOB and CAR were infused.
Results. After HF, DOB caused a 21% increase in EES (5.1±1.5 vs 4.2±0.9mmHg/ml), a 19% increase in MSW (53.8±4.9 vs 45.3±3.7 mmHg), and a 12% decrease in the time constant of LV relaxation (ô) (40.4±2.6 vs 45.8±2.5 ms). DOB followed by CAR resulted in significantly greater effects with a 23 % decrease in ô (34.3±3.4 vs 44.5±2.5 ms), a 42% increase in EES (6.1±2.3 vs 4.3±1.9 mmHg/ml), and a 37% increase in MSW (61.7±5.9 vs 45.0±3.9 mmHg). Compared with DOB alone, DOB plus CAR caused no significant changes in heart rate (127±13 vs 130±10 bpm) and LV end-systolic P (108±8.7 vs 110±6.8 mmHg), but significantly decreased mean left atrial P (27.4±5.2 vs 32.7±5.2 mmHg), and increased stroke volume (28%, 13.1±1.9 vs 10.2±2.9 ml). DOB plus CAR also produced about 23% increased LV mechanical efficiency, measured as the ratio of stroke work to total P-V area (0.58±0.17 vs 0.47±0.19) (p<0.05).
Conclusions. In pacing-induced HF, Na+-H+ exchange inhibition by cariporide enhances LV positive inotropic and lusitropic responses to DOB. This suggests that combination therapy with intravenous cariporide and DOB may be appropriate in HF, thus providing a potential method of enhancing β-adrenergic responsiveness of the failing myocardium.