Abstract 9515: Cariporide, a Selective Na+-H+ Exchange Inhibitor, Enhances Cardiac Positive Inotropic and Lusitropic Responses to Dobutamine in Heart Failure: Assessment by Pressure-Volume Analysis

Abstract

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 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 6 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 17% increase in E ES (5.3 ±1.5 vs 4.4±0.8 mmHg/ml), a16% increase in M SW (53.8±4.9 vs 45.3±3.7 mmHg), and an 11% decrease in the time constant of LV relaxation (τ) (40.4±2.6 vs 45.8±2.5 ms). DOB followed by CAR resulted in significantly greater effects with a 42% increase in E ES (6.1±2.3 vs 4.3±1.9 mmHg/ml) and a 37% increase in M SW (61.4±5.9 vs 45.1±3.2 mmHg), and a 23 % decrease in τ (34.1±3.6 vs 44.5±2.4 ms). Compared with DOB alone, DOB plus CAR caused no significant changes in heart rate (126±11 vs 130±12 bpm) and LV end-systolic P (110±8.6 vs 112±6.5 mmHg), but significantly decreased mean left atrial P (27.2±5.0 vs 32.9±5.4 mmHg), and increased stroke volume (32%, 13.3±1.7 vs 10.1±2.7 ml). DOB plus CAR also produced about 28% increased LV mechanical efficiency, measured as the ratio of stroke work to total P-V area (0.59±0.15 vs 0.46±0.17) ( 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.