Abstract 13228: Nitroxyl (HNO) donated via Slow-Release Oral Pro-Drug Improves Ventriculo-Arterial Coupling in Conscious Dogs with Induced Heart Failure: Enhanced Load-Independent Mechano-Energetics
Introduction: Reduction of myocardial loading and energetic demand while enhancing function are primary needs for the treatment of heart failure (HF). Nitroxyl (HNO) produces cAMP-independent unloading and inotropic/lusitropic support in both laboratory animals and patients with HF. To date, however, the cardiovascular activity of HNO has only been investigated using short-acting parenteral donors.
Aim: This study assessed the feasibility of non-parenteral (oral) HNO delivery, by evaluating the cardiovascular responses to a novel slow-release HNO prodrug given to conscious dogs with induced HF.
Methods: Dogs were either used for pharmacokinetic assessments or chronically instrumented for arterial pressures and LV pressure-volume (LVPV) recordings; instrumented dogs had HF induced via chronic pacing (e.g., EF: 38 ± 1%, PRSW: 51.2 ± 0.9 mmHg+, EDP: 23 ± 2 mmHg and NT-proBNP > 2500 pM/L). Data were obtained before/after oral (22.5 mg/kg) and/or before/during continuous IV infusion (65 μg/kg/min) treatment with a slow-release HNO prodrug (~30min in vitro t1/2 for release of HNO); load-independent systolic/diastolic function was examined by LVPV relationships obtained for up to 180min after the onset of dosing.
Results: The slow-release HNO prodrug was bioavailable orally (%F: 40 ± 4), presenting rapid absortion (Tmax: 0.1 ± 0.5 hr, Cmax: 3.6 ± 1.3 ug/mL) and clearance (t1/2: 0.40 ± 0.01 hr, AUCinf: 4.1±0.8 hr·ug/mL). Oral HNO reduced LV preload (EDV: -7 ± 1%*), filling (EDP: -29 ± 7%*) and end-systolic pressures (ESP: -17 ± 2 %*), without concomitant changes in heart rate (HR: -4 ± 2%). Oral HNO increased stroke volume (SV: 14 ± 3%*) and ejection fraction (EF: 22 ± 3%*), while decreasing arterial elastance (Ea: -27 ± 2 %). Oral HNO enhanced load-independent inotropy (PRSW, +12 ± 2%*) and lusitropy (tau: -15 ± 3 %*, EDPVR: -50 ± 8%*), improved ventriculo-arterial coupling and decreased estimated myocardial demand (PVA: -66 ± 4%*). These effects were comparable to those obtained via IV administration (PRSW: +12 ± 1%*, Ea: -23 ± 3%*, and PVA: -51 ± 8%*). (*: P < 0.05 vs. pre-dosing).
Conclusions: These results demonstrate the feasibility of delivering HNO orally to improve myocardial loading and enhance systolic/diastolic function in the setting of HF.
Author Disclosures: C.L. del Rio: Employment; Significant; QTest Labs. Research Grant; Significant; Cardioxyl Pharmaceuticals. R.S. George: None. B.L. Youngblood: None. Y. Ueyama: None. J.R. May: None. D.J. Humphries: None. C. Hartman: Employment; Significant; Cardioxyl Pharmaceuticals. D.F. Cully: Employment; Significant; Cardioxyl Pharmaceuticals. R.L. Hamlin: Consultant/Advisory Board; Significant; QTest Labs. J.E. Reardon: Employment; Significant; Cardioxyl Pharmaceuticals.
- © 2014 by American Heart Association, Inc.