Abstract 3709: Intravenous GP531, an Adenosine Regulating Agent, Improves Left Ventricular Function in Dogs With Chronic Heart Failure
Background: Adenosine Regulating Agents (ARAs) are compounds that selectively increase local endogenous adenosine release during episodes of cellular stress in which ATP breakdown exceeds ATP synthesis, as in myocardial ischemia and hypoxia. We tested the hypothesis that acute intravenous infusion of GP531, an ARA, will improve LV function in dogs with chronic heart failure (HF).
Methods: Studies were performed in 6 dogs with coronary microembolization-induced HF (LV ejection fraction, EF<30%). Each dog underwent 2 acute 6-hour studies performed at random one week apart. In one study GP531 was infused at a dose of 10 ìg/kg/min and in the other saline was infused and served as a control. Heart rate (HR), mean aortic pressure (mAoP), LV end-systolic volume (ESV), EF, cardiac output (CO), and the plasma biomarkers nt-pro-brain natriuretic peptide (BNP) and troponin-I (TnI) were measured at baseline and every hour after initiation of drug or saline infusion. Myocardial oxygen consumption (MVO2) and the slope of the end-systolic pressure-volume relationship (ESPVR), assessed with a conductance catheter during inferior Vena Cava occlusion, weree measured at baseline and 6 hours.
Results: GP531 had no effects on HR or mAoP. Compared to baseline, GP531 significantly decreased ESV and increased EF and CO in a time-dependent manner (Table⇓). These benefits were apparent as early as 1–3 hours after initiating therapy. GP531 had no effect on MVO2 but significantly increased the slope of the ESPVR consistent with improved LV systolic function. Both nt-Pro BNP and TnI decreased significantly with GP531 but not with saline infusion (Table⇓). Saline infusion had no effect on any of the other measured parameters.
Conclusions: In dogs with chronic HF, acute intravenous administration of GP531 improves LV function without eliciting chronotropic effects, hypotension or an increase in MVO2. The results favor continued development of GP531 for the treatment of acute HF syndromes.