Acute Intravenous Infusion of an Adenosine Regulating Agent Improves Left Ventricular Function in Dogs with Advanced Heart Failure

Abstract

GP531 is a second generation adenosine regulating agent (ARA) that increases concentrations of endogenous adenosine, a natural cardioprotective agent, in ischemic/hypoxic tissue. This study examined the effects of acute intravenous infusions of GP531 on left ventricular (LV) systolic and diastolic function in dogs with advanced chronic heart failure (HF) (LV ejection fraction, EF <30%). Six dogs with intracoronary microembolization-induced HF received a constant intravenous infusion of GP531 (10μg/kg/min) or vehicle (normal saline) for 6h in random order 1week apart. Hemodynamic measurements were made at baseline and at 1, 2, 3, 4, 5 and 6h after initiating drug infusion. Myocardial oxygen consumption (MVO2) was measured at baseline and 4 and 6h. LV pressure-volume relationship (PVR) was measured at baseline and 6h. Vehicle infusions had no effect on indexes of LV systolic and diastolic function. GP531 infusion had no effect on heart rate or mean aortic pressure but significantly decreased LV end-diastolic pressure, end-diastolic volume, end-systolic volume and end-diastolic wall stress. GP531 significantly increased LV EF (27 ± 1 at baseline to 34 ± 1 after 6h of drug infusion, p < 0.05), deceleration time of early mitral inflow velocity and the slope of end-systolic PVR without increasing MVO2. Results of the study indicate that approaches which increase the local release of adenosine in failing LV myocardium, such as ARAs, have a favorable impact on LV performance. These observations support the continued development of ARA's for the treatment of acute HF syndromes.