GP-531

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 (10 μg/kg/min) or vehicle (normal saline) for 6 h in random order 1 week apart. Hemodynamic measurements were made at baseline and at 1, 2, 3, 4, 5 and 6 h after initiating drug infusion. Myocardial oxygen consumption (MVO2) was measured at baseline and 4 and 6 h. LV pressure-volume relationship (PVR) was measured at baseline and 6 h.

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 6 h 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.

GP531, a potent, second-generation adenosine-regulating agent, is pharmacologically silent under basal conditions but increases localized endogenous adenosine during ischemia. GP531 improves functional recovery after myocardial ischemia, but its effects on infarct size and no-reflow have not been reported. The objective was to determine whether GP531 reduces necrosis and the anatomic no-reflow defect and to evaluate its effects on regional myocardial blood flow (RMBF). GP531 was given as a loading dose plus infusion at 2 doses (700 μg/kg and 10 μg/kg per minute or 2100 μg/kg and 30 μg/kg per minute) or vehicle, starting 12 minutes before a 30-minute coronary occlusion and throughout 3 hours reperfusion in rabbits. Risk zone was delineated by blue dye, necrosis by tetrazolium staining, RMBF by radioactive microspheres, and no-reflow defect by thioflavin S. The extent of the ischemic risk zone was similar in all groups. Low-dose GP531 reduced infarct size by 34% (0.33 ± 0.4 of the risk zone) compared with vehicle (0.50 ± 0.4, P < .01) and reduced the extent of the anatomic no-reflow zone by 31% compared with vehicle (0.25 ± 0.3 of the risk zone vs 0.36 ± 0.4 in the vehicle group, P < .05). Infarct size and zone of no-reflow in the high dose were reduced by 22% and 16%, respectively (P = NS vs the other 2 groups). GP531 did not affect hemodynamics or blood flow. Thus, GP531 was effective at the lower dose evaluated in this study, reducing the severity of ischemic/reperfusion injury, without inducing the adverse hemodynamic effects associated with adenosine administration such as bradycardia and hypotension.