Transfusion of polynitroxylated pegylated hemoglobin stabilizes pial arterial dilation and decreases infarct volume after transient middle cerebral artery occlusion

Background--Polynitroxylation of hemoglobin confers superoxide dismutase-mimetic and peroxidase activity and may protect from reperfusion injury in addition to facilitating oxygen transport. We determined whether transfusion of polynitroxylated PEGylated hemoglobin (PNPH) is protective in the rat filament model of 2 hours of middle cerebral artery occlusion (MCAO). Methods and Results--Transfusion of 10 mL/kg of PNPH at 20 minutes of MCAO reduced infarct volume by over 70% (n=10). To determine whether PNPH might act by promoting vasodilation, pial arteriolar diameter in the distal MCA border region was measured in closed cranial windows. With no transfusion, MCAO induced an initial dilation (36±2% ±SE) that subsided by 2 hours (5±4%; n=8). With PNPH transfusion at 20 minutes of MCAO, the initial dilation (31±3%) was better maintained at 2 hours (21±4%; n=7; P < 0.02). Delaying PNPH transfusion until 90 minutes of MCAO increased perfusion in the border region from 48±6% of the preischemic baseline to 67±8% (n=8; P < 0.005). The effect of PNPH transfusion after reperfusion was also tested. Compared with the control median hemispheric infarct volume of 22% (13% to 34% interquartiles; n=15), infarct volume was reduced to 7% (3% to 13%; n=14 P < 0.05) when PNPH was transfused at 4 hours after MCAO (2 hours of reperfusion) but not significantly when transfused at 6 hours (8%; 3% to 35%; n=14) or at 8 hours (12%; 10% to 25%; n=14) after MCAO. Conclusions--PNPH transfusion has a significant therapeutic window for protection during and after transient MCAO and may act, in part, by stabilizing vascular function and improving collateral blood flow.