EFFECTS OF THE ALLOSTERIC MODIFICATION OF HEMOGLOBIN ON BRAIN OXYGEN AND INFARCT SIZE IN A FELINE MODEL OF STROKE

Background and Purpose Cerebral ischemia and stroke are leading causes of morbidity and mortality. An approach to protecting the brain durin g ischemia is to try to increase the delivery of oxygen via the residu al blood flow through and around ischemic tissue. To test this hypothe sis, we used a novel oxygen delivery agent, RSR-13 nilino)carbonyl]-me thyl]phenoxy]-2-methylpropionic acid). Intravenous administration of R SR-13 increases oxygen delivery through allosteric modification of the hemoglobin molecule, resulting in a shift in the hemoglobin/oxygen di ssociation curve in favor of oxygen delivery. Methods We studied RSR-1 3 in a feline model of permanent middle cerebral artery occlusion to a ssess its effects on cerebral oxygenation and infarct size. A randomiz ed, blinded study of RSR-13 (n=6) versus 0.45% saline (n=12) was condu cted, after an RSR-13 dose-escalation study (n=4). Drug was administer ed as a preocclusion bolus followed by a continuous infusion for the d uration of the experiment (5 hours). Brain oxygen was measured continu ously with the use of a Clark oxygen electrode. Infarct size was measu red at 5 hours after occlusion with computer-assisted volumetric analy sis. Results The drug treatment group had consistently higher mean bra in oxygen tension than controls (33+/-5 and 27+/-6 mm Hg, respectively ) and significantly smaller infarcts (21+/-9% versus 33+/-9%, respecti vely; P<.008). We observed an inverse relationship between the dose re sponse of RSR-13 (the shift in the hemoglobin/oxygen dissociation curv e) and infarct size. Conclusions These results are evidence that allos teric hemoglobin modification is protective to the brain after acute f ocal ischemia, providing a new opportunity for neuroprotection and rai sing the possibility of enhancing the protective effect of thrombolysi s and ion channel blockade.