Is oxygen insufficiency compensated during acute ischemia? - A PET study in an ischemic model of non-human primates

Abstract

Insufficient delivery of oxygen to tissue is the central core of ischemia. A large number of observations in rodents revealed that compensatory responses against ischemia occurs at cellular or biochemical level, however, there is a lack of in vivo evidences of biological responses to fulfil oxygen demand. Among them, vascular response to maintain the delivery (e.g. vasodilatation) and transport efficiency of metabolic substrates from blood to tissue assumed to be fundamental (Hayashi et al. 2003). Here, we show using PET whether there is response in vasculature or in the diffusion efficiency of oxygen in an acute stroke model in non-human primates. We used four adult male macaque monkeys (macaca fascicularis, body weight = 5 kg). The study was approved by the local committee of animal experiments. Experiments were performed under general anesthesia using propofol. A single PET scan with dual tracer/integration (DTI) method for CBF/CMRO2 and a PET scan for CBV were repeatedly performed before and 360 min after the artificial embolization of intracerebral artery. Embolization was produced by injecting autologous blood clot through a thin catheter placed at middle cerebral artery or internal carotid artery. Ischemic of interest (ROI) were defined by searching voxels with the highest values in the oxygen extraction fraction (OEF) images at the time point of 5 min or 180 min after embolization. CBF, CMRO2 and CBV values were also obtained by placing the same ROI to the corresponding images. CBV values were used for the assessment of vascular response, whereas effective oxygen diffusibility (EOD) that was calculated from measured CBF, OEF and arterial haemoglobin content (Hb) and oxygen saturation fraction (Sa) was used as a marker of efficiency of oxygen transport from blood to brain tissues (Hayashi et al. 2003). The values were normalized by ROI values in cerebellum for each image and by the values at the time point of pre-embolization for each subject to minimize measurement- and subject-specific variability. The mirror contralateral to the ROI were used for control. Ischemic (n = 7) showed decrease in CBF (-30%, -32% at 5 min and 180 min, respectively) and CMRO2 (-18%, -10%) and increase in OEF (+18%, +26%) compared to the control. CBV values showed no change (+1%, +2%) whereas EOD decreased (-12%, -11%). When the regions were divided in two categories by the final tissue outcome (non-infarcted or infarcted), significant decreases in CBF, CMRO2 and EOD were found in the of final infracted, but no difference in CBV were seen between the two categories. Similar results were also obtained in the other time points (30, 60, 120, 210 and 360 min post embolization). These results reveal that in acute ischemic there is little response in vasculature and that change in diffusion efficiency of oxygen does not act as a compensatory response rather passively depends on the metabolic demand, although oxygen extraction fraction is increased. The findings indicate that brain tolerance for oxygen insufficiency is not so large that oxygen metabolism during ischemia correlates final tissue outcome.