Underlying mechanism of subcortical brain protection during hypoxia and reoxygenation in a sheep model - Influence of α1-adrenergic signalling

Abstract

While the cerebral autoregulation sufficiently protects subcortical brain regions during hypoxia or asphyxia, the cerebral cortex is not as adequately protected, which suggests that regulation of the cerebral blood flow (CBF) is area-specific. Hypoxia was induced by inhalation of 5% oxygen, for reoxygenation 100% oxygen was used. Cortical and subcortical CBF (by laser Doppler flowmetry), blood gases, mean arterial blood pressure (MABP), heart rate and renal blood flow were constantly monitored. Low dosed urapidil was used for α1A-adrenergic receptor blockade. Western blotting was used to determine adrenergic receptor signalling mediators in brain arterioles. During hypoxia cortical CBF decreased to 72 ± 11% (mean reduction 11 ± 3%, p < 0.001) of baseline, whereas subcortical CBF increased to 168±18% (mean increase 43 ± 5%, p < 0.001). Reoxygenation led to peak CBF of 194 ± 27% in the subcortex, and restored cortical CBF. α1A-Adrenergic blockade led to minor changes in cortical CBF, but massively reduced subcortical CBF during hypoxia and reoxygenation–almost aligning CBF in both brain regions. Correlation analyses revealed that α1A-adrenergic blockade renders all CBF-responses pressure-passive during hypoxia and reoxygenation, and confirmed the necessity of α1A-adrenergic signalling for coupling of CBF-responses to oxygen saturation. Expression levels and activation state of key signalling-mediators of α1-receptors (NOSs, CREB, ERK1/2) did not differ between cortex and subcortex. The dichotomy between subcortical and cortical CBF during hypoxia and reoxygenation critically depends on α1A-adrenergic receptors, but not on differential expression of signalling-mediators: signalling through the α1A-subtype is a prerequisite for cortical/subcortical redistribution of CBF.

Altered Cerebral Blood Flow and Potential Neuroprotective Effect of Human Relaxin-2 (Serelaxin) During Hypoxia or Severe Hypovolemia in a Sheep Model

“…We confirmed the dichotomy of cortical and subcortical CBF in control animals during hypoxia ( Figure 4A) [19]. The subcortical CBF increased over the course of hypoxia, whereas the cortical CBF decreased in comparison to baseline values (both p < 0.001), resulting in a significant difference in CBF between the two brain regions (p < 0.05).…”

“…Sheep were elected as the experimental model for our studies because of their similarities to humans, including body weight, physiological parameters, and organization of the brain. Using this model, we have previously shown that hemorrhage [20] or hypoxia [19], respectively, trigger differential CBF responses in the cortex and subcortex. Both damage models resulted in lower cortical CBF in comparison with subcortical CBF, which was replicated in this present study.…”

Sleep in the Supine Position During Pregnancy is Associated with Fetal Cerebral Redistribution

“…Indeed, there is now considerable evidence that fetal cerebral redistribution is associated with adverse outcomes, including perinatal death, even in appropriately grown fetuses [ 29 , 54 , 55 , 56 ]. In animal models, it has been proposed that the regulation of cerebral blood flow is area-specific, with some areas more prone to cerebral injury in the event of a hypoxic event [ 57 , 58 ]. It has also been proposed that fetal brain injury may actually be initiated as a consequence of cerebral redistribution, with increased flow as a particular risk factor [ 59 , 60 ].…”

The relationship between cytochrome c oxidase, CBF and CMRO2 in mouse cortex: A NIRS-MRI study

“…Moreover, it was reported that CBF response to hypoxia is brain area-specific. 78 During hypoxia (5% O 2 ), subcortical brain regions showed a high protection mechanism through cerebral autoregulation, but in the cerebral cortex the protection mechanism failed and CBF decreased with hypoxia. 78 Mild and severe hypoxia induced by reducing S a O 2 resulted in a reduction in cellular oxygen availability.…”