Increased Oxyhemoglobin Binding Affinity Improves Cerebrovascular Responses To Hypoxia In Sprague-Dawley Rats

Abstract

PURPOSE: This study evaluated the effect of increased oxyhemoglobin (O-H) affinity on cerebrovascular response to normobaric hypoxia. METHODS: Cerebrovascular response was assessed in 18 mechanically-ventilated Sprague-Dawley rats during acute exposure to normobaric hyperoxia (FiO2 1.0), normoxic air (FiO2 0.21), and hypoxic air (FiO2 0.10). Prior to exposure, the rats were administered GBT-1118 (GBT, 100mg/kg) or normal saline via oral gavage. Pial microcirculation was assessed and quantified through a cranial window created in the parietal bone of anesthetized rats. Cardiopulmonary parameters were measured throughout the exposures. Oxyhemoglobin binding affinity (p50) was assessed following the final gas exposure using a Hemox Analyzer. RESULTS: The mean p50 of GBT- and saline-treated animals was 31.46 and 37.63, respectively, demonstrating increased O-H affinity with GBT (p=0.0017). During steady state normoxia (FiO2 0.21), mean pial artery diameter decreased from baseline (FiO2 1.0) by 0.26% in saline animals compared to a 3.99% increase in GBT animals (p=0.1807). Additionally, GBT-treated animals demonstrated an 11.7% increase in blood O2 saturation (p<0.0001), an 11.4% increase in peak CO2 (p=0.0692), and an 8% increase in heart rate (HR) (p=0.015) compared to saline controls. During steady state hypoxia (FiO2 0.10), mean pial artery diameter decreased from baseline by 23.83% in saline animals compared to a 3.78% increase in GBT animals (p<0.0001). Additionally, GBT-treated animals demonstrated an 11.4% increase in blood O2 saturation (p=0.012), a 14.1% increase in peak CO2 (p=0.074), and a 9.3% decrease in HR (p=0.018) compared to saline controls. CONCLUSIONS: Collectively, the data show that impairments in cerebrovascular and cardiopulmonary function resulting from exposure to severe hypoxia can be mitigated through increased O-H binding and subsequent increases in blood oxygenation.