Study aimed to examine the limitation of cardiac function (CF) by oxygenation and strategies to improve CF in two cases of reduced oxygen supply : 1) hemodilution by hemorrhagic shock (HS) 2) hypoxia. CF indices where obtained by changes in pressure and volume (PV) through the insertion of a miniaturized conductance catheter into the left ventricle (LV) in a Golden Syrian hamster model. 1) HS was simulated by extracting 30% of blood volume and equal volume reinfusion with either Dextran 70 (Dxt70) or polymerized hemoglobin (PolyHb), the latter is a Hemoglobin (Hb)-based oxygen carrier(HBOC). HS resulted in the fall of CF, decrease cardiac output (CO), stroke volume (SV) and stroke work (SW), with slow recovery to baseline after reinfusion. PolyHb did not show beneficial effects in the CF and resulted in vasoconstriction, with a 116% and 46% increase in systemic vascular resistance (SVR) for 11.5g/dL and 8.5g/dL PolyHb respectively. 2) Effects of hypoxia in the heart were investigated by subjecting animals to 30 min stepwise changes of 15%, 10% and 5% O2. Before hypoxia, hamster was given a vehicle or 100mg/kg of 5-hydroxymethyl-2-furfural (5-HMF). 5-HMF produced no significant differences on moderate hypoxia. At 5\% O2, 5-HMF resulted in increased SW, SV, CO and ejection fraction (EF) of 38%, 53%, 30% and 37% from normoxia; vehicle group resulted in a slight decrease from normoxia. Tissue hypoxia was examined by pimonidazole staining, 5-HMF reduced tissue hypoxia by 64%. Overall 5- HMF reduced the amount of hypoxic tissue and improved CF during acute hypoxia

Acclimatization to hypoxia or high altitude involves physiological adaptation processes, to influence oxygen (O₂) transport and utilization. Several natural products, including aromatic aldehydes and isothiocyanates stabilize the R-state of hemoglobin (Hb), increasing Hb-O₂ affinity and Hb-O₂ saturation. These products are a counter intuitive therapeutic strategy to increase O₂ delivery during hypoxia. 5-Hydroxymethylfurfural (5-HMF) is well known Amadori compound formed during the Maillard reaction (the non-enzymatic browning and caramelization of carbohydrate-containing foods after thermal treatment), with well documented effects in Hb-O₂ affinity. This study explores the therapeutic potential of 5-HMF on left ventricular (LV) cardiac function (LVCF) during hypoxia. Anesthetized Golden Syrian hamsters received 5-HMF i.v., at 100 mg/kg and were subjected to stepwise increased hypoxia (15, 10, and 5%) every 30 min. LVCF was assessed using a closed chest method with a miniaturized conductance catheter via continuous LV pressure-volume (PV) measurements. Heart hypoxic areas were studied using pimonidazole staining. 5-HMF improved cardiac indices, including stroke volume (SV), cardiac output (CO), ejection fraction (EF), and stroke work (SW) compared to the vehicle group. At 5% O₂, SV, CO, EF, and SW were increased by 53, 42, 33, and 51% with 5-HMF relative to vehicle. Heart chronotropic activity was not statistically changed, suggesting that differences in LV-CF during hypoxia by 5-HMF were driven by volume dependent effects. Analysis of coronary blood flow and cardiac muscle metabolism suggest no direct pharmacological effects from 5-HMF, therefore these results can be attributed to 5-HMF-dependent increase in Hb-O₂ affinity. These studies establish that naturally occurring aromatic aldehydes, such as 5-HMF, produce modification of hemoglobin oxygen affinity with promising therapeutic potential to increase O₂ delivery during hypoxic hypoxia.

To better understand human adaptation to stress, and in particular to hypoxia, we took advantage of one of nature's experiments at high altitude (HA) and studied Ethiopians, a population that is well-adapted to HA hypoxic stress. Using whole-genome sequencing, we discovered that EDNRB (Endothelin receptor type B) is a candidate gene involved in HA adaptation. To test whether EDNRB plays a critical role in hypoxia tolerance and adaptation, we generated EdnrB knockout mice and found that when EdnrB (-/+) heterozygote mice are treated with lower levels of oxygen (O2), they tolerate various levels of hypoxia (even extreme hypoxia, e.g., 5% O2) very well. For example, they maintain ejection fraction, cardiac contractility, and cardiac output in severe hypoxia. Furthermore, O2 delivery to vital organs was significantly higher and blood lactate was lower in EdnrB (-/+) compared with wild type in hypoxia. Tissue hypoxia in brain, heart, and kidney was lower in EdnrB (-/+) mice as well. These data demonstrate that a lower level of EDNRB significantly improves cardiac performance and tissue perfusion under various levels of hypoxia. Transcriptomic profiling of left ventricles revealed three specific genes [natriuretic peptide type A (Nppa), sarcolipin (Sln), and myosin light polypeptide 4 (Myl4)] that were oppositely expressed (q < 0.05) between EdnrB (-/+) and wild type. Functions related to these gene networks were consistent with a better cardiac contractility and performance. We conclude that EDNRB plays a key role in hypoxia tolerance and that a lower level of EDNRB contributes, at least in part, to HA adaptation in humans.