Exogenous Sphingosine-1-Phosphate Boosts Acclimatization in Rats Exposed to Acute Hypobaric Hypoxia: Assessment of Haematological and Metabolic Effects

Abstract

BackgroundThe physiological challenges posed by hypobaric hypoxia warrant exploration of pharmacological entities to improve acclimatization to hypoxia. The present study investigates the preclinical efficacy of sphingosine-1-phosphate (S1P) to improve acclimatization to simulated hypobaric hypoxia.Experimental ApproachEfficacy of intravenously administered S1P in improving haematological and metabolic acclimatization was evaluated in rats exposed to simulated acute hypobaric hypoxia (7620m for 6 hours) following S1P pre-treatment for three days.Major FindingsAltitude exposure of the control rats caused systemic hypoxia, hypocapnia (plausible sign of hyperventilation) and respiratory alkalosis due to suboptimal renal compensation indicated by an overt alkaline pH of the mixed venous blood. This was associated with pronounced energy deficit in the hepatic tissue along with systemic oxidative stress and inflammation. S1P pre-treatment improved blood oxygen-carrying-capacity by increasing haemoglobin, haematocrit, and RBC count, probably as an outcome of hypoxia inducible factor-1α mediated erythropoiesis and renal S1P receptor 1 mediated haemoconcentation. The improved partial pressure of oxygen in the blood could further restore aerobic respiration and increase ATP content in the hepatic tissue of S1P treated animals. S1P could also protect the animals from hypoxia mediated oxidative stress and inflammation.ConclusionThe study findings highlight S1P’s merits as a preconditioning agent for improving acclimatization to acute hypobaric hypoxia exposure. The results may have long term clinical application for improving physiological acclimatization of subjects venturing into high altitude for occupational or recreational purposes.

S1P prophylaxis mitigates acute hypobaric hypoxia‐induced molecular, biochemical, and metabolic disturbances: A preclinical report

“…The boosted hypoxia‐adaptive responses observed in our study were attributed to S1P receptor‐mediated hemo concentration and stabilization of hypoxia‐inducible factor (HIF)−1α, although there could exist, yet unexplored, biological mechanism for its preconditioning efficacy. With our earlier proof‐of‐concept study, we have thus substantiated that systemically raised levels of S1P confer adaptive advantage during hypoxia exposure .…”

“…group, the hypoxic energy deficit is salvaged by reinstated aerobic enzymes activities, upregulated anaerobic enzyme activities, and improved glucose utilization. The raised aerobic energy production is conceived to be an outcome of higher bioavailable oxygen due to S1P preconditioning, as reported earlier , and to the S1P‐mediated HIF‐1α and Hsp70 accumulation, which in turn boost anaerobic enzyme activities (Fig. ; refs.…”

“…Acute phase HA exposure, thus, leads to precipitation of several pathological disturbances, which although may not be solely responsible for the onset of HA diseases, and are associated clinically with AMS, HAPE, HACE, thrombosis, etc (15)(16)(17). Our group is investigating potential pharmacological HA acclimatization inducing prophylactics and have previously reported boost in S1P preconditioning-mediated hypoxia-adaptive responses, leading to higher bioavailable oxygen systemically (7,10). In this study, we extend our investigation to evaluate the protective efficacy of S1P preconditioning against the hypoxia-associated pathological disturbances.…”

“…The cardioprotective consequences of S1P preconditioning, as well as its protective benefits in pulmonary/cerebral tissues, stem, at least in part, from induction HIF-1a and HSP 70 (7,10,(26)(27)(28). HIF-1a is a classical hypoxia-adaptive marker, functionally controlling the transcription of hypoxia-adaptive gene expression, including HSP70.…”

Joint neutron crystallographic and NMR solution studies of Tyr residue ionization and hydrogen bonding: Implications for enzyme-mediated proton transfer

“…The pH of normal blood is 7.35-7.50, which is slightly above the pK a for Tyr7, suggesting that roughly half the population would be deprotonated (28). Given this pK a that is within the physiological pH range, there are profound implications for the role of Tyr7 in PT under normal conditions.…”