Pharmacokinetics of Trelagliptin in Rats after Exposure to Acute and Chronic High Altitude Hypoxia.

Tian, Lu, Guiqin Liu, Qin Zhao, Junjun Han, Yue Lin, Qian Wang, Qiangqiang Jia, Delong Duo, Duan Yabin, Zhu Junbo, and Li Xiangyang. Pharmacokinetics of midazolam in plasma and brain tissue of rats after exposure to acute and chronic high altitude hypoxia. High Alt Med Biol. 26:273-282, 2025. Background: Midazolam effectively improves sleep quality under high altitude hypoxia by reducing central nervous system excitability. Methods: Field modeling and sample collection were performed at an altitude of 4,300 m in a high altitude hypoxic environment with a pressure of inspired oxygen of 107 mmHg. Pharmacokinetic alterations of midazolam in high altitude hypoxic rats are determined by high performance liquid chromatography-mass spectrometry. Quantitative real-time polymerase chain reaction and Western blot were used to confirm the connection with drug metabolism and alterations in hypoxia CYP3A4 and P-glycoprotein (P-gp) expression. Results: This study demonstrated that high altitude hypoxia increased blood-brain barrier permeability in rats, caused brain tissue damage, and altered the expression of inflammatory cytokines in the brain. In the acute high altitude group and the chronic high altitude group, the area under the curve and Tmax of plasma midazolam revealed substantial increases of 88.6% and 283% and 28.6% and 85.3%, respectively. The clearance rate reduced by 47.3% and 90.0%, while the brain-blood drug concentration ratio (Cbrain/Cplasma) diminished by 11.4% and 82.1%, respectively. The relative expression of CYP3A1 mRNA in the brain tissue of high altitude rats decreased by 42.4% and 66.8%, respectively, and the protein expression was downregulated, while the relative expression of P-gp mRNA increased by 61.3% and 91.2%, respectively (p < 0.05 for all parameters), and the protein expression was upregulated. High altitude hypoxia altered CYP3A1 and P-gp expression and activity, causing alterations in midazolam metabolism. Conclusions: This research provided a new reference for the rational use of midazolam in highland areas.

Lifelong high‐altitude hypoxia induces arterial baroreflex adaptations: new insights and future directions

The effects of exposure to acute and chronic high altitude hypoxia on the activity and expression of CYP2E1 and CYP3A1 were examined in rats. Rats were divided into low altitude (LA, 400 m), acute moderate altitude hypoxia (AMH, 2800 m), chronic moderate altitude hypoxia (CMH, 2800 m), acute high altitude hypoxia (AHH, 4300 m), and chronic high altitude hypoxia groups (CHH, 4300 m). Probe drugs were administrated orally to all five groups. Then the serum concentration of probe drug and its metabolite was determined by RP-HPLC. The activity of CYP2E1 and CYP3A1 was evaluated using the ratio of the metabolite to chlorzoxazone and testosterone, respectively. ELISA and real-time PCR were used to analyze the protein and mRNA expression of CYP2E1 and CYP3A1 in liver microsomes, respectively. Chronic high altitude hypoxia caused significant decreases in the activity and protein and mRNA expression of rat CYP2E1 and CYP3A1 in vivo. Acute high altitude hypoxia was not found to change the activity, protein or mRNA expression of rat CYP2E1 or CYP3A1. This study showed significant changes in the activity and protein and mRNA expression of CYP2E1 or CYP3A1 in rats after exposure to chronic high altitude hypoxia.

ABSTRACTS 7th World Congress of Mountain & Wilderness Medicine A combined meeting of the International Society for Mountain Medicine and the Wilderness Medical Society July 30-August 4, 2016 Telluride, Colorado.

We have shown that in pulmonary vessels, cGMP acts through cGMP-dependent protein kinase (PKG) dependent and independent mechanisms to mediate vasodilation (JAP, 2000), and that cGMP-induced relaxation of pulmonary vessels is greater in normoxia compared to acute hypoxia (AJP, 2003). In this study, we examined the effect of chronic high altitude hypoxia (HAH) on cGMP-PKG-mediated relaxation. Isolated ovine intrapulmonary arteries (PAs) from pregnant ewes exposed to HAH (ewes kept at 12,470 ft altitude from ~35d to 145d gestation; term 150d) or matched normoxic controls were preconstricted with endothelin-1 and relaxed to 8-Bromoguanosine 3′,5′-cyclic monophosphate (8-Br-cGMP), a cell membrane-permeable analog of cGMP, or to DETA NONOate, a stable nitric oxide donor. We found that PAs relaxed to NO through both cGMP-dependent and independent mechanisms in normoxia. In chronic hypoxia, NO-mediated relaxation increased significantly, suggesting that guanylyl cyclase activity may be upregulated in these vessels. We observed minimal PKG-mediated relaxation both in normoxia or hypoxia. Furthermore, the inhibition of ROCK with a Rho-kinase-specific inhibitor (Y27632), induced increased relaxation of PAs to cGMP in chronic HAH PAs, but not in normoxic PAs, suggesting altered Rho/ROCK signaling under chronic HAH. We hypothesize that chronic high altitude hypoxia may induce sustained pulmonary vasoconstriction via increased protein expression and/or post-translational modification of ROCK or through altered protein-protein interactions involving Rho/ROCK, and that there is a compensatory upregulation of NO-cGMP mediated relaxation. HL059435, MIRS to S. Negash.

Hypoxia causes pulmonary vasoconstriction. Regional hypoxic vasoconstriction improves the matching of perfusion to alveolar ventilation. Global hypoxic vasoconstriction increases right ventricular afterload. The hypoxic pulmonary pressor response is universal in mammals and in birds, but with considerable interspecies and interindividual variability. Chronic hypoxia induces pulmonary hypertension in proportion to initial vasoconstriction. Prolonged hypoxic exposure is also associated with an increase in red blood cell mass, which aggravates pulmonary hypertension by an increase in blood viscosity. Hypoxic pulmonary hypertension in humans is usually mild to moderate, but pulmonary vascular pressure-flow relationships are steep, which corresponds to a substantial afterload on the right ventricle during exercise. A partial recovery of 10-25% of the hypoxia-induced decrease in maximal oxygen uptake has been reported with intake-specific pulmonary vasodilating interventions. Hypoxia has been reported to decrease myocardial fibre contractility in vitro. However, the acutely hypoxic right ventricle remains able to preserve the coupling of its contractility to increased afterload in intact animals. Echocardiographic studies of the right ventricle in healthy hypoxic human subjects show altered diastolic function, but systolic function that is preserved or even increased acutely and slightly depressed chronically. These findings are more pronounced in patients with chronic mountain sickness. Their clinical significance remains incompletely understood. Almost no imaging studies of right ventricular function have been reported in a minority of subjects who develop severe pulmonary hypertension and clinical right ventricular failure in hypoxia. No imaging studies of right ventricular function during hypoxic exercise in normal subjects are yet available. Thus, while it is plausible that the right ventricle limits exercise capacity in hypoxia, this still needs to be firmly established.

Hypoxia can alter the Pharmacokinetic (PK) characteristics of drugs, thereby affecting drug absorption, distribution, metabolism, and excretion. Environmental characteristics at high altitude include but are not limited to hypobaric hypoxia, low temperature, high solar radiation, and arid climate, all of which can adversely affect normal bodily functions. Therefore, it is important to study the pharmacokinetic changes of drugs at high altitude. A systematic review of published studies was carried out to investigate the effects of hypoxia on the metabolic characteristics of some drugs and the activity and expression of drug-metabolizing enzymes in high-altitude hypoxic environments, and discussed the relevant mechanisms. The metabolism of most drugs decreases in high-altitude hypoxia, whereas Mean Residence Time (MRT), Half Time (T1/2), and Area Under the Curve (AUC) increase and Clearance (CL) decrease in this environment. The effect of hypoxia on CYP450 enzymes in animals is still a subject of debate. With the exception of CYP2C11 and CYP2C22, the widespread belief is that high-altitude hypoxia decreased the activity and expression of CYP1A1, CYP1A2, CYP2E1, and CYP3A1, and increased those of CYP3A6 and CYP2D1 in rats. The changes in the activity and expression of drug metabolizing enzymes are consistent with the changes in pharmacokinetics of some enzyme substrates in the high-altitude hypoxia environment. The findings of this review have indicated that hypoxia may play a key role in the PK changes of drugs at high altitude. It is suggested that patient living at or traveling to high altitude should be closely monitored, and the dosages of some drugs metabolized should be reduced.

Does Ibuprofen Prevent Acute Mountain Sickness?

Point: Counterpoint: Hypobaric hypoxia induces/does not induce different responses from normobaric hypoxia

ObjectiveObesity is common in highland areas owing to lifestyle alterations. There are pieces of evidence to suggest that both obesity and hypoxia may promote oxidative stress, leading to hypogonadism in males. These findings indicate an increased risk of hypogonadism in obese males following hypoxia exposure. However, the mechanisms underlying the disease process remain unclear. The current study aims to explore the mechanism of testosterone production dysfunction in obese male mice exposed to a chronic high-altitude hypoxia environment.MethodsAn obese male mouse model was generated by inducing obesity in mice via a high-fat diet for 14 weeks, and the obese mice were then exposed to a high-altitude hypoxia environment for 24 days. Sera and testicular tissues were collected to detect serum lipids, sex hormone level, and testicular oxidative stress indicators. Morphological examination was performed to assess pathological alterations in testicular tissues and suborganelles in leydig cells. Proteomic alterations in testicular tissues were investigated using quantitative proteomics in Obese/Control and Obese-Hypoxia/Obese groups.ResultsThe results showed that chronic high-altitude hypoxia exposure aggravated low testosterone production in obese male mice accompanied by increased testicular oxidative stress and histological damages. In total, 363 and 242 differentially expressed proteins (DEPs) were identified in the two comparison groups, Obese/Control and Obese-Hypoxia/Obese, respectively. Functional enrichment analysis demonstrated that several significant functional terms and pathways related to testosterone production were altered in the two comparison groups. These included cholesterol metabolism, steroid hormone biosynthesis, peroxisome proliferator-activated receptor (PPAR) signaling pathway, oxidative stress responses, as well as retinol metabolism. Finally, 10 representative DEPs were selected for parallel reaction monitoring verification. Among them, StAR, DHCR7, NSDHL, CYP51A1, FDPS, FDX1, CYP11A1, ALDH1A1, and GPX3 were confirmed to be downregulated in the two groups.ConclusionsChronic hypoxia exposure could exacerbate low testosterone production in obese male mice by influencing the expression of key proteins involved in steroid hormone biosynthesis, cholesterol biosynthesis, oxidative stress responses and retinol metabolism.

High-altitude hypoxic environments have critical implications on cardiovascular system function as well as blood pressure regulation. Such environments place patients with hypertension at risk by activating the sympathetic nervous system, which leads to an increase in blood pressure. In addition, the high-altitude hypoxic environment alters the in vivo metabolism and antihypertensive effects of antihypertensive drugs, which changes the activity and expression of drug-metabolizing enzymes and drug transporters. The present study reviewed the pharmacodynamics and pharmacokinetics of antihypertensive drugs and its effects on patients with hypertension in a high-altitude hypoxic environment. It also proposes a new strategy for the rational use of antihypertensive drugs in clinical practice in high-altitude hypoxic environments. The increase in blood pressure on exposure to a high-altitude hypoxic environment was mainly dependent on increased sympathetic nervous system activity. Blood pressure also increased proportionally to altitude, whilst ambulatory blood pressure increased more than conventional blood pressure, especially at night. High-altitude hypoxia can reduce the activities and expression of drug-metabolizing enzymes, such as CYP1A1, CYP1A2, CYP3A1, and CYP2E1, while increasing those of CYP2D1, CYP2D6, and CYP3A6. Drug transporter changes were related to tissue type, hypoxic degree, and hypoxic exposure time. Furthermore, the effects of high-altitude hypoxia on drug-metabolism enzymes and transporters altered drug pharmacokinetics, causing changes in pharmacodynamic responses. These findings suggest that high-altitude hypoxic environments affect the blood pressure, pharmacokinetics, and pharmacodynamics of antihypertensive drugs. The optimal hypertension treatment plan and safe and effective medication strategy should be formulated considering high-altitude hypoxic environments.

Altitude physiology then (1921) and now (2021): Meat on the bones.

High-altitude chronic hypoxia prevents myocardial dysfunction in experimental model of type 2 diabetes.

Objective To study the function of the rennin-angiotensin-aldoterone system(RAAS) under high altitude hypoxia environment and objective to investigate the effects of high altitude hypoxia on the angiotensin conversion enzyme 2(ACE2) mRNA and protein expressions in SD rat right ventricle. Methods Forty male adult Sprague Dawley( SD) rats, under high altitude hypoxia environment were divided randomly into 4 groups: the control group(D group, Xi'an area 5m above sea leve1), the 1-day (A group)hypoxia group, the 3-day(B group) hypoxia group and the 30-day (C group)hypoxia group. To move the standardized healthy male SD rats to high altitude environment 1d brings up Qinghai Gelmu ( height above sea level 2700m ) and 3d to bring up Tibet Naqu( height above sea level 4500m ) and 30d Tibet Naqu when 3 experimentals group animals from plain(5m above sea leve1). and use radiating immunity law ( RAI ) is ascertained by measuring great rat plasma the concentration of PRA, AT II, ALD in 4 groups. ACE2 mRNA and p rotein of right ventricle were measured by RT-PCR and Western blot. Results A's series plasma PRA's content act as 5.15 ±s 0.86, AT II's content act as 92.10±10.25, ALD's content act as 85.60 ±s 29.40; B's series plasma PRA's content is 7.12 ±s 0.31, AT II's content act as 160.53±10.84, ALD's content act as 56.30±25.23;C's series plasma PRA's content is 5.37 ±s 0.28, AT II's content act as 127.45±30.6, ALD's content act as 82.54±26.78.ACE2 mRNA and ACE2 protein synthesis in right ventricle were increased accordingly after 30-day exposure to high altitude hypoxia (P &#60; 0.01). Conclusion RAAS is concerned with acclimatization hige altitude hypoxia environment and have important effect. ACE2 mRNA of the right ventricule and ACE2 protein synthesis were increased under high altitude hypoxia environment, suggesting that ACE2 may play a role in high altitude hypoxic adap tation of the heart.

High-altitude (HA) hypoxia may alter the structural-functional integrity of the neurovascular unit (NVU). Herein, we compared male lowlanders (n=9) at sea level (SL) and after 14days acclimatization to 4300m (chronic HA) in Cerro de Pasco (CdP), Péru (HA), against sex-, age- and body mass index-matched healthy highlanders (n=9) native to CdP (lifelong HA). Venous blood was assayed for serum proteins reflecting NVU integrity, in addition to free radicals and nitric oxide (NO). Regional cerebral blood flow (CBF) was examined in conjunction with cerebral substrate delivery, dynamic cerebral autoregulation (dCA), cerebrovascular reactivity to carbon dioxide (CVRCO2 ) and neurovascular coupling (NVC). Psychomotor tests were employed to examine cognitive function. Compared to lowlanders at SL, highlanders exhibited elevated basal plasma and red blood cell NO bioavailability, improved anterior and posterior dCA, elevated anterior CVRCO2 and preserved cerebral substrate delivery, NVC and cognition. In highlanders, S100B, neurofilament light-chain (NF-L) and T-tau were consistently lower and cognition comparable to lowlanders following chronic-HA. These findings highlight novel integrated adaptations towards regulation of the NVU in highlanders that may represent a neuroprotective phenotype underpinning successful adaptation to the lifelong stress of HA hypoxia. KEY POINTS: High-altitude (HA) hypoxia has the potential to alter the structural-functional integrity of the neurovascular unit (NVU) in humans. For the first time, we examined to what extent chronic and lifelong hypoxia impacts multimodal biomarkers reflecting NVU structure and function in lowlanders and native Andean highlanders. Despite lowlanders presenting with a reduction in systemic oxidative-nitrosative stress and maintained cerebral bioenergetics and cerebrovascular function during chronic hypoxia, there was evidence for increased axonal injury and cognitive impairment. Compared to lowlanders at sea level, highlanders exhibited elevated vascular NO bioavailability, improved dynamic regulatory capacity and cerebrovascular reactivity, comparable cerebral substrate delivery and neurovascular coupling, and maintained cognition. Unlike lowlanders following chronic HA, highlanders presented with lower concentrations of S100B, neurofilament light chain and total tau. These findings highlight novel integrated adaptations towards the regulation of the NVU in highlanders that may represent a neuroprotective phenotype underpinning successful adaptation to the lifelong stress of HA hypoxia.