Antihypoxic effect of almid-containing metal-complex compounds in the experiment

BACKGROUND: To increase resistance to hypoxia, various methods of hypoxic training, mental effects, and use of pharmacological antihypoxants are employed.

AIM: To test new metal-complex compounds containing the antihypoxant almid in mice under conditions of acute hypoxia to determine their protective properties.

MATERIALS AND METHODS: In the first stage of the study, four new metal-complex compounds of magnesium, calcium, titanium, and vanadium containing the antihypoxant almid were screened in experiments on mice (n = 550) under acute hypoxic conditions with hypercapnia. The antihypoxants almid and amtizole were used as comparison substances. Acute hypoxia was induced by placing the animals in pharmacy glasses with a volume of 0.25 L with closed lapped stoppers. The substances were administered intraperitoneally at doses of 25, 50, and 100 mg/kg previously dissolved in 0.3 mL of NaCl solution. The incubation period was 60 min. The antihypoxic effect was considered confirmed if the lifespan increased by ≥20%. “Lifespan” refers to the time interval from the moment the mice were placed in a pharmacy glass to the development of the first agonal inhalation, after which the animals were quickly removed to preserve life. The rectal temperature of the animals was measured before the introduction of substances, immediately before being exposed to acute hypoxic conditions with hypercapnia, and after removal. Twenty-four hours after the first stage of the experiment, mice of the control group and mice that proved their ability to resist acute hypoxia with hypercapnia were repeatedly exposed to acute hypoxic conditions with hypercapnia after the use of substances.

RESULTS: A distinct antihypoxic effect exceeding the effectiveness of the comparison substances was obtained only in one substance—πQ2460 with titanium as a metal-complexing agent—and a ligand in the form of fumaric acid. After the administration of πQ2460, a dose-dependent decrease in rectal temperature was observed in mice. The lifespan of animals increased with an increase in the dosage of πQ2460, i.e., by 43.9%, 103.1%, and 152.8% for doses of 25, 50, and 100 mg/kg, respectively. The results of the second stage of the experiment confirmed the stable protective effect of πQ2460 but with an equalization of the effect of the studied doses, which increased the lifespan under acute hypoxic conditions with hypercapnia to an average of 60–70 min (control group, 40.5 min).

CONCLUSION: Among the compounds containing the antihypoxant almid in the complex molecule, πQ2460 (metal, titanium; ligand, fumaric acid) was found to have a stable protective dose-dependent effect on the development of acute hypoxia with hypercapnia in mice exceeding that for almid and the reference antihypoxant amtizole. The antihypoxic effect of πQ2460 persisted 24 h after its administration but leveled off for the studied doses—25, 50, and 100 mg/kg. Considering the data obtained during the comparison of the indicators of resistance to acute hypoxia in the control group, a hypothesis was proposed regarding the possibility of forming a preconditioning effect in animals from the primary effects of acute hypoxia.