Antihypoxic properties of endorphins, enkephalins and their analogs

The models of hypoxic hypoxia have been created in the experiments on mice by two ways: placing them into hermetic chamber or "lifting" them to 10.500-10.700 metres in the altitude chamber. The influence of enkephalins and their 12 analogs on the resistance of mice to hypoxia was tested. Enkephalin analogs with antihypoxic activities were detected using both models. It was shown that the mechanism of antihypoxic influence of opioids involves stimulation of their mu- and sigma-receptors and that other neurochemical systems of the body also take part in the realization of antihypoxic effects of the peptides. It is suggested that leu-enkephalin and des-tyr1-gamma-endorphin play, most likely, a role of endogenous antihypoxic agents.     

Comparative study of several preparations in different models of cerebral hypoxia

The antihypoxic effects of gutimine, piracetam, sodium hydroxybutyrate and lithium hydroxybityrate were studied on different models of brain hypoxia. All the drugs under study produced a remarkable antihypoxic effect in experimental asphyxic hypoxia, increasing brain resistance to oxygen deficiency and rapidly restituting brain function. Drug pretreatment of the animals with carotid artery occlusion raised the number of animals which survived 24 h after the operation. GABA salts appeared the most effective. Sodium hydroxybutyrate increased the lifespan of rats under histotoxic hypoxia.     

Experimental study of the antihypoxic properties of ibuprofen and other nonsteroidal anti-inflammatory preparations

The antihypoxic properties of ibuprofen, diclofenac sodium, acetylsalicylic acid and phenylbutazone have been studied. Ibuprofen significantly increases survival of mice in the model of hypoxic hypoxia with hypercapnia. In addition, ibuprofen and diclofenac sodium possess antihypoxic protective activity in the models of circulatory and anoxic hypoxia in rats.     

Differences in the mechanism of the antihypoxic action of benzodiazepine receptor agonists and muscimol

Neuropharmacological analysis of previously revealed antihypoxic activity of benzodiazepines (BDZ) has been performed in experiments on mice exposed to hypoxia. Antihypoxic effect of diazepam is shown to be antagonized by the central BDZ receptor blocker, Ro 15-1788. A certain degree of antihypoxic activity also abolished by Ro 15-1788 is exhibited by hypothetical ligands of BDZ receptors: inosin, nicotinamide, ethyl-beta-carboline-3-carboxylate. The effect of dipyridamole, a drug with high affinity for BDZ receptors of the peripheral type is not antagonized by Ro 15-1788, another evidence of Ro 15-1788 affinity precisely to the central BDZ receptors. GABA-mimetics (muscimol and GABA cetyl ester) were also found to have marked antihypoxic activity. Unlike BDZ receptor agonists, this effect is reduced by bicuculline and not by Ro 15-1788. The data obtained suggest that antihypoxic activity of BDZ is caused by their direct interaction with the central BDZ receptors, probably with the type which is not modulated by GABAA receptors.     

NO-dependent mechanisms of adaptation to hypoxia.

In studying NO-dependent mechanisms of resistance to hypoxia, it was shown that (1) acute hypoxia induces NO overproduction in brain and leaves unaffected NO production in liver of rats; (2) adaptation to hypoxia decreases NO production in liver and brain; and (3) adaptation to hypoxia prevents NO overproduction in brain and potentiates NO synthesis in liver in acute hypoxia. Dinitrosyl iron complex (DNIC, 200 microg/kg, single dose, iv), a NO donor, decreases the resistance of animals to acute hypoxia by 30%. Nomega-nitro-L-arginine (L-NNA, 50 mg/kg, single dose, ip), a NO synthase inhibitor, and diethyl dithiocarbamate (DETC, 200 mg/kg, single dose, iv), a NO trap, increases this parameter 1.3 and 2 times, respectively. Adaptation to hypoxia developed against a background of accumulation of heat shock protein HSP70 in liver and brain. A course of DNIC reproduced the antihypoxic effect of adaptation. A course of L-NNA during adaptation hampered both accumulation of HSP70 and development of the antihypoxic effect. Therefore, NO and the NO-dependent activation of HSP70 synthesis play important roles in adaptation to hypoxia.     

The significance of the mu- and delta-opiate receptors in realizing enkephalin action on the course of hypoxic hypoxia]

New enkephalins analogues have been synthesized. They are characterized by linear, cyclic and branched peptide chain. A relationship has been established between antihypoxic activity of opioid peptides an their interaction with opiate receptors. Compounds efficiently interacting with mu-receptors irrespective of delta-receptors affinity, promote longer survival of mice in hypoxia. The antihypoxic effect of opioids is proportional to their specificity to mu-receptors.     

Effect of melatonin and epithalamin on activity of marker enzymes in the cell membrane in the forebrain of rats under acute hypoxia

The effects of a single-shot intraperitoneally administration of melatonin in a dose of 1 mg per kg body weight and epithalamin in a dose of 2.5 mg per kg body weight on the activities of Na+, K(+)-ATPase and 5'-nucleotidase were investigated in the forebrain of juvenile male white rats under the acute hypobaric hypoxia. The melatonin and epithalamin administration against the background of acute hypoxia prevented an acute hypoxia inducing decrease in the activity of Na+, K(+)-ATPase as well as increased in the activity of 5'-nucleotidase. Such effects of pineal hormones can promote antihypoxic protection of neurons.     

Protective effect of adrenergic alpha 2-receptor agonists in hypoxic hypoxia

The antihypoxic effect of alpha 2-adrenoceptor agonists was studied by two different approaches: reproduction of the effect by a number of alpha 2-agonists and its blockade with selective antagonists. The data obtained suggest that alpha 2-adrenoceptor agonists increase the survival and the lifespan of mice in all the models of acute hypoxic hypoxia under study. A close correlation between antihypoxic action of alpha 2-adrenoceptor agonists and their anticalorigenic effect was established (r = +0.87; P less than 0.01).     

Antihypoxic effect of glucosamine in acute hypoxic states in mice]

The preventive glucosamine injection causes an increase in the survival of mice with acute hypobaric hypoxia. The injection of glucosamine, combined with sodium hydroxybutyrate greatly increased their antihypoxic activities.     

Effect of drugs on the resistance of the myocardium to hypoxia

A method for the investigation of drug effects in the myocardium resistance to hypoxia has been suggested. It is based on the determination of drug effects on the performance of the isolated spontaneously contracting atrium (ISCA) of rats under hypoxic conditions. Hypoxia was induced by oxygen displacement from the nutritional solution by nitrogen. ISCA resistance to hypoxia was assessed by the mechanogram of the heart preparation (the duration and volume of ISCA performance being up to 50% of the initial amplitude). Using the inhibitor analysis, it has been demonstrated that the given model of myocardial hypoxia adequately reflects the role of energy cellular metabolism in the regulation of ISCA resistance to hypoxia and can be used in the search for myocardial antihypoxic agents.     

Antihypoxic and antioxidative properties of bemitil

The authors discovered antihypoxic properties of the bemitil (pretreatment injections 50 mg/kg intraperitoneally) in the experiments on rats with the circulatory or hypoxic hypoxia. There was limitation of pO decrease and diene conjugates and Schiff bases production increase with the drug in the circulatory hypoxia conditions. Bemitil restricted malondialdehyde accumulation in the rat brain homogenate under the activation of free radicals processes. In the mitochondrial suspension incubation similar effect of the medicine was accompanied with limitation of organelle degradation. Bemitil showed no antiradical activity.     

Effect of the antihypoxic agent ionol on the morphofunctional state of the air-blood barrier of the lungs in hypoxic anoxia

It is shown that antihypoxic ionol has promoted normalization of the air-blood lung barrier ultrastructure, activation of the surfactant system under acute hypoxic hypoxia effect as well as compensatory redistribution of the thickness of separate barrier layers due to intensified synthesis of phospholipids which are the components of cytoplasmic membranes and pulmonary surfactant.     

New paths in the pathogenetic correction of hemic hypoxia]

It is stated that prophylactic administration of ional (dibunol) and taurine to rats exerts an antihypoxic effect in case of acute hemic hypoxia. It is expressed in a decrease of methemoglobin level in blood, increase of pO2, in the skeletal muscles, normalization of the structure of hematoparenchymatous barriers, prevention or decrease in a fall of the rate of oxygen consumption by tissues.     

Effect of the Pro-Gly-Pro peptide on resistance of rats to acute hypobaric hypoxia and posthypoxic behavioral disorders

Outbred white rats were subjected to acute hypobaric hypoxia in an altitude chamber at a reduced pressure of 145 mm Hg. Parameters of behavioral activity were evaluated in the tests of elevated cross maze and hole chamber and by the Porsolt method. Posthypoxic behavioral changes were characterized by an increase in the level of anxiety and depression and by a decrease in the level of orienting and exploratory activity. Preliminary intraperitoneal administration of the peptide 15 min before the hypoxia at a dose of 3.7 mol/kg increased the coefficient of individual resistance of the animals owing to a decrease in restitution time and significantly decreased posthypoxic behavioral disorders. We previously found that the Pro-Gly-Pro peptide had positive influence on homeostasis and maintained an adequate blood supply to organs and tissues. It was proposed that this ability of the Pro-Gly-Pro peptide could be one of the important mechanisms for its protective antihypoxic effect.     

Antihypoxic activity of cytochrome c heme peptides

A comparative study of antihypoxic activity of five and two cytochrome c derivatives was performed during their single prophylactic administration on the model of acute hypobaric hypoxia (AHBH) and during rehabilitation period after AHBH, respectively. Antihypoxic efficiency of cytochrome c derivatives was shown to be dependent on doses, time of drug administration, and type of experimental animal resistance. The heme-nonapeptide of cytochrome c proved to be of maximum efficiency during prophylactic administration and rehabilitation period after AHBH.     

Modifications by 1-eburnamonine and vincamine on 2,3-diphosphoglycerate blood levels in the presence or absence of histotoxic hypoxia produced by potassium cyanide in the awake rat]

The influence of 1-éburnamonine (1-E) and vincamine (Vi) on 2,3-disphosphoglycerate (2,3-DPG) blood level was investigated in awake rats when cyanide (KCN) induced hypoxia was present or not. Used alone, KCN, 1-E and Vi (i.p. route) increased 2,3-DPG blood level. Used with KCN, 1-E or Vi produced a very more important increase of 2,3-DPG than that observed when both drugs were used alone. In all cases, the observed increase was attributed to red cells 2,3-DPG since hematocrite, red-cells count and hemoglobin level were unmodified. The results suggest that the KCN induced increase of 2,3-DPG constitutes a response to hypoxia. On the contrary, that of 1-E or Vi seems to be the result of a metabolic stimulation and could explain in part their antihypoxic properties previously described at cerebral level.     

Acute adaptation of mice to hypoxic hypoxia.

Tolerance to hypoxia in vivo and in vitro was significantly increased by acute and repetitive exposure of mice to autoprogressive hypoxia. The average tolerance times of the successive 2nd, 3rd, 4th and 5th runs of exposure were, respectively, 2, 4, 6 and 8 times as long as that of the first exposure. The survival times under hypobaric chamber and cyanide toxification in the 4th exposure were, respectively, 10 (and even as much as 86) and 4 times those in control mice without exposure to hypoxia. Mandibular respiration and spinal reflex in vitro in hypoxia-resistant animals lasted 5-6 times as long as in control animals not previously exposed to hypoxia. Animals that received brain homogenate from hypoxia-resistant mice remained alive in a hypobaric chamber 2 times as long as those that received homogenate from controls and those that received saline. These results indicate that a kind of quickly developing adaptation with increased tolerance is achieved by acute and repetitive exposure of mice to progressive autohypoxia and some plastic or adaptive changes occur in the brain of hypoxia-resistant animals, including the production of some kind of water-soluble antihypoxic factors.     

Antihypoxic effect of vitamin E and its derivative in rats under modeling of hypoxic conditions of different origin

The increase of ubiquinone content in myocardial mitochondria and succinateubiquinone reductase activity in rat blood leucocytes under hypoxic hypoxia and acute microfocal myocardial damage [table: see text] have been shown. At the same time the succinateubiquinone reductase activity of rat myocardial mitochondria do not change substantially. We simultaneously observe the dramatic drop in NADH-ubiquinone reductase activity under experimental myocarditis. This fact demonstrates higher stability of succinateubiquinone reductase system and differences in metabolical processes under hypoxic conditions of different origin. All vitamin E derivatives studied demonstrate substantial antihypoxic activity, which is connected with increased animals' survivability, ubiquinone content in myocardial mitochondria and stabilization and leveling of succinateubiquinone reducatse activity in rat blood leucocytes. alpha-Tocopherolacetate with shortened to six carbon atoms side chain is the most effective in this respect. We discuss possible mechanisms for the realization of vitamin E and its active derivative's antihypoxic effect.     

Taurine improves the recovery of neuronal function following cerebral hypoxia: an in vitro study

Rat hippocampal slices were used in the present study to assess the effect of a pretreatment with the amino acid taurine on their ability to recover synaptic function following a standardized hypoxic insult. After 10 min hypoxia, 47% of all control (untreated) slices exhibited recovery of synaptic function (orthodromically evoked CA1 population spike). Of slices pretreated with 0.5, 1.0 or 2.0 mM taurine, 63, 88 and 97% recovered from the same hypoxic insult. This dose-dependent protective effect was biphasic, as 5.0 mM taurine produced no protection. When hypoxia was extended to 15 min, only 20% of the untreated slices recovered, while 88% of slices treated with 1.0 mM taurine recovered their population spike. The same pretreatment attenuated the fall in the population spike amplitude upon Ca2+ depletion. We hypothesize that taurine plays an important role in an endogenous antihypoxic mechanism through the attenuation of Ca2+ movement across the neuronal membrane.     

Radiation protection of mice with hypoxic gas mixtures after administration of anti-hypoxic agents

It is shown that such substances as gutimine, antizol and mexamine increases the resistance of animals to short-term breathing of gas mixtures containing 6 and 5% oxygen. Even if some of them decrease the degree of radioprotective effect of hypoxia, they afford the possibility to safe use of breathing mixtures with lower oxygen content than endured by intact animals, with the resulting increase in radioprotection. Thus the antihypoxic substances can be tested during hypoxiradiotherapy of human tumors.