Delayed antihypoxic effect of leu enkephalin in mice

Hypobaric hypoxic hypoxia conditions were simulated by raising mice in the altitude chamber to the level of 10,500-10,700 m. Enkephalin, its analogues, morphine and naloxone were injected once 1, 2, 3, 6 and 14 days prior to the experiment, and then their effects on stability to hypoxia were investigated depending on the time of drug administration. Only leu-enkephalin after a single injection was found to have antihypoxic properties for a week. Naloxone, but not phentolamine hydrochloride, blocked delayed antihypoxic effect of penta-peptide. Leu-enkephalin is thought to be endogenous antihypoxant.     

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).     

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.     

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.     

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.     

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.     

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.     

Synthesis and evaluation of new carbonic anhydrase inhibitors

A series of new sulfamide derivatives have been synthesized, their structures were confirmed by (1)H NMR and ESI-MS. Some target compounds were assessed by the tool of Dock6, and inhibition effects of all the new compounds on carbonic anhydrase II have been investigated. In addition, some compounds have been investigated for their antihypoxic effects in mice. Results indicated that nine target compounds exhibit as effectively as acetazolamide and 10 compounds have more potent inhibition effects on carbonic anhydrase II than acetazolamide. Three of them (I-8, I-18 and I'-3) can prolong markedly the survival time of mice in hypoxia, which are worth carrying out further studies.     

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.     

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.     

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.     

Radioprotective effect of inosine and its enhancement by magnesium and global hypoxia.

The slight radioprotective action of inosine, when injected intraperitoneally to mice shortly before gamma-irradiation, can be enhanced by the administration of magnesium aspartate. This effect can be explained by the additivity of the vasodilatory actions of both agents. Inosine increases the radioprotective effectiveness of hypobaric hypoxia (10% O2), probably due to the additivity of the hypoxic effects in radiosensitive tissues. Acute hypoxic toxicity, however, is decreased by inosine administration. The cumulation of radioprotective effects of inosine and of its antihypoxic action in vitally important organs can have a favourable influence in hypoxic radiotherapy.     

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.     

Nootropic activity of nicotinamide and its structural analogs

It is known that endogenic nicotinamide has a tranquilizing and stress-protective activity. The present investigations show the nootropic effect of this drug and its analogs nicomorpholine and acethylnicotinate on acute models of hypoxia and amnesia. The present results revealed that the observed nootropic activity of nicotinamide and its analogs is more expressed than this of piracetam, pyritinol and meclofenoxate. Having in mind the similarity of pharmacological effects of piracetam and nicotinamide (antihypoxic, antiamnestic and anxiolytic) we try if these drugs have electronic-structure similarities. The analysis revealed some similarity of these drugs' molecules in relation to the composition and distribution of polar centres pi- and p-electronic areas) distance between them, topography of separate molecule parts.     

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.     

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.     

Synthesis of new camptothecin analogs with improved antitumor activities

Novel hexacyclic camptothecin analogs containing cyclic amidine, urea, or thiourea moiety were designed and synthesized based on the proposed 3D-structure of the topoisomerase I (Topo I)/DNA/camptothecin ternary complex. The analogs were prepared from 9-nitrocamptothecin via 7,9-diaminocamptothecin derivatives as a key intermediate. Among them, 7c exhibited in vivo antitumor activities superior to CPT-11 in human cancer xenograft models in mice at their maximum tolerated doses though its in vitro antiproliferative activity was comparable to SN-38 against corresponding cell lines.     

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.     

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.     

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.