Drugs that increase the energy potential of cells

In a simplified form, the energy state of cells (tissues) can be characterized as the ratio of the active masses of the ATP system - ATP/ADP. In essence, it reflects the current balance between the energy expenditure on maintaining the viability and functions of the cell and the production of ATP during substrate (glycolytic) and oxidative phosphorylation. The latter, of course, plays a decisive role and completely depends on the preservation of the normal functional structure of the mitochondria (ionic permeability of the outer and inner membranes, their charge, the orderliness of the arrangement and operation of the enzymes of the respiratory chain and ADP phosphorylation, etc.), the supply of oxygen in an amount exceeding the threshold of use by mitochondria, the supply of oxidation substrates and a number of other reasons, considered in great detail by biochemists. Disturbances in the mechanism of energy production in a "shock cell" are ambiguous, as are the reasons that cause them. Undoubtedly, the leading role is played by hypoxia, which is complex in nature and results from disorders of external respiration, pulmonary circulation, oxygen transport function of blood, disorders of systemic, regional circulation and microcirculation, endotoxemia. Therefore, the fight against hypoxia at different levels of oxygen cascade restoration with the help of infusion therapy, various cardiovascular and antithrombotic agents remains the main way of its prevention and treatment. The second most important cause of bioenergetic disorders, largely secondary to hypoxia - damage to membrane structures, in particular mitochondria, was discussed above.

Violation of the energy homeostasis of the cell and damage to its membrane structures poses the problem of developing means for pharmacologists to protect the cell during shock and normalize its energy metabolism. "Resuscitation at the cellular level" in trauma and shock is one of the ways to solve the problem of preventing irreversible conditions. The development of this direction is associated with the implementation of new ideas and hopes for a satisfactory solution to the problem of pharmacological protection of the body during trauma and shock. The development of antihypoxants, drugs capable of reducing or eliminating the effects of oxygen starvation, can become one of such promising approaches and play a key role in metabolic "reanimation of the cell" in shock.

Improvement of the energy status of the cell can be achieved either by reducing the ATP expenditure on specific work (for example, high doses of barbiturates in cerebral ischemia, beta-adrenolytics or calcium antagonists in myocardial ischemia), or by optimizing the use of deficient oxygen by mitochondria and the cell as a whole and increasing ATP production during glycolysis, and finally, by replenishing the intracellular ATP pool with high-energy compounds introduced from outside. Medicines that increase the energy potential of the cell in one way or another can be divided into four groups with respect to the prevention and therapy of shock:

1. antihypoxants of the gutimin group (they are united by common protective properties, established or postulated mechanisms of action);
2. exogenous high-energy compounds;
3. oxidation substrates, enzymes and coenzymes of the respiratory chain;
4. drugs of other pharmacological groups.

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Oxidation substrates, enzymes and coenzymes of the respiratory chain

Massive release of catecholamines in shock is accompanied by decreased glucose tolerance, which is caused not only by glycogenolysis, but also, especially in the initial phase of shock, by decreased insulin levels due to stimulation of alpha receptors of pancreatic B cells. Therefore, pharmacological regulation of cellular metabolism in shock and ischemia should provide for improved delivery of glucose to the cell and its inclusion in energy metabolism. An example of such a therapeutic approach is the targeted effect of a “repolarizing solution” (glucose + insulin + potassium) on myocardial metabolism, switching myocardial metabolism from fatty acid oxidation to energetically more favorable glucose. Such a combination is successfully used to treat shock in myocardial infarction and in cardiovascular failure of other etiologies. The use of a "repolarizing solution" in myocardial infarction stimulates the absorption of glucose by the heart, inhibits the oxidation of NEFA, promotes the penetration of potassium into myocardiocytes, stimulates oxidative phosphorylation and ATP synthesis. Gutimin has a similar effect in the presence of insulin, but not glucose.

In anaerobic conditions, in addition to glycolysis, ATP synthesis is possible by reversing reactions in the dicarboxylic part of the tricarboxylic acid cycle to form succinate as the end product. In this case, during the reduction of fumarate to succinate, in addition to ATP, oxidized NAD is formed, but acidosis, accumulation of succinate, and deficiency of hexoses limit this reaction. Attempts to use phosphorylated hexoses of the Cori ester type (glucose-1-phosphate, fructose-1,6-diphosphate) in the clinic have proven to be of little practical success.

One of the reasons for substrate starvation in shock is the occurrence of a kind of block on the way of pyruvate entry into the tricarboxylic acid cycle. Therefore, one of the ways to increase the energy potential of the cell can be the use of substrates of the tricarboxylic acid cycle, primarily succinate and fumarate. The use of succinate in various forms of oxygen starvation is theoretically well substantiated by M. N. Kondrashova et al. (1973). During oxygen starvation, the cell mainly uses succinic acid, since its oxidation is not associated with NAD +. This is the undoubted advantage of succinate over NAD-dependent substrates (for example, alpha-ketoglutarate). The oxidation reaction of succinate in the cell to fumarate is a kind of "side entrance" to the respiratory chain and does not depend on competition with other substrates for NAD +. The formation of succinate is also possible in the Robertson cycle, the intermediate metabolites of which are GABA, GHB and succinic semialdehyde. The antihypoxic effect of sodium oxybutyrate is also associated with the stimulation of succinate formation. The inclusion of succinate and fumarate in the formulations of anti-shock plasma-substituting solutions allows for a significant increase in their hemodynamic effects and therapeutic effect in hemorrhagic and burn shock.

Disruption of electron transport along the respiratory chain in shock urgently dictates the need to use agents that selectively affect oxidation-reduction processes in the cell. It can be assumed that the use of antihypoxants with electron-acceptor properties such as the natural electron carrier cytochrome C or synthetic carriers will allow to some extent to compensate for the deficiency of the final electron acceptor - oxygen and partially restore oxidative phosphorylation. In this case, certain goals are pursued: "removal" of electrons from intermediate links of the respiratory chain and oxidation of pyridine nucleotides in the cytosol; prevention of accumulation of high concentrations of lactate and inhibition of glycolysis, creation of conditions for additional, in addition to glycolysis, reactions of substrate phosphorylation that supply ATP.

Preparations capable of forming artificial redox systems must meet the following requirements:

1. have an optimal redox potential;
2. have conformational accessibility for interaction with respiratory enzymes;
3. have the ability to perform both one- and two-electron transfer.

Such properties are found in some orthobenzoquinones and 1,4-naphthoquinones.

Thus, a representative of ortho-benzoquinones, anilo-methyl-ortho-benzoquinone, is able to interact both with the mitochondrial fund of pyridine nucleotides and with exogenous NAD and NADH. This drug has been shown to have the ability to transfer electrons from coenzyme Q or methadone reductase not only to cytochrome C, but also directly to oxygen. The ability of benzoquinones to carry out extramitochondrial oxidation of NADH formed during glycolipide prevents the accumulation of high concentrations of lactate and its inhibition of glycolysis. Positive characteristics of artificial electron carriers include their ability to inhibit lactate production, which is more pronounced than in gutimine group drugs, and to increase the pH of the cell. Along with this, derivatives of orthobenzoquinones are able to implement functional connections between complexes of the respiratory chain, including conjugation points, while performing "shuttle functions", similar to ubiquinone.

Ubiquinone or coenzyme Q is a fat-soluble quinone structurally associated with the inner mitochondrial membrane, performing a collector function in the cell, collecting reduced equivalents not only from NADH dehydrogenase, but also from a number of other flavin-dependent dehydrogenases. The use of endogenous ubiquinone in an experiment with acute myocardial ischemia reduced the size of the myocardial infarction zone, decreased the lactate content in the blood and the activities of serum creatine kinase and lactate dehydrogenase. Ubiquinone "mitigated" the depletion of CPK and LDH reserves in the ischemic zone of the myocardium and the content of phosphocrettin in the myocardium. A positive effect of ubiquinone was noted in liver ischemia.

Antihypoxants of the gutimin group

The mechanism of antihypoxic action of drugs of this group is polyvalent and has not been clarified at the molecular level. In a large number of experimental and a smaller number of clinical studies, the evidence of the rather high efficiency of drugs is phenomenological. In this group, the protective action of gutimin and amtizol in shock, myocardial and cerebral ischemia, kidneys, liver, and intrauterine hypoxia of the fetus has been studied better than others. Gutimin and its analogues reduce the oxygen demand of tissues, and this reduction is easily reversible and is achieved as a result of economical use of oxygen, rather than a decrease in the functional activity of organs.

In shock, as is known, the accumulation of glycolysis products (mainly lactate) in combination with a deficit of oxidation substrates and an increase in the reduction of pyridine nucleotides limit the intensity of glycolysis by inhibiting the activity of lactate dehydrogenase. Under these conditions, it is possible to achieve the transfer of glycolysis to the alactate pathway either by mobilizing gluconeogenesis or by switching the Krebs cycle to the oxidation of pyruvate instead of fatty acids. The use of gutimin and its analogues allows implementing, mainly, the first pharmacological approach. The drugs of this group increase glucose transport into cells under hypoxia, activate glycolysis in the brain, heart, liver and small intestine. At the same time, they reduce the accumulation of lactate in organs and the depth of metabolic acidosis. Under conditions of sufficient oxygen supply to the liver and kidneys, the drugs of the gutimin group stimulate gluconeogenesis, inhibit lipolysis induced by catecholamines and ACTH.

Gutimin and its analogues stabilize biological membranes, maintaining their electrical potential and osmotic resistance, reduce the release of a number of enzymes from cells (LDH, CPK, transferases, phosphatases, cathepsin). One of the most significant manifestations of the protective effect of antihypoxants of the gutimin group on membrane structures is the preservation of the structural integrity and functional activity of mitochondria during oxygen starvation. Gutimin prevents disruption of the calcium transport function of mitochondrial membranes, thereby promoting the maintenance of conjugation and phosphorylation.

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Exogenous high-energy compounds

Numerous attempts have been made to use parenteral administration of ATP to regulate cellular metabolic processes during shock and ischemia. Expecting a significant energy contribution of exogenous ATP to cellular energy is unrealistic, since it is rapidly hydrolyzed when the drug is administered into the vascular bed. Incorporation of ATP into liposomes has made it possible to prolong the drug's action and increase its antihypoxic activity.

A large number of studies are devoted to the use of the ATP-M5C12 complex in various forms of acute cellular "energy crisis": hemorrhagic shock and severe burns, sepsis and peritonitis, endotoxin shock and ischemic liver damage. It has been convincingly proven that in shock and ischemia of various organs (heart, liver, kidneys), ATP-M5C12 normalizes energy homeostasis and cell functions, correcting metabolic disorders and stimulating endogenous ATP synthesis processes, but there is no information on its clinical use. The mechanism of action of ATP-M5C12 at the cellular level is not entirely clear. It is known that in the cytoplasm, which is characterized by a high content of Mg2+ ions, ATP and ADP are present mainly in the form of complexes with magnesium - M5-ATP2~ and MgADP~. In many enzymatic reactions in which ATP participates as a donor of a phosphate group, the active form of ATP is precisely its complex with magnesium - M5ATP2~. Therefore, it can be assumed that the exogenous ATP-M5C12 complex is capable of reaching the cell.

Another representative of high-energy phosphates, phosphocreatine (neoton), is successfully used for therapeutic purposes in myocardial ischemia. The protective effect of phosphocreatine in myocardial ischemia is due to its accumulation by the myocardium, preservation of the adenine nucleotide pool, and stabilization of cell membranes. It is believed that less pronounced damage to the sarcolemma of cardiomyocytes and less pronounced hydrolysis of adenine nucleotides in the ischemic myocardium after the introduction of phosphocreatine are apparently associated with the inhibition of the activity of 5-nucleotidase and phosphatase. Phosphocreatine also causes similar effects in myocardial ischemia.

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Drugs of other pharmacological groups

Sodium ousibutyrate and piracetam should be included in this group of drugs.

Sodium oxybutyrate (gamma-hydroxybutyric acid, GHB) has a pronounced antihypoxic activity and increases the body's resistance, including the tissues of the brain, heart and retina, to oxygen starvation, and has an anti-shock effect in severe injuries and blood loss. The spectrum of its effects on cell metabolism is very broad.

The regulatory effect of GHB on cellular metabolism is achieved by activating controlled mitochondrial respiration and increasing the rate of phosphorylation. The drug is capable of activating cytochrome oxidase, protecting the extramitochondrial ATP pool from hydrolysis by ATPase, and inhibiting the accumulation of lactate in tissues. The mechanism of the antihypoxic effect of GHB is not limited to stimulation of oxidative metabolism. GHB and its reduction product, succinic semialdehyde, prevent the development of nitrogen metabolism disorders characteristic of hypoxia, preventing the accumulation of ammonia and alanine in brain and heart tissues and increasing the concentration of glutamate.

Piracetam (nootropil) is a cyclic form of GABA, but its pharmacological properties are not associated with the effect on GABA receptors. The drug stimulates oxidation-reduction processes in the brain and increases its resistance to hypoxia. Experience with the use of the drug in experiments and clinical studies for cerebral ischemia indicates that the best effect is observed with its early use in combination with protease inhibitors (trasylol or godox).