Medicines 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 effective masses of the ATP system - ATP / ADP. Essentially, it reflects the current balance between energy expenditure for maintaining the viability and function of the cell and the production of ATP during substrate (glycolytic) and oxidative phosphorylation. The latter plays a decisive role, of course, and completely depends on the preservation of the normal functional structure of the mitochondria (ion permeability of the outer and inner membranes, their charge, ordering of the location and work of the respiratory chain enzymes and phosphorylation of ADP, etc.), oxygen intake in excess of the threshold of use mitochondria, from the supply of oxidation substrates and a number of other causes that are considered in great detail by biochemists. Disruptions in the mechanism of energy production in the "shock cell" are ambiguous, as are the causes that cause them. Undoubtedly, the leading role is played by a complex by nature hypoxia due to disorders of external respiration, blood circulation in the lungs, oxygen transport function of the blood, violations of systemic, regional blood circulation and microcirculation, endotoxemia. Therefore, the fight against hypoxia at different levels of recovery of the oxygen cascade 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 disturbances, 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 sets the task for pharmacologists to develop means that protect the cell in 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. With the development of this direction, the implementation of new ideas and hopes for a satisfactory solution of the problem of pharmacological protection of the organism in trauma and shock are associated. The development of antihypoxants, drugs that can reduce or eliminate the effects of oxygen starvation, can be one of such promising approaches and play a key role in the metabolic "resuscitation of the cell" in shock.

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

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

[1], [2], [3], [4], [5], [6], [7], [8], [9]

Substrates of oxidation, enzymes and coenzymes of the respiratory chain

Massive release of catecholamines in shock is accompanied by a decrease in the organism's tolerance to glucose, which is caused not only by glycogenolysis, but also, especially in the initial phase of shock, by the decrease in insulin content due to stimulation of the alpha receptors of pancreatic B cells. Therefore, the pharmacological regulation of the metabolism in the cell in shock and ischemia should provide for an improvement in the delivery of glucose to the cell and its inclusion in energy metabolism. As an example of such a therapeutic approach, directional effects on the metabolism of the myocardium "repolarizing solution" (glucose + insulin + potassium), which switches myocardial metabolism from the oxidation of fatty acids to energetically more favorable glucose, can be cited. This combination is successfully used to treat shock with myocardial infarction and with cardiovascular insufficiency of another etiology. The use of the "repolarizing solution" for myocardial infarction stimulates the absorption of glucose by the heart, inhibits the oxidation of NEFLC, promotes the adhesion of potassium to myocardiocytes, stimulates oxidative phosphorylation and the synthesis of ATP. A similar effect in the presence of insulin, but not glucose, is exerted by guatimine.

Under anaerobic conditions, in addition to glycolysis, the synthesis of ATP is possible when reactions are reversed in the dicarboxylic portion of the tricarboxylic acid cycle, with the formation of succinate as the final product. Moreover, during the reduction of fumarate to succinate, in addition to ATP, oxidized NAD is formed, however, acidosis, accumulation of succinate and deficiency of hexose limit this reaction. Attempts to use phosphorylated hexoses such as Coryi ether (glucose-1-phosphate, fructose-1,6-diphosphate) in the clinic proved to be practically unsuccessful.

One of the reasons for substrate starvation in shock is the emergence of a kind of block on the way of pyruvate entering the cycle of tricarboxylic acids. Therefore, one of the ways to increase the energy potential of the cell can be the use of substrates of the cycle of tricarboxylic acids and, first of all, succinate and fumarate. The use of succinate for various forms of oxygen starvation is theoretically well founded by MN Kondrashova and co-authors. (1973). In oxygen starvation, the cell mainly uses succinic acid, since its oxidation is not associated with NAD +. This is the undoubted advantage of succinate in NAD-dependent substrates (eg, alpha-ketoglutarate). The oxidation reaction in the succinate cell to the fumarate is, as it were, a "lateral entry" into 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 amber half-aldehyde. The stimulation of succinate formation is also associated with the antihypoxic effect of sodium oxybutyrate. The inclusion of antishock plasma-substituting solutions of succinate and fumarate in the formulations makes it possible to significantly increase their hemodynamic effects and therapeutic effect with hemorrhagic and burn shock.

Disruption in the shock of electron transport along the respiratory chain strongly dictates the need for the use of drugs that selectively affect the oxidation-reduction processes in the cell. It can be assumed that the use of antihypoxic agents with electron-withdrawing properties, such as a natural electron carrier of cytochrome C or synthetic carriers, will in some measure compensate for the deficiency of the final electron acceptor-oxygen and partially restore oxidative phosphorylation. At the same time, certain goals are pursued: "removal" of electrons from the 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, substrate phosphorylation reactions supplying 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 carry out both single- and double-electron transfer.

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

Thus, the representative of ortho-benzoquinones anilomethyl-ortho-benzoquinone is able to interact with both the mitochondrial fusion of pyridine nucleotides and exogenous NAD and NADH. This drug has been found to have the ability to transfer electrons from coenzyme Q or methadione reductase not only to cytochrome C, but also directly to oxygen. The ability of benzoquinones to carry out the extra-mitochondrial oxidation of NADH formed during glycolip prevents accumulation of high concentrations of lactate and inhibition of glycolysis. Positive characteristics of artificial electron carriers are their ability to inhibit the production of lactate, which are more pronounced than those of the guatimine group, and to increase the pH of the cells. Along with this, the derivatives of orthobenzoquinones are able to perform functional connections between the respiratory chain complexes, including the conjugation points, while performing "shuttle functions", similarly to ubiquinone.

Ubiquinone or coenzyme Q is fat-soluble quinone structurally bound to the inner mitochondrial membrane performing a collector function in the cell, collecting the 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 infarction zone of the myocardium, reduced the lactate content in the blood and the activity of serum creatine kinase and lactate dehydrogenase. Ubihinon "softened" depletion in the ischemic zone of the myocardium of stocks of CK and LDH and the content of phosphocreatine in the myocardium. The positive effect of ubiquinone was noted in cases of liver ischemia.

Antihypoxants of the guatimine group

The mechanism of antihypoxic action of the preparations of this group is polyvalent and at the molecular level is not actually elucidated. In a large number of experimental and smaller - clinical studies, evidence of a rather high efficacy of drugs is phenomenological in nature. In this group, the protective effect of guatimine and amtisol is better than others in the shock, myocardial and brain ischemia, kidneys, liver, intrauterine fetal hypoxia. Gutimin and its analogues reduce the oxygen demand of tissues, and this reduction is easily reversible and is achieved as a result of the economical use of oxygen, and not a decrease in the functional activity of organs.

In shock, as is known, the accumulation of glycolysis products (mainly lactate) in combination with a deficiency 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, glycolysis can be converted to the alakta pathway by mobilizing gluconeogenesis, or by switching the Krebs cycle to oxidizing pyruvate instead of fatty acids. The use of guatimine and its analogs allows us to realize, basically, the first pharmacological approach. Preparations of this group increase the transport of glucose to cells under hypoxic conditions, activate glycolysis in the brain, heart, liver and small intestine. At the same time, they reduce the accumulation of lactate in the organs and the depth of metabolic acidosis. In conditions of sufficient supply of liver and kidneys with oxygen, drugs of the guimeim 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 yield of a number of enzymes from the cells (LDH, CK, transferases, phosphatases, cathepsin). One of the most significant manifestations of the protective effect of antihypoxants of the guatimine group on membrane structures is the preservation of the structural integrity and functional activity of mitochondria in oxygen starvation. Gutimine inhibits the disruption of the calcium transport function of mitochondrial membranes, thereby promoting the maintenance of conjugation and phosphorylation.

[10], [11], [12], [13], [14]

Exogenous high-energy compounds

Numerous attempts have been made to use parenteral administration of ATP in order to regulate metabolic processes in the cell during shock and ischemia. Calculation of the weighty energy contribution of exogenous ATP to the energy of the cell is low, since when the drug is injected into the vascular bed, it rapidly hydrolyzes. The inclusion of ATP in liposomes allowed prolonging the effect of the drug and increasing its antihypoxic activity.

A large number of studies are devoted to the use of the ATP-M5C12 complex in various forms of acute "energy crisis" of the cell: with hemorrhagic shock and severe burns, sepsis and peritonitis, endotoxin shock and ischemic liver damage. It is convincingly proved that in the shock and ischemia of various organs (heart, liver, kidneys), ATP-M ^ C ^ normalizes the energy homeostasis and functions of the cell, correcting the disturbances of its metabolism, stimulating the synthesis of endogenous ATP, but there is no information on its clinical application. The mechanism of action of ATP-M5C12 at the cell level is not completely clear. It is known that in the cytoplasm, which is characterized by a high content of Mg2 + ions, ATP and ADP are mainly present in the form of complexes with magnesium - M5-ATP2 ~ and MgADP ~. In many enzymatic reactions in which ATP participates as a donor of the phosphate group, the active form of ATP is precisely its complex with magnesium-M5ATP2 ~. Therefore, it can be assumed that the exogenous complex ATP-M5C12 is able to reach 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, the preservation of the adenine nucleotide pool and the 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 administration of phosphocreatine is apparently associated with inhibition of the activity of 5-nucleotidase and phosphatase. Similar effects with myocardial ischemia are caused by phosphocreatine.

[15], [16], [17], [18], [19], [20], [21], [22], [23], [24]

Preparations of other pharmacological groups

To this group of drugs include sodium oushibutyrate and piracetam.

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

The regulating effect of GHB on cellular metabolism is carried out by activating the controlled respiration of mitochondria and increasing the rate of phosphorylation. In this case, the drug is able to activate cytochrome oxidase, protect the extra-mitochondrial ATP from ATP-ase hydrolysis, inhibit accumulation in lactate tissues. The mechanism of antihypoxic effect of GHB is not limited to the stimulation of oxidative metabolism. GHB and the product of its reduction - amber semialdehyde - prevent the development of hypoxia-specific disturbances in nitrogen metabolism, preventing the accumulation of ammonia, alanine in the brain and heart tissues and increasing the concentration of glutamate.

Pyracetam (nootropil) is a cyclic form of GABA, however its pharmacological properties are not related to the effect on GABA receptors. The drug stimulates redox processes in the brain and increases its resistance to hypoxia. The experience of using the drug in an experiment and in a clinic with cerebral ischemia indicates that the best effect is observed with its early application in combination with protease inhibitors (trasilol or gadox).