The central problem in modern obstetrics is the regulation of labor, since clarifying the nature of the mechanisms that stimulate the contractile activity of the uterus is a necessary prerequisite for reducing the number of pathological births, surgical interventions, hypo- and atonic bleeding, and reducing perinatal mortality. Groups of pregnant women of high risk for the development of abnormalities of labor were identified.
The introduction of new pharmacological drugs and methods of non-medicamentous influence into medical practice significantly expanded the possibilities of practical doctors in the treatment of abnormalities of labor. However, this did not solve the problem of regulation of smooth muscle tone, as it is largely related to the prevalence of empirical methods in the search for new drugs, especially in the search for drugs of myotropic action, and the lack at the present time of a sufficiently deep knowledge of the mechanisms that form the tone of smooth muscles in complicated flow pregnancy and childbirth and contractile activity of the uterus in the process of the generic act.
In the course of many years of research into the nature of muscle contraction, significant advances have been made in solving the central problems of biological mobility:
- the ultrastructure of the contractile apparatus;
- study of physicochemical properties and mechanisms of interaction of the main contractile proteins - actin and myosin;
- search for ways to convert the chemical energy of adenosine triphosphate (ATP) into a mechanical one;
- in the comparative analysis of morphofunctional properties of contractile systems of various muscle cells.
The problems of regulating muscular activity began to be addressed only in the last decade, and these studies are concentrated mainly on elucidating the trigger mechanisms of the contractile act itself.
It is now generally accepted that the mechanical work performed by various contractile systems of a living cell, including the mechanical work of the contracting muscle, is performed due to the accumulated energy in ATP and is associated with the functioning of actomyosin adenosine triphosphatase (ATPase). The relationship between the process of hydrolysis and reduction is undoubted. In addition, understanding the molecular mechanism of muscle contraction, which also requires an accurate knowledge of the nature of muscle contraction and the structural interaction between actin and myosin, will further deepen the knowledge of the molecular processes associated with the work of actomyosin ATPase.
The biochemical mechanisms that regulate the energy and contractile apparatus of the muscle cell are analyzed, the relationship of these biochemical mechanisms of ATPase control to the phenomenon of muscle fatigue is discussed. The indicators of fatigue in the contracting muscle are a decrease in the force of contraction and the rate of its growth, as well as a decrease in the rate of relaxation. Thus, the magnitude of the force developed by the muscle with a single contraction or in an isometric mode, like the maximum rate of muscle contraction, is proportional to the activity of ATPase of actomyosin, and the relaxation rate correlates with the activity of the ATPase of the reticulum.
In recent years, more and more researchers are paying attention to the study of the features of the regulation of smooth muscle contraction. This led to the emergence of various, often contradictory points of view, concepts, hypotheses. Smooth muscles, like any other, contract in the rhythm of the interaction of proteins - myosin and actin. In smooth muscles, a double system of Ca 2+ - the regulation of actin-myosin interaction, and consequently, the contraction - is demonstrated . The presence of several ways of regulating the actin-myosin interaction seems to have a great physiological significance, since the reliability of regulation increases with the activity of two or more control systems. This seems extremely important in maintaining such homeostatic mechanisms as control of blood pressure, labor and other smooth muscles.
A number of regular changes in physiological and biochemical indices characterizing the relaxation of smooth muscles under the influence of drugs, especially antispasmodics: an increase in the membrane potential observed simultaneously with the suppression of spontaneous or induced peak activity, a decrease in the consumption of oxygen by smooth muscles and the content of ATP in them, an increase in the concentration of adenosine diphosphate (ADP), adenosine monophosphoric acid (AMP) and cyclic 3,5-AMP.
To understand the nature of intracellular events involved in the process of contraction of the myometrium and its regulation, the following model is proposed, which includes four interrelated processes:
- signal interaction (eg, oxytocin, PGEg) with membrane receptors of the myometrium cell or with electrical depolarization of the cell membrane;
- calcium-stimulated overflow of phosphotidylinositol within the membrane and the release of inositol triphosphate (a potent intracellular activator) and arachidonic acid;
- prostaglandin synthesis (PHF PGEg and 2 ) in the myometrium, which leads to an increase in intracellular calcium concentration and formation of connection points in the intercellular spaces;
- calcium-dependent phosphorylation of the myosin light chain and muscle contraction.
Relaxation of the myometrium is achieved through processes dependent on cyclic AMP and protein kinase C. Endogenous arachidonic acid released during muscle contraction can be metabolized in PG1 2, which stimulates the production of cAMP by activated receptors. Cyclic AMP activates A-kinase, which catalyzes the phosphorylation of light chain kinosomes of myosin and phospholipase C (phosphodiesterase, involved in the metabolism of phosphotidylinositol), inhibiting their activity. Cyclic AMP also stimulates the deposition of calcium into the sarcoplasmic reticulum and the expulsion of calcium from the cell.
Prostaglandins (both endogenous and exogenous) have a number of stimulating effects on myometrium.
First, they can act on the secretory receptors of the membrane, stimulating the flow of phosphotidylinositol within the membrane and subsequent events leading to calcium mobilization and uterine contraction.
Secondly, excitatory prostaglandins (PGE 2 and PGF 2 ) synthesized in myometrium after the release of arachidonic acid can mobilize more calcium from the sarcoplasmic network and increase the over-membrane movement of calcium, acting as ionophores.
Third, prostaglandins increase the electrical binding of cell contours by inducing the formation of attachment points in the intercellular spaces.
Fourthly, prostaglandins have a high diffusion capacity and can diffuse through cell membranes, thereby enhancing the adhesion of cells biochemically.
It is known that myometrium is sensitive to the action of exogenous prostaglandins during pregnancy. The introduction of prostaglandins or their precursor - arachidonic acid - allows to circumvent the local suppression of biosynthesis of prostaglandins by the inhibitory effect of phospholipase. Therefore, exogenous prostaglandins can access and stimulate a cascade of intracellular events leading to synchronization and enhancement of myometrium contractions.
Such effects of prostaglandins will lead to an increase in the initial stimulating signal (regardless of whether it is fetal or maternal oxytocin, or prostaglandins from the amnión or from the dying shell of the uterus) and to an increase in the contraction intensity due to an increase in both the number of active cells and the power of contraction , generated by one cell.
The processes contributing to the development of labor-related uterine contractions are interrelated, and each process can have additional metabolic bypass at any level, which may result in the desired actions of a number of drugs (for example, tocolytics) not being achieved.
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