After studying the material in the chapter, the student should:
know
Principles of the structure and functioning of the autonomic nervous system;
be able to
- to demonstrate on preparations and tables the sympathetic trunk and cranial vegetative nodes;
- schematically depict the structure of the reflex arc of the autonomic nervous system;
own
Skills in predicting functional disorders with damage to the structures of the autonomic nervous system.
The vegetative (autonomic) nervous system provides innervation to internal organs, glands, blood vessels, smooth muscles and performs an adaptive trophic function. Just like the somatic nervous system, it carries out its activity through reflexes. For example, when gastric receptors are irritated, impulses are sent to this organ through the vagus nerve, increasing the secretion of its glands and activating motility. As a rule, autonomic reflexes are not controlled by consciousness, i.e. occur automatically after certain irritations. A person cannot arbitrarily increase or decrease the heart rate, increase or inhibit the secretion of glands.
As in a simple somatic reflex arc, there are three neurons in the autonomic reflex arc. The body of the first of them (sensory, or receptor) is located in the spinal node or in the corresponding sensory node of the cranial nerve. The second neuron, an associative cell, lies in the autonomic nuclei of the brain or spinal cord. The third neuron - effector, is located outside the central nervous system in the paravertebral and prevertebral - sympathetic or intramural and cranial - parasympathetic nodes (ganglia). Thus, the arcs of somatic and autonomic reflexes differ in the location of the effector neuron. In the first case, it lies within the central nervous system (the motor nuclei of the anterior horns of the spinal cord or the motor nuclei of the cranial nerves), and in the second, on the periphery (in the vegetative nodes).
The autonomic nervous system is also characterized by a segmental type of innervation. The centers of autonomic reflexes have a certain localization in the central nervous system, and impulses to the organs pass through the corresponding nerves. Complex autonomic reflexes are performed with the participation of the suprasegmental apparatus. The supra-segmental centers are located in the hypothalamus, limbic system, reticular formation, cerebellum and in the cerebral cortex.
In functional terms, the sympathetic and parasympathetic divisions of the autonomic nervous system are distinguished.
Sympathetic nervous system
As part of the sympathetic part of the autonomic nervous system, the central and peripheral sections are distinguished. The central one is represented by nuclei located in the lateral horns of the spinal cord from the 8th cervical to the 3rd lumbar segment. All fibers that go to the sympathetic ganglia begin from the neurons of these nuclei. They leave the spinal cord as part of the anterior roots of the spinal nerves.
The peripheral part of the sympathetic nervous system includes nodes and fibers located outside the central nervous system.
Sympathetic trunk- a paired chain of paravertebral nodes, running parallel to the spinal column (Fig. 9.1). It extends from the base of the skull to the coccyx, where the right and left trunks converge and end in a single coccygeal node. White connecting branches from the spinal nerves, containing preganglionic fibers, approach the nodes of the sympathetic trunk. Their length, as a rule, does not exceed 1–1.5 cm. These branches are present only in those nodes that correspond to the segments of the spinal cord containing sympathetic nuclei (8th cervical - 3rd lumbar). The fibers of the white connecting branches are switched to the neurons of the corresponding ganglia or pass through them in transit to the higher and lower nodes. In this regard, the number of nodes of the sympathetic trunk (25–26) exceeds the number of white connecting branches. Some fibers do not end in the sympathetic trunk, but, bypassing it, go to the abdominal aortic plexus. They form the large and small celiac nerves. Between adjacent nodes of the sympathetic trunk there are inter-node branches, providing information exchange between its structures. Myelin-free postganglionic fibers emerge from the ganglia - gray connecting branches, which return to the spinal nerves, and the bulk of the fibers are sent to the organs along the large arteries.
The large and small visceral nerves pass in transit (without switching) through the 6-9th and 10-12th thoracic nodes, respectively. They are involved in the formation of the abdominal aortic plexus.
According to the segments of the spinal cord, the cervical (3 nodes), thoracic (10-12), lumbar (5) and sacral (5) sections of the sympathetic trunk are distinguished. A single coccygeal node is usually rudimentary.
Upper cervical knot - the biggest. Its branches go mainly along the external and internal carotid arteries, forming plexuses around them. They carry out the sympathetic innervation of the organs of the head and neck.
Middle cervical knot, unstable, lies at the level of the VI cervical vertebra. It gives branches to the heart, thyroid and parathyroid glands, to the vessels of the neck.
Lower cervical knot located at the level of the neck of the I rib, often merges with the first chest and has a stellate shape. In this case, it is called cervicothoracic (star-shaped) knot. Gives branches for innervation of the organs of the anterior mediastinum (including the heart), thyroid and parathyroid glands.
Branches that participate in the formation of the thoracic aortic plexus depart from the thoracic part of the sympathetic trunk. They provide innervation to the organs of the chest cavity. In addition, from it begin big and small viscera (celiac) nerves, which consist of pretanglionic fibers and pass through the 6-12th nodes. They pass through the diaphragm into the abdominal cavity and end on the celiac plexus neurons.
Rice. 9.1.
1 - ciliary node; 2 - pterygopalatine node; 3 - sublingual node; 4 - ear node; 5 - nodes of the celiac plexus; 6 - pelvic visceral nerves
The lumbar nodes of the sympathetic trunk are connected to each other not only by longitudinal, but also by transverse internodal branches that connect the ganglia of the right and left sides (see Fig. 8.4). Fibers leave the lumbar ganglia to form the abdominal aortic plexus. Along the course of the vessels, they provide sympathetic innervation to the walls of the abdominal cavity and lower extremities.
The pelvic region of the sympathetic trunk is represented by five sacral and rudimentary coccygeal nodes. The sacral nodes are also connected by transverse branches. The nerves extending from them provide the sympathetic innervation of the pelvic organs.
Abdominal aortic plexus located in the abdominal cavity on the anterior and lateral surfaces of the abdominal part of the aorta. It is the largest plexus of the autonomic nervous system. It is formed by several large prevertebral sympathetic nodes, branches of the large and small internal nerves approaching them, numerous nerve trunks and branches extending from the nodes. The main nodes of the abdominal aortic plexus are paired celiac and aortorenal and unpaired superior mesenteric nodes. As a rule, postganglionic sympathetic fibers depart from them. Numerous branches extend from the celiac and superior mesenteric nodes in different directions, like the rays of the sun. This explains the old name of the plexus - "solar plexus".
The branches of the plexus continue on the arteries, forming secondary vegetative plexuses of the abdominal cavity (vascular vegetative plexuses) around the vessels. These include unpaired: celiac (braids the celiac trunk) splenic (splenic artery), hepatic (own hepatic artery), top and inferior mesenteric (along the arteries of the same name) plexus. Paired are gastric, adrenal, renal, testicular (ovarian )plexus, located around the vessels of the named organs. In the course of the vessels, postganglionic sympathetic fibers reach the internal organs and innervate them.
The superior and inferior hypogastric plexuses. The superior hypogastric plexus is formed from the branches of the abdominal aortic plexus. In shape, it is a triangular plate located on the anterior surface of the V lumbar vertebra, under the aortic bifurcation. Down the plexus gives up the fibers that are involved in the formation of the lower hypogastric plexus. The latter is located above the muscle that lifts the anus, at the site of division of the common iliac artery. Branches branch off from these plexuses, providing sympathetic innervation to the pelvic organs.
Thus, the autonomic nodes of the sympathetic nervous system (para- and prevertebral) are located near the spinal cord at a certain distance from the innervated organ. Accordingly, the preganglionic sympathetic fiber is short, and the postganglionic fiber is more significant. In the neurotissue synapse, the transmission of a nerve impulse from the nerve to the tissue is carried out due to the release of the norepinephrine mediator.
Parasympathetic nervous system
As part of the parasympathetic part of the autonomic nervous system, the central and peripheral sections are distinguished. The central section is represented by the parasympathetic nuclei III, VII, IX and X of the cranial nerves and the parasympathetic sacral nuclei of the spinal cord. The peripheral section includes parasympathetic fibers and nodes. The latter, in contrast to the sympathetic nervous system, are located either in the wall of the organs that they innervate, or next to them. Accordingly, preganglionic (myelin) fibers are longer than postganglionic ones. The transmission of impulses in the neurotissue synapse in the parasympathetic nervous system is provided mainly by the mediator acetylcholine.
Parasympathetic fibers ( additional ) kernels III pairs of cranial nerves(oculomotor nerve) in the orbit ends on cells ciliary node. From it, postganglionic parasympathetic fibers begin, which penetrate the eyeball and innervate the muscle that constricts the pupil and the ciliary muscle (provides accommodation). Sympathetic fibers extending from the upper cervical node of the sympathetic trunk innervate the muscle that dilates the pupil.
The bridge contains parasympathetic nuclei ( upper salivary and lacrimal ) VII pair of cranial nerves(facial nerve). Their axons branch off from the facial nerve and composition large stony nerve reach pterygopalatine node, located in the hole of the same name (see Fig. 7.1). From it, postganglionic fibers begin, carrying out parasympathetic innervation of the lacrimal gland, glands of the mucous membranes of the nasal cavity and palate. Some of the fibers not included in the large stony nerve are sent to drum string. The latter carries preganglionic fibers to submandibular and sublingual nodes. The axons of the neurons of these nodes innervate the salivary glands of the same name.
Lower salivary nucleus belongs to the glossopharyngeal nerve ( IX pair). Its preganglionic fibers pass first as part of drum, and then - small stony nerves To ear node. Branches depart from it, providing parasympathetic innervation of the parotid salivary gland.
From dorsal nucleus vagus nerve (X pair) parasympathetic fibers in its branches pass to numerous intramural nodes located in the wall of the internal organs of the neck, [ore and abdominal cavities. Postganglionic fibers depart from these nodes, carrying out parasympathetic innervation of the organs of the neck, chest cavity, and most of the abdominal organs.
Sacral parasympathetic nervous system represented by sacral parasympathetic nuclei located at the level of II – IV sacral segments. From them originate fibers pelvic visceral nerves, which carry impulses to the intramural nodes of the pelvic organs. Postganglionic fibers extending from them provide parasympathetic innervation of the internal genital organs, bladder and rectum.
The sympathetic and parasympathetic nervous systems are parts of one whole, the name of which is ANS. That is, the autonomic nervous system. Each component has its own objectives and should be considered.
general characteristics
The division into divisions is due to morphological as well as functional characteristics. In human life, the nervous system plays a huge role, performing a lot of functions. The system, it should be noted, is quite complex in its structure and is divided into several subspecies, as well as departments, each of which is assigned certain functions. It is interesting that the sympathetic nervous system was designated as such back in 1732, and at first this term meant the entire autonomic NS. However, later, with the accumulation of experience and knowledge of scientists, it was possible to determine that there is a deeper meaning, and therefore this type was “downgraded” to a subspecies.
Sympathetic NS and its features
She is assigned a large number of functions important for the body. Some of the most significant are:
- Regulation of resource consumption;
- Mobilization of forces in emergency situations;
- Controlling emotions.
If such a need arises, the system can increase the amount of energy expended - so that a person can fully function and continue to carry out his tasks. This is what we mean when we talk about hidden resources or opportunities. The state of the whole organism directly depends on how well the SNS copes with its tasks. But if a person remains in an agitated state for too long, this will also not be beneficial. But for this there is another subspecies of the nervous system.
Parasympathetic NS and its features
The accumulation of strength and resources, restoration of strength, rest, relaxation are its main functions. The parasympathetic nervous system is responsible for the normal functioning of a person, and regardless of the surrounding conditions. I must say that both of the above systems complement each other, and only working harmoniously and inseparably. they can provide the body with balance and harmony.
Anatomical features and functions of the SNS
So, the sympathetic NA is characterized by a branched and complex structure. The spinal cord contains its central part, and the endings and nerve nodes are connected by the periphery, which, in turn, is formed thanks to sensitive neurons. From them, special processes are formed that extend from the spinal cord, collecting in the paravertebral nodes. In general, the structure is complex, but it is not necessary to delve into its specifics. It is better to talk about how broad the functions of the sympathetic nervous system are. It was said that she begins to actively work in extreme, dangerous situations.
At such moments, as you know, adrenaline is produced, which serves as the main substance that enables a person to quickly respond to what is happening around him. By the way, if a person has a pronounced predominance of the sympathetic nervous system, then he usually has an excess of this hormone.
Athletes can be considered an interesting example - for example, watching the game of European players, you can see how many of them start to play much better after they have been scored. That's right, adrenaline is released into the bloodstream, and what was said above is obtained.
But an excess of this hormone negatively affects a person's condition later - he begins to feel tired, tired, there is a great desire to sleep. But if the parasympathetic system prevails, this is also bad. The person becomes too apathetic, overwhelmed. So it is important that the sympathetic and parasympathetic systems interact with each other - this will help maintain balance in the body, as well as wisely spend resources.
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General characteristics of the autonomic nervous system: functions, anatomical and physiological features
The autonomic nervous system provides innervation to the internal organs: digestion, respiration, excretion, reproduction, blood circulation and endocrine glands. It maintains the constancy of the internal environment (homeostasis), regulates all metabolic processes in the human body, growth, reproduction, therefore it is called vegetable– vegetative.
Vegetative reflexes, as a rule, are not under the control of consciousness. A person cannot arbitrarily slow down or speed up the heart rate, inhibit or increase the secretion of the glands, therefore the autonomic nervous system has another name - autonomous , i.e. not controlled by consciousness.
Anatomical and physiological features of the autonomic nervous system.
The autonomic nervous system consists of sympathetic and parasympathetic parts that act on organs in the opposite direction. Agreed the work of these two parts ensures the normal function of various organs and allows the human body to adequately respond to changes in external conditions.
There are two divisions in the autonomic nervous system:
A) Central department , which is represented by autonomic nuclei located in the spinal cord and brain;
B) Peripheral department which includes autonomic nervous knots (or ganglia ) and autonomic nerves .
· Vegetative knots (ganglia ) - these are accumulations of bodies of nerve cells located outside the brain in different parts of the body;
· Autonomic nerves leave the spinal cord and brain. They first approach ganglia (nodes) and only then - to the internal organs. As a result, each autonomic nerve consists of preganglionic fibers and postganglionic fibers .
CNS GANGLIAN BODY
Preganglionic Postganglionic
Fiber fiber
The preganglionic fibers of the autonomic nerves leave the spinal cord and brain as part of the spinal and some cranial nerves and approach the ganglia ( L., rice. 200). In the ganglia, a switch of nervous excitement occurs. Postganglionic fibers of the autonomic nerves depart from the ganglia and go to the internal organs.
The autonomic nerves are thin, nerve impulses are transmitted along them at a low speed.
The autonomic nervous system is characterized by the presence of numerous nerve plexuses ... The plexuses include sympathetic, parasympathetic nerves and ganglia (nodes). Autonomic nerve plexuses are located in the aorta, around arteries, and near organs.
Sympathetic autonomic nervous system: functions, central and peripheral divisions
(L., rice. 200)
Functions of the sympathetic autonomic nervous system
The sympathetic nervous system innervates all internal organs, blood vessels and skin. It dominates during periods of body activity, stress, severe pain, emotional states such as anger and joy. The axons of the sympathetic nerves produce norepinephrine which affects adrenergic receptors internal organs. Norepinephrine has a stimulating effect on the organs and increases the level of metabolism.
To understand how the sympathetic nervous system acts on the organs, you need to imagine a person running away from danger: his pupils dilate, sweating increases, heart rate increases, blood pressure rises, bronchi dilate, respiratory rate increases. At the same time, the processes of digestion are slowed down, the secretion of saliva and digestive enzymes is inhibited.
Divisions of the sympathetic autonomic nervous system
As part of the sympathetic part of the autonomic nervous system, there are isolated central and peripheral departments.
Central department represented by sympathetic nuclei located in the lateral horns of the gray matter of the spinal cord along the length from 8 cervical to 3 lumbar segments.
Peripheral department includes sympathetic nerves and sympathetic nodes.
Sympathetic nerves leave the spinal cord as part of the anterior roots of the spinal nerves, then separate from them and form preganglionic fibers heading towards sympathetic nodes. Comparatively long ones extend from the nodes. postganglionic fibers, which form the sympathetic nerves that go to the internal organs, blood vessels and skin.
· Sympathetic nodes (ganglia) are divided into two groups:
· Paravertebral nodes lie on the spine and form right and left chains of knots. The chains of paravertebral nodes are called sympathetic trunks ... There are 4 sections in each trunk: cervical, thoracic, lumbar and sacral.
From nodes cervical the nerves that provide the sympathetic innervation of the organs of the head and neck (lacrimal and salivary glands, the muscle that dilates the pupil, the larynx and other organs) depart. Also depart from the cervical nodes cardiac nerves heading to the heart.
· From the nodes thoracic nerves leave to the organs of the chest cavity, heart nerves and celiac(internals) nerves heading into the abdominal cavity to the nodes celiac(solar) plexus.
From nodes lumbar depart:
Nerves heading to the nodes of the autonomic plexus of the abdominal cavity; - nerves that provide sympathetic innervation to the walls of the abdominal cavity and lower extremities.
· From the nodes sacral nerves that provide sympathetic innervation to the kidneys and pelvic organs depart.
Prevertebral nodes are located in the abdominal cavity as part of the autonomic nerve plexuses. These include:
Celiac nodes which are part of celiac(solar) plexus... The celiac plexus is located on the abdominal part of the aorta around the celiac trunk. Numerous nerves (like the rays of the sun, which explains the name "solar plexus") extend from the celiac nodes, providing sympathetic innervation to the abdominal organs.
· Mesenteric nodes , which are part of the vegetative plexuses of the abdominal cavity. Nerves depart from the mesenteric nodes, providing sympathetic innervation to the abdominal organs.
Parasympathetic autonomic nervous system: functions, central and peripheral divisions
Functions of the parasympathetic autonomic nervous system
The parasympathetic nervous system innervates the internal organs. It dominates at rest, providing "everyday" physiological functions. The axons of the parasympathetic nerves produce acetylcholine which affects cholinergic receptors internal organs. Acetylcholine slows down the functioning of organs and reduces metabolic rate.
The predominance of the parasympathetic nervous system creates conditions for the rest of the human body. Parasympathetic nerves cause constriction of the pupils, decrease the frequency and strength of heart contractions, and reduce the frequency of respiratory movements. At the same time, the work of the digestive organs is enhanced: peristalsis, the secretion of saliva and digestive enzymes.
Departments of the parasympathetic autonomic nervous system
As part of the parasympathetic part of the autonomic nervous system, there are isolated central and peripheral divisions .
Central department presented by:
brain stem;
Parasympathetic nuclei located in sacral spinal cord.
Peripheral department includes parasympathetic nerves and parasympathetic nodes.
Parasympathetic nodes are located next to organs or in their walls.
Parasympathetic nerves:
· Come out of brain stem composed of the following cranial nerves :
Oculomotor nerve (3 pair of cranial nerves), which penetrates the eyeball and innervates the muscle that narrows the pupil;
Facial nerve(7 pair of cranial nerves), which innervates the lacrimal gland, submandibular and sublingual salivary glands;
Glossopharyngeal nerve(9 pair of cranial nerves), which innervates the parotid salivary gland;
The nuclei of the parasympathetic part of the autonomic nervous system are located in the brain stem and in the lateral columns of the sacral spinal cord S II-IV (Fig. 529).
Brainstem nuclei: a) Accessory nucleus of the oculomotor nerve (nucl. Accessorius n. Oculomotorii). It is located on the ventral surface of the cerebral aqueduct in the midbrain. Preganglionic fibers from the brain leave as part of the oculomotor nerve and leave it in the orbit, heading to the ciliary node (gangl. Ciliare) (Fig. 529).
The ciliary node is located at the back of the orbit on the outer surface of the optic nerve. The sympathetic and sensory nerves pass through the node. After switching parasympathetic fibers in this node (neuron II), postganglionic fibers leave the node together with sympathetic ones, forming nn. ciliares breves. These nerves enter the posterior pole of the eyeball to innervate the muscle that constricts the pupil and the ciliary muscle that causes accommodation (parasympathetic nerve), the muscle that dilates the pupil (sympathetic nerve). Through gang. ciliare and sensory nerves pass. Sensory nerve receptors are found in all formations of the eye (except for the lens, vitreous body). Sensitive fibers leave the eye as part of nn. ciliares longi et breves. Long fibers are directly involved in the formation of n. ophthalmicus (I branch of the V pair), and the short ones go through gangl. ciliare and then only go into n. ophthalmicus.
b) The upper salivary nucleus (nucl.salivatorius superior). Its fibers leave the core of the pons along with the motor part of the facial nerve. In one portion, separating in the facial canal of the temporal bone near hiatus canalis n. petrosi majoris, it lies in sulcus n. petrosi majoris, after which the nerve gets the same name. Then it passes through the connective tissue of the lacerated opening of the skull and connects to n. petrosus profundus (sympathetic), forming the pterygoid nerve (n. pterygoideus). The pterygoid nerve passes through the canal of the same name into the pterygopalatine fossa. Its preganglionic parasympathetic fibers are switched into gangl. pterygopalatinum (). Postganglionic fibers in the branches of n. maxillaris (II branch of the trigeminal nerve) reach the mucous glands of the nasal cavity, ethmoid cells, the mucous membrane of the airways, cheeks, lips, oral cavity and nasopharynx, as well as the lacrimal gland, to which they pass along n. zygomaticus, then through the anastomosis into the lacrimal nerve.
The second portion of the parasympathetic fibers of the facial nerve through the canaliculus chordae tympani leaves it already under the name chorda tympani, connecting with n. lingualis. As part of the lingual nerve, parasympathetic fibers reach the submandibular salivary gland, having previously switched to gangl. submandibular and gangl. sublinguale. Postganglionic fibers (axons of the II neuron) provide secretory innervation to the sublingual, submandibular salivary glands and mucous glands of the tongue (Fig. 529). Sympathetic fibers pass through the pterygopalatine node, which, without switching, reach the innervation zones along with the parasympathetic nerves. Sensitive fibers from receptors in the nasal cavity, oral cavity, soft palate and in the composition of n pass through this node. nasalis posterior and nn. palatini reach the node. They leave this node as part of nn. pterygopalatini, including n. zygomaticus.
c) Lower salivary nucleus (nucl. salivatorius inferior). It is the nucleus of the IX pair of cranial nerves, located in the medulla oblongata. Its parasympathetic preganglionic fibers leave the nerve in the region of the inferior lingopharyngeal nerve node, which lies in the fossula petrosa on the inferior surface of the temporal bone pyramid, and enter the tympanic canal under the same name. The tympanic nerve exits to the anterior surface of the temporal bone pyramid through the hiatus canalis n. petrosi minoris. The part of the tympanic nerve that leaves the tympanic canal is called n. petrosus minor, which follows the furrow of the same name. Through the laceration, the nerve passes to the outer base of the skull, where about for. ovale switches in the parotid node (gangl.oticum). At the node, preganglionic fibers are switched to postganglionic fibers, which are n. auriculotemporalis (branch of the III pair) reach the parotid salivary gland, providing it with secretory innervation. Fewer fibers n. tympanicus switches in the lower node of the glossopharyngeal nerve, where, along with sensory neurons, there are parasympathetic cells of the II neuron. Their axons end in the mucous membrane of the tympanic cavity, forming together with the sympathetic drum-carotid nerves (nn. Caroticotympanici) the tympanic plexus (plexus tympanicus). Sympathetic fibers from plexus a. meningeae mediae pass gangl. oticum, connecting to its branches to innervate the parotid gland and oral mucosa. In the parotid gland and the mucous membrane of the oral cavity there are receptors from which sensory fibers begin, passing through the node in n. mandibularis (III branch of the V pair).
d) Dorsal nucleus of the vagus nerve (nucl.dorsalis n.vagi). Located in the dorsal part of the medulla oblongata. It is the most important source of parasympathetic innervation of internal organs. Switching of preganglionic fibers occurs in numerous, but very small intraorgan parasympathetic nodes, in the upper and lower nodes of the vagus nerve, throughout the entire trunk of this nerve, in the autonomic plexuses of internal organs (except for the pelvic organs) (Fig. 529).
e) Dorsal intermediate nucleus (nucl. intermedius spinalis). Located in the side pillars SII-IV. Its preganglionic fibers exit through the anterior roots into the ventral branches of the spinal nerves and form nn. splanchnici pelvini, which enter the plexus hypogastricus inferior. Their switching to postganglionic fibers occurs in the intraorgan nodes of the intraorgan plexuses of the pelvic organs (Fig. 533).
533. Innervation of the genitourinary organs.
Red lines - pyramidal path (motor innervation); blue - sensory nerves; green - sympathetic nerves; purple - parasympathetic fibers.
Acetylcholine. Acetylcholine serves as a neurotransmitter in all autonomic ganglia, in postganglionic parasympathetic nerve endings and in postganglionic sympathetic nerve endings that innervate the exocrine sweat glands. The enzyme choline acetyltransferase catalyzes the synthesis of acetylcholine from acetyl CoA produced in nerve endings and from choline, which is actively absorbed from the extracellular fluid. Inside cholinergic nerve endings, acetylcholine stores are stored in discrete synaptic vesicles and are released in response to nerve impulses that depolarize the nerve endings and increase the flow of calcium into the cell.
Cholinergic receptors. Various receptors for acetylcholine exist on postganglionic neurons in autonomic ganglia and in postsynaptic autonomic effectors. The receptors located in the autonomic ganglia and in the adrenal medulla are stimulated mainly by nicotine (nicotinic receptors), while those receptors located in the vegetative cells of the effector organs are stimulated by the alkaloid muscarinic (muscarinic receptors). Ganglion blocking agents act against nicotinic receptors, while atropine blocks muscarinic receptors. Muscarinic (M) receptors are classified into two types. Mi receptors are localized in the central nervous system and, possibly, in the parasympathetic ganglia; M 2 receptors are non-neuronal muscarinic receptors located on smooth muscle, myocardium and glandular epithelium. Bnechol is a selective agonist of M 2 receptors; Pirenzepine in progress is a selective M 1 receptor antagonist. This drug causes a significant decrease in gastric acid secretion. Phosphatidylinositol and inhibition of adenylate cyclase activity can serve as other mediators of muscarinic effects.
Acetylcholinesterase. Hydrolysis of acetylcholine by acetylcholinesterase inactivates this neurotransmitter at cholinergic synapses. This enzyme (also known as specific or true cholinesterase) is present in neurons and differs from butyrocholinesterase (serum cholinesterase or pseudocholinesterase). The latter enzyme is present in blood plasma and in non-neuronal tissues and does not play a primary role in the termination of the action of acetylchiline in autonomic effectors. The pharmacological effects of anticholinesterase drugs are due to the inhibition of neuronal (true) acetylcholinesterase.
Physiology of the parasympathetic nervous system. The parasympathetic nervous system is involved in the regulation of the functions of the cardiovascular system, digestive tract, and genitourinary system. Tissues of organs such as the liver, night, pancreas and thyroid glands also have parasympathetic innervation, which suggests that the parasympathetic nervous system is also involved in the regulation of metabolism, although the cholinergic effect on metabolism has not been well characterized.
The cardiovascular system. The parasympathetic effect on the heart is mediated through the vagus nerve. Acetylcholine reduces the rate of spontaneous depolarization of the sinus-atrial node and decreases the heart rate. Heart rate in various physiological conditions is the result of a coordinated interaction between sympathetic stimulation, parasympathetic oppression and automatic activity of the sinus-atrial pacemaker. Acetylcholine also delays the conduction of excitation in the atrial muscles while shortening the effective refractory period; this combination of factors can cause the development or persistence of atrial arrhythmias. In the atrioventricular node, it reduces the rate of conduction of excitation, increases the duration of the effective refractory period and thereby weakens the reaction of the ventricles of the heart during atrial flutter or atrial fibrillation (Chapter 184). The weakening of inotropic action caused by acetylcholine is associated with presynaptic inhibition of sympathetic nerve endings, as well as with a direct inhibitory effect on the atrial myocardium. The ventricular myocardium is less affected by acetylcholine, since its innervation by cholinergic fibers is minimal. A direct cholinergic effect on the regulation of peripheral resistance seems unlikely due to the weak parasympathetic innervation of the peripheral vessels. However, the parasympathetic nervous system can influence peripheral resistance indirectly by inhibiting the release of norepinephrine from sympathetic nerves.
Digestive tract. Parasympathetic innervation of the intestines is carried out through the vagus nerve and the pelvic sacral nerves. The parasympathetic nervous system increases the tone of the smooth muscles of the digestive tract, relaxes the sphincters, and enhances peristalsis. Acetylcholine stimulates exogenous secretion of gastrin, secretin and insulin by the epithelium of the glands.
Genitourinary and respiratory systems. The sacral parasympathetic nerves supply the bladder and genitals. Acetylcholine enhances ureteral peristalsis, causes contraction of the bladder emptying muscles, and relaxes the urogenital diaphragm and bladder sphincter, thereby playing a major role in the coordination of the urinary process. The airways are innervated by parasympathetic fibers that extend from the vagus nerve. Acetylcholine increases secretion in the trachea and bronchi and stimulates bronchospasm.
Pharmacology of the parasympathetic nervous system. Cholinergic agonists. The therapeutic value of acetylcholine is small due to the wide dispersion of its effects and short duration of action. Substances similar to it are less sensitive to hydrolysis by cholinesterase and have a narrower range of physiological effects. bnechol, the only systemic cholinergic agonist used in daily practice, stimulates the smooth muscles of the digestive tract and urinary tract. with minimal effect on the cardiovascular system. It is used in the treatment of urinary retention in the absence of urinary tract obstruction and, less commonly, in the treatment of gastrointestinal dysfunctions such as gastric atony after vagotomy. Pilocarpine and carbachol are topical cholinergic agonists used to treat glaucoma.
Acetylcholinesterase inhibitors. Cholinesterase inhibitors enhance the effects of parasympathetic stimulation by reducing the inactivation of acetylcholine. The therapeutic value of reversible cholinesterase inhibitors depends on the role of acetylcholine as a neurotransmitter in the skeletal muscle synapses between neurons and effector cells and in the central nervous system and includes the treatment of myasthenia gravis (Chapter 358), the termination of the neuromuscular blockade that developed after anesthesia, and the reversal of intoxication caused by substances with central anticholinergic activity. Physostigmine, a tertiary amine, readily penetrates the central nervous system, while its related quaternary amines [proserin, pyridostigmine bromide, oxazyl and Edrophonium] do not. Organophosphate cholinesterase inhibitors cause irreversible blockade of cholinesterase; these substances are mainly used as insecticides and are mainly of toxicological interest. With regard to the autonomic nervous system, cholinesterase inhibitors are of limited use in the treatment of intestinal and bladder smooth muscle dysfunction (eg, paralytic bowel obstruction and bladder atony). Cholinesterase inhibitors cause a vagotonic reaction in the heart and can be effectively used to stop attacks of paroxysmal supraventricular tachycardia (Chapter 184).
Substances that block cholinergic receptors. Atropine blocks muscarinic cholinergic receptors and slightly affects cholinergic neurotransmission in the autonomic ganglia and neuromuscular synapses. Many of the effects of atropine and atropine-like drugs on the central nervous system can be attributed to the blockade of the central muscarinic synapses. The homogeneous alkaloid scopolamine is similar in its action to atropine, but causes drowsiness, euphoria and amnesia - effects that make it possible to use it for premedication before anesthesia.
Atropine increases heart rate and increases atrioventricular conduction; this makes it advisable to use it in the treatment of bradycardia or heart block associated with an increased tone of the vagus nerve. In addition, atropine relieves bronchospasm mediated through cholinergic receptors and reduces secretion in the respiratory tract, which makes it possible to use it for premedication before anesthesia.
Atropine also reduces gastrointestinal motility and secretion. Although various atropine derivatives and related substances [for example, propantheline (Propantheline), isopropamide (Isopropamide) and glycopyrrolate (Glycopyrrolate)] have been promoted as agents for the treatment of patients with gastric ulcer or diarrheal syndrome, long-term use of these drugs is limited to such manifestations of parasympathetic oppression like dry mouth and urinary retention. Pirenzepine, a selective Mi-inhibitor undergoing testing, inhibits gastric secretion, used in doses that have minimal anticholinergic effects in other organs and tissues; this drug may be effective in treating stomach ulcers. When inhaled, atropine and its related substance ipratropium (Ipratropium) cause the expansion of the bronchi; they have been used in experiments for the treatment of bronchial asthma.
CHAPTER 67. ADENYLATCYCLASE SYSTEM
Henry R. Bourne
Cyclic 3`5`-monophosphate (cyclic AMP) acts as an intracellular secondary mediator for a wide variety of peptide hormones and biogenic amines, drugs and toxins. Therefore, the study of the adenylate cyclase system is necessary for understanding the pathophysiology and treatment of many diseases. Research into the role of a secondary mediator of cyclic AMP has expanded our knowledge of endocrine, nervous, and cardiovascular regulation. Conversely, research aimed at unraveling the biochemical basis of certain diseases has contributed to the understanding of the molecular mechanisms that regulate the synthesis of cyclic AMP.
Biochemistry. The sequence of action of enzymes involved in the realization of the effects of hormones (primary mediators) through cyclic AMP is shown in Fig. 67-1, and a list of hormones acting through this mechanism is given in table. 67-1. The activity of these hormones is initiated by their binding to specific receptors located on the outer surface of the plasma membrane. The hormone-receptor complex activates the membrane-bound enzyme adenylate cyclase, which synthesizes cyclic AMP from intracellular ATP. Inside the cell, cyclic AMP transmits information from the hormone by binding to its own receptor and activating this receptor-dependent cyclic AMP protein kinase. The activated protein kinase transfers terminal phosphorus ATP to specific protein substrates (usually enzymes). Phosphorylation of these enzymes enhances (or in some cases inhibits) their catalytic activity. The altered activity of these enzymes causes the characteristic effect of a certain hormone on its target cell.
The second class of hormones acts by binding to membrane receptors that inhibit adenylate cyclase. The action of these hormones, designated Ni, as opposed to stimulating hormones (He), is described in more detail below. In fig. 67-1 also shows additional biochemical mechanisms limiting the action of cyclic AMP. These mechanisms can also be regulated by hormones. This allows fine tuning of cell function using additional neural and endocrine mechanisms.
The biological role of cyclic AMP. Each of the protein molecules involved in the complex mechanisms of stimulation - inhibition, presented in Fig. 67-1, represents a potential site for the regulation of hormonal responses to the therapeutic and toxic effects of drugs and to pathological changes arising in the course of the disease. Specific examples of such interactions are discussed in subsequent sections of this chapter. To bring them together, it is necessary to consider the general biological functions of AMP as a secondary mediator, which is advisable to do on the example of the regulation of the process of glucose release from glycogen stores contained in the liver (the biochemical system in which cyclic AMP was found) using glucagon and other hormones.
Rice. 67-1. Cyclic AMP is a secondary intracellular mediator for hormones.
The figure shows an ideal cell containing protein molecules (enzymes) involved in the mediator actions of hormones through cyclic AMP. Black arrows indicate the path of information flow from stimulating hormone (He) to the cellular response, while light arrows indicate the direction of opposite processes that modulate or inhibit the flow of information. Extracellular hormones stimulate (He) or inhibit (Ni) a membrane enzyme - adenylate cyclase (AC) (see the description in the text and Fig. 67-2). AC converts ATP into cyclic AMP (cAMP) and pyrophosphate (PPi). The intracellular concentration of cyclic AMP depends on the ratio between the rate of its synthesis and the characteristics of two other processes aimed at removing it from the cell: cleavage by cyclic nucleotide phosphodiesterase (PDE), which converts cyclic AMP into 5'-AMP, and the removal of energy-dependent transport The intracellular effects of cyclic AMP are mediated or regulated by proteins of at least five additional classes, the first of which, the cAMP-dependent protein kinase (PK), consists of regulatory (P) and catalytic (K) subunits. In the PK holoenzyme, the K subunit is catalytically inactive ( inhibited by P subunit) Cyclic AMP acts by binding to P subunits, releasing K subunits from the cAMP-P complex. Free catalytic subunits (K +) catalyze the transfer of terminal phosphorus ATP to specific protein substrates (C), for example, phosphorylase kinase. (C ~ F) these protein substrates Aates (usually enzymes) initiate the characteristic effects of cyclic AMP within the cell (eg, activation of glycogen phosphorylase, inhibition of glycogen synthetase). The proportion of protein substrates of kinase in the phosphorylated state (C ~ F) is regulated by proteins of two additional classes: the kinase inhibiting protein (IKB) reversibly binds to K ^, making it catalytically inactive (IKB-K) Phosphatases (F-ase) convert C ~ F back in C, subtracting the covalently bound phosphorus.
Transport of hormonal signals across the plasma membrane. The biological stability and structural complexity of peptide hormones like glucagon make them carriers of a variety of hormonal signals between cells, but impair their ability to penetrate cell membranes. Hormone-sensitive adenylate cyclase allows the information content of the hormonal signal to penetrate the membrane, although the hormone itself cannot penetrate through it.
Table 67-1. Hormones for which cyclic AMP serves as a secondary mediator
| Hormone | Target: organ / fabric | Typical action |
| Adrenocorticotropic hormone | Adrenal cortex | Corti-ash production |
| Calcitonin | Bones | Serum calcium concentration |
| Catecholamines (b-adrenergic) | Heart | Heart rate, myocardial contractility |
| Chorionic gonado-tropin | Ovaries, testes | Production of sex hormones |
| Follicle-stimulating hormone | Ovaries, testes | Gametogenesis |
| Glucagon | Liver | Glycogenolysis, glucose release |
| Luteinizing hormone | Ovaries, testes | \ Production of sex hormones |
| Luteinizing hormone releasing factor | Pituitary | f Release of luteinizing hormone |
| Melanocyte-stimulating hormone | Skin (melanocytes) | T Pigmentation |
| Parathyroid hormone | Bones, kidneys | T Serum calcium concentration [serum phosphorus concentration |
| Prostacyclin, prosta-glandin e | | Platelets | [Platelet aggregation |
| Thyroid-stimulating hormone | Thyroid | T Production and release of T3 and T4 |
| Thyroid Tropic Hormone Releasing Factor | Pituitary | f Release of thyrotropic hormone |
| Vasopressin | Kidney | f Urine concentration |
Note. Here are listed only the most convincingly confirmed effects mediated by cyclic AMP, although many of these hormones exhibit multiple actions in various target organs.
Gain. By binding to a small number of specific receptors (probably less than 1000 per cell), glucagon stimulates the synthesis of many more cyclic AMP molecules. These molecules, in turn, stimulate the cyclic AMP-dependent protein kinase, which activates thousands of molecules of liver phosphorylase (an enzyme that limits the breakdown of glycogen) and the subsequent release of millions of glucose molecules from a single cell.
Metabolic coordination at the level of a single cell. In addition to the fact that protein phosphorylation due to cyclic AMP stimulates phosphorylase and promotes the conversion of glycogen to glucose, this process simultaneously deactivates the enzyme that synthesizes glycogen (glycogen synthetase) and stimulates enzymes that induce gluconeogenesis in the liver. Thus, a single chemical signal - glucagon - mobilizes energy reserves through several metabolic pathways.
Conversion of various signals into a single metabolic program. Since the adenylate cyclase contained in the liver can be stimulated by adrenaline (acting through b-adrenergic receptors) as well as glucagon, cyclic AMP allows two hormones with different chemical structures to regulate carbohydrate metabolism in the liver. If a secondary neurotransmitter did not exist, then each of the regulatory enzymes involved in the mobilization of liver carbohydrates would have to be able to recognize both glucagon and adrenaline.
Rice. 67-2. Molecular mechanism of regulation of cyclic AMP synthesis by hormones, hormonal receptors and G-proteins. Adenylate cyclase (AC) in its active form (AC +) converts ATP into cyclic AMP (cAMP) and pyrophosphate (PPi). AC activation and inhibition are mediated by formally identical systems shown in the left and right parts of the figure. In each of these systems, the G-protein fluctuates between an inactive state, being associated with GDP (G-HDF), and an active state, being associated with GTP (G 4 "-GTP); only proteins that are in an active state can stimulate ( Gs) or inhibit (Gi) activity of AC.Each G-GTP complex has an intrinsic GTPase activity, which converts it into an inactive G-GDP complex.To return the G-protein to its active state, stimulating or inhibiting hormone-receptor complexes (HcRc and NiRi, respectively) promote the replacement of GDP for GTP at the site of the G-protein binding to guanine nucleotide.While the GnR complex is required for the initial stimulation or inhibition of AC by the Gs or Hz proteins, the hormone can detach from the receptor independently of the regulation of the AC, which, on the contrary, depends on the duration of the state of binding between GTP and the corresponding G-protein, regulated by its internal GTPase. Two bacterial toxins regulate the activity of adenylate cyclase, catalyzing ADP-ribose ylation of G-proteins (see. text). ADP-ribosylation of G with cholera toxin inhibits the activity of its GTPase, stabilizing Gs in its active state and thereby increasing the synthesis of cyclic AMP. In contrast, ADP-ribosylation of Gi with pertussis toxin prevents its interaction with the rot complex and stabilizes Gi in an inactive state associated with HDP; as a result, pertussis toxin prevents hormonal suppression of AC.
Coordinated regulation of various cells and tissues by the primary mediator. In the classic fight-or-flight stress response, catecholamines bind to b-adrenergic receptors located in the heart, adipose tissue, blood vessels, and many other tissues and organs, including the liver. If cyclic AMP did not mediate most of the reactions to the action of b-adrenergic catecholamines (for example, an increase in heart rate and myocardial contractility, dilatation of blood vessels supplying blood to skeletal muscles, mobilization of energy from carbohydrate and fat stores), then the totality of a huge number of individual enzymes in tissues would have to have specific binding sites for catecholamine regulation.
Similar examples of the biological functions of cyclic AMP could be given in relation to other primary mediators given in Table. 67-1. Cyclic AMP acts as an intracellular mediator for each of these hormones, indicating their presence on the cell surface. Like all effective mediators, cyclic AMP provides a simple, cost-effective and highly specialized pathway for the transmission of heterogeneous and complex signals.
Hormone-sensitive adenylate cyclase. The main enzyme mediating the corresponding effects of this system is hormone-sensitive adenylate cyclase. This enzyme consists of at least five classes of separable proteins, each of which is embedded in the fatty bilayer plasma membrane (Fig. 67-2).
On the outer surface of the cell membrane, two classes of hormonal receptors are found, Pc and Pu. They contain specific recognition sites for the binding of hormones that stimulate (Hc) or inhibit (Ni) adenylate cyclase.
The catalytic element adenylate cyclase (AC), found on the cytoplasmic surface of the plasma membrane, converts intracellular ATP into cyclic AMP and pyrophosphate. There are also two classes of guanine-nucleotide-binding regulatory proteins on the cytoplasmic surface. These proteins, Gs and Gu, mediate the stimulating and inhibitory effects perceived by the Pc and Pu receptors, respectively.
Both the stimulating and depressing paired functions of proteins depend on their ability to bind guanosine triphosphate (GTP) (see Fig. 67-2). Only GTP-bound forms of G-proteins regulate the synthesis of cyclic AMP. Neither stimulation nor suppression of AC is a permanent process; instead, the terminal phosphorus GTP in each G-GTP complex is ultimately hydrolyzed, and Gs-HDF or Gi-HDF cannot regulate the AC. For this reason, persistent processes of stimulation or inhibition of adenylate cyclase require continuous conversion of G-HDP to G-GTP. In both pathways, hormone-receptor complexes (HcRc or NiRu) enhance the conversion of GDP to GTP. This temporally and spatially recirculating process separates the binding of hormones to receptors from the regulation of cyclic AMP synthesis, using energy reserves in the terminal phosphorus bond of GTP to enhance the action of hormone-receptor complexes.
This diagram explains how several different hormones can stimulate or inhibit the synthesis of cyclic AMP within a single cell. Since receptors differ in their physical characteristics from adenylate cyclase, the set of receptors located on the cell surface determines a specific picture of its sensitivity to external chemical signals. A single cell can have three or more different receptors that perceive the inhibitory effect, and six or more different receptors that perceive the stimulating effect. Conversely, all cells seem to contain similar (possibly identical) components G and AC.
The molecular components of hormone-sensitive adenylate cyclase provide reference points for altering the sensitivity of a given tissue to hormonal stimulation. Both the P and G components are critical factors in the physiological regulation of hormone sensitivity, and changes in the G proteins are considered as the primary lesion that occurs in the four diseases discussed below.
Regulation of sensitivity to hormones (see also chapter 66). Re-introduction of any hormone or drug, as a rule, causes a gradual increase in resistance to their action. This phenomenon has different names: hyposensitization, refractoriness, tachyphylaxis, or tolerance.
Hormones or mediators can cause the development of receptor-specific hyposensitization, or "homologous". For example, the administration of b-adrenergic catecholamines causes a specific refractoriness of the myocardium to re-administration of these amines, but not to those drugs that do not act through b-adrenergic receptors. Receptor specific hyposensitization involves at least two distinct mechanisms. The first of them, rapidly developing (within a few minutes) and rapidly reversible when the injected hormone is removed, functionally "uncouples" the receptors and the Gc-protein and, therefore, reduces their ability to stimulate adenylate cyclase. The second process involves actually decreasing the number of receptors on the cell membrane - a process called receptor-downregulation. The process of receptor-decreasing regulation requires several hours for its development and is difficult to reverse.
Hyposensitization processes are part of normal regulation. Elimination of normal physiological stimuli can lead to an increase in the sensitivity of the target tissue to pharmacological stimulation, as occurs with the development of hypersensitivity caused by denervation. A potentially important clinical correlation of such an increase in the number of receptors can develop in patients with sudden discontinuation of treatment with anaprilin, which is a b-adrenergic blocking agent. Such patients often have transient signs of increased sympathetic tone (tachycardia, increased blood pressure, headaches, tremors, etc.) and symptoms of coronary insufficiency may develop. In the leukocytes of the peripheral blood of patients receiving anaprilin, an increased number of b-adrenergic receptors is found, and the number of these receptors slowly returns to normal values when the drug is discontinued. Although the more numerous other leukocyte receptors do not mediate cardiovascular symptoms and phenomena that occur in the case of discontinuation of anaprilin, receptors in the myocardium and other tissues are likely to undergo the same changes.
The sensitivity of cells and tissues to hormones can also be regulated in a "heterologous" way, that is, when the sensitivity to one hormone is regulated by another hormone acting through a different set of receptors. The regulation of the sensitivity of the cardiovascular system to β-adrenergic amines by thyroid hormones is the best known clinical example of heterologous regulation. Thyroid hormones cause the accumulation of an excessive amount of β-adrenergic receptors in the myocardium. This is an increase. the number of receptors partly explains the increased sensitivity of the heart of patients with hyperthyroidism to catecholamines. However, the fact that in experimental animals the increase in the number of β-adrenergic receptors caused by the administration of thyroid hormones is not enough to attribute the increased sensitivity of the heart to catecholamines, suggests that the components of the reaction to hormones are also subject to the influence of thyroid hormones. acting distal to the receptors, possibly including Gs, but not limited to these subunits. Other examples of heterologous regulation include estrogen and progesterone control of the sensitivity of the uterus to the relaxing effects of β-adrenergic agonists and the increased reactivity of many tissues to adrenaline caused by glucocorticoids.
The second type of heterologous regulation consists in the inhibition of hormonal stimulation of adenylate cyclase by substances acting through Ri and Gu, as noted above. Acetylcholine, opiates, and a-adrenergic catecholamines act through distinct classes of receptors that perceive an inhibitory effect (muscarinic, opiate, and a-adrenergic receptors), reducing the sensitivity of adenylate cyclase of certain tissues to the stimulating action of other hormones. Although the clinical significance of heterologous regulation of this type has not been established, the inhibition of cyclic AMP synthesis by morphine and other opiates could be the cause of some aspects of tolerance to drugs of this class. Likewise, the elimination of such oppression may play a role in the development of the syndrome following the cessation of opiate administration.
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