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
- demonstrate the sympathetic trunk and cranial vegetative nodes on preparations and tables;
- schematically depict the structure of the reflex arc of the autonomic nervous system;
own
Skills in predicting functional disorders due to damage to the structures of the autonomic nervous system.
The autonomic (autonomic) nervous system provides innervation to internal organs, glands, blood vessels, smooth muscles and performs an adaptive-trophic function. Like the somatic nervous system, it operates through reflexes. For example, when the stomach receptors are irritated, impulses are sent to this organ through the vagus nerve, enhancing 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 voluntarily increase or decrease the heart rate, increase or suppress the secretion of glands.
As in the simple somatic reflex arc, the autonomic reflex arc contains three neurons. The body of the first of them (sensitive, or receptor) is located in the spinal ganglion or in the corresponding sensory ganglion of the cranial nerve. The second neuron is an association cell, located in the autonomic nuclei of the brain or spinal cord. The third neuron is the effector neuron, 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 from each other by the location of the effector neuron. In the first case, it lies within the central nervous system (motor nuclei of the anterior horns of the spinal cord or motor nuclei of the cranial nerves), and in the second - on the periphery (in the vegetative ganglia).
The autonomic nervous system is also characterized by a segmental type of innervation. The centers of autonomic reflexes have a specific 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. Suprasegmental centers are localized in the hypothalamus, limbic system, reticular formation, cerebellum and in the cerebral cortex.
Functionally, the sympathetic and parasympathetic divisions of the autonomic nervous system are distinguished.
Sympathetic nervous system
The sympathetic part of the autonomic nervous system is divided into central and peripheral sections. The central one is represented by nuclei located in the lateral horns of the spinal cord along the length from the 8th cervical to the 3rd lumbar segment. All fibers going to the sympathetic ganglia begin from the neurons of these nuclei. They exit the spinal cord as part of the anterior roots of the spinal nerves.
The peripheral division 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 come together 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 switch to the neurons of the corresponding ganglia or pass through them in transit to the superior and underlying 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 greater and lesser splanchnic nerves. Between adjacent nodes of the sympathetic trunk there are internodal branches, ensuring the exchange of information between its structures. Unmyelinated 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 greater and lesser splanchnic nerves pass in transit (without switching) through the 6–9th and 10–12th thoracic nodes, respectively. They participate 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. The single coccygeal ganglion is usually rudimentary.
Upper cervical knot - the biggest. Its branches run mainly along the external and internal carotid arteries, forming plexuses around them. They provide sympathetic innervation to the organs of the head and neck.
Middle cervical node unstable, lies at the level of the VI cervical vertebra. 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 first rib, often merges with the first thoracic and has a star-shaped shape. In this case it is called cervicothoracic (star-shaped) knot. Gives off 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 extend from the thoracic sympathetic trunk. They provide innervation to the organs of the thoracic cavity. In addition, it starts from big And small visceral (celiac) nerves, which consist of pretanglionic fibers and transit through the 6th–12th nodes. They pass through the diaphragm into the abdominal cavity and end on the neurons of the celiac plexus.
Rice. 9.1.
1 – ciliary node; 2 – pterygopalatine node; 3 – sublingual node; 4 – ear node; 5 – nodes of the celiac plexus; 6 – pelvic splanchnic 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 extend from the lumbar ganglia into the abdominal aortic plexus. Along the vessels, they provide sympathetic innervation to the walls of the abdominal cavity and lower extremities.
The pelvic section of the sympathetic trunk is represented by five sacral and rudimentary coccygeal nodes. The sacral nodes are also interconnected by transverse branches. The nerves extending from them provide sympathetic innervation to the pelvic organs.
Abdominal aortic plexus located in the abdominal cavity on the anterior and lateral surfaces of the abdominal aorta. This is the largest plexus of the autonomic nervous system. It is formed by several large prevertebral sympathetic ganglia, branches of the greater and lesser splanchnic nerves approaching them, and numerous nerve trunks and branches extending from the nodes. The main nodes of the abdominal aortic plexus are paired pregnant 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 artery, forming secondary autonomic plexuses of the abdominal cavity (choroid autonomic plexuses) around the vessels. These include unpaired: celiac (entwines the celiac trunk), splenic (splenic artery), hepatic (proprietary hepatic artery) top And inferior mesenteric (along the course of the arteries of the same name) plexus. Paired are gastric, adrenal, renal, testicular (ovarian )plexus, located around the vessels of these organs. Along the vessels, postganglionic sympathetic fibers reach the internal organs and innervate them.
Superior and inferior hypogastric plexuses. The superior hypogastric plexus is formed from 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 bifurcation of the aorta. Downwards the plexus gives off fibers that participate in the formation of the inferior hypogastric plexus. The latter is located above the levator ani muscle, at the site of division of the common iliac artery. Branches extend 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 has a short length, and the postganglionic fiber has a longer length. At a neurotissue synapse, the transmission of a nerve impulse from a nerve to a tissue occurs due to the release of the mediator norepinephrine.
Parasympathetic nervous system
The parasympathetic part of the autonomic nervous system is divided into central and peripheral sections. The central section is represented by the parasympathetic nuclei of the III, VII, IX and X cranial nerves and the parasympathetic sacral nuclei of the spinal cord. The peripheral section includes parasympathetic fibers and nodes. The latter, unlike 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 fibers. Impulse transmission at the neurotissue synapse in the parasympathetic nervous system is ensured primarily by the mediator acetylcholine.
Parasympathetic fibers ( additional ) kernels III pair of cranial nerves(oculomotor nerve) in the orbit end on cells ciliary node. Postganglionic parasympathetic fibers begin from it, which penetrate the eyeball and innervate the muscle that constricts the pupil and the ciliary muscle (provides accommodation). Sympathetic fibers arising from the superior cervical ganglion of the sympathetic trunk innervate the muscle that dilates the pupil.
The pons contains the parasympathetic nuclei ( upper salivary And tearful ) VII pairs of cranial nerves(facial nerve). Their axons branch from the facial nerve and comprise greater petrosal nerve reach pterygopalatine node, located in the pit of the same name (see Fig. 7.1). Postganglionic fibers begin from it, carrying out parasympathetic innervation of the lacrimal gland, glands of the mucous membranes of the nasal cavity and palate. Some of the fibers that are not included in the greater petrosal nerve are directed 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.
Inferior salivary nucleus belongs to the glossopharyngeal nerve ( IX pair). Its preganglionic fibers first pass through drum, and then - lesser petrosal nerve To ear node. Branches extend from it, providing parasympathetic innervation of the parotid salivary gland.
From dorsal nucleus of the vagus nerve (X pair), parasympathetic fibers as part of 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, providing parasympathetic innervation to the organs of the neck, chest cavity, and most abdominal organs.
Sacral division of the parasympathetic nervous system represented by sacral parasympathetic nuclei located at the level of II–IV sacral segments. Fibers originate from them pelvic splanchnic 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 components of one whole, the name of which is the ANS. That is, the autonomic nervous system. Each component has its own tasks, and they should be considered.
general characteristics
The division into departments is determined by morphological as well as functional characteristics. In human life, the nervous system plays a huge role, performing many functions. The system, it should be noted, is quite complex in its structure and is divided into several subtypes, 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 nervous system. However, later, with the accumulation of experience and knowledge of scientists, it was possible to determine that there was a deeper meaning hidden here, and therefore this type was “downgraded” to a subspecies.
Sympathetic nervous system and its features
It is assigned a large number of important functions for the body. Some of the most significant are:
- Regulation of resource consumption;
- Mobilization of forces in emergency situations;
- Control of 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. When talking about hidden resources or opportunities, this is what is meant. The condition of the entire organism directly depends on how well the SNS copes with its tasks. But if a person remains in an excited state for too long, this will also not be beneficial. But for this there is another subtype of the nervous system.
Parasympathetic nervous system and its features
Accumulation of strength and resources, restoration of strength, rest, relaxation - these are its main functions. The parasympathetic nervous system is responsible for the normal functioning of a person, regardless of the conditions surrounding him. It must be said that both of the above systems complement each other, and only by working harmoniously and inextricably. they can provide balance and harmony to the body.
Anatomical features and functions of the SNS
So, the sympathetic nervous system is characterized by a branched and complex structure. Its central part is located in the spinal cord, and the endings and nerve nodes are connected by the periphery, which, in turn, is formed thanks to sensory 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’s better to talk about how broad the functions of the sympathetic nervous system are. It was said that she begins to work actively in extreme, dangerous situations.
At such moments, as is known, adrenaline is produced, which serves as the main substance that gives a person the opportunity to quickly react 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 European football players play, you can see how many of them begin to play much better after they score a goal. That's right, adrenaline is released into the blood, and what was said above happens.
But an excess of this hormone negatively affects a person’s condition later - he begins to feel tired, tired, and has a great desire to sleep. But if the parasympathetic system predominates, this is also bad. The person becomes overly apathetic and overwhelmed. So it is important that the sympathetic and parasympathetic systems interact with each other - this way it will be possible to maintain balance in the body, as well as spend resources wisely.
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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, which is why it is called vegetable– vegetative.
Autonomic reflexes, as a rule, are not controlled by consciousness. A person cannot voluntarily slow down or increase the heart rate, suppress or increase the secretion of 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 changing external conditions.
·The autonomic nervous system has two divisions:
A) Central department , which is represented by vegetative nuclei located in the spinal cord and brain;
B) Peripheral department , which includes the autonomic nervous nodes (or ganglia ) And autonomic nerves .
· Vegetative nodes (ganglia ) are clusters of nerve cell bodies located outside the brain in different places of the body;
· Autonomic nerves come out of 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 GANGLION ORGAN
Preganglionic Postganglionic
Fiber fiber
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). Switching of nervous excitation occurs in the ganglia. Postganglionic fibers of the autonomic nerves depart from the ganglia, heading to the internal organs.
Autonomic nerves are thin, nerve impulses are transmitted through them at 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 on the aorta, around arteries and near organs.
Sympathetic autonomic nervous system: functions, central and peripheral parts
(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, and 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 organs and increases the level of metabolism.
To understand how the sympathetic nervous system acts on organs, you need to imagine a person running away from danger: his pupils dilate, sweating increases, heart rate increases, blood pressure rises, bronchi dilate, breathing rate increases. At the same time, digestion processes slow 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 central And peripheral sections.
Central department represented by sympathetic nuclei located in the lateral horns of the gray matter of the spinal cord over the course of the 8th cervical to 3rd lumbar segments.
Peripheral department includes sympathetic nerves and sympathetic ganglia.
Sympathetic nerves emerge from the spinal cord as part of the anterior roots of the spinal nerves, then separate from them and form preganglionic fibers, heading to the sympathetic nodes. Relatively long ones extend from the nodes postganglionic fibers, which form sympathetic nerves going to 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 nodes. The chains of paravertebral nodes are called sympathetic trunks . Each trunk has 4 sections: cervical, thoracic, lumbar and sacral.
·From nodes cervical region Nerves depart that provide sympathetic innervation to the organs of the head and neck (the lacrimal and salivary glands, the muscle that dilates the pupil, the larynx and other organs). They also originate from the cervical nodes cardiac nerves, heading towards the heart.
· From nodes thoracic nerves extend to the organs of the chest cavity, cardiac nerves and pregnant(visceral) nerves, heading into the abdominal cavity to the nodes celiac(solar) plexuses.
·From nodes lumbar region depart:
Nerves going to the nodes of the autonomic plexuses of the abdominal cavity; - nerves that provide sympathetic innervation to the walls of the abdominal cavity and lower extremities.
· From nodes sacral region Nerves depart that provide sympathetic innervation to the kidneys and pelvic organs.
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) plexuses. The celiac plexus is located on the abdominal aorta around the celiac trunk. Numerous nerves depart from the celiac ganglia (like the rays of the sun, which explains the name “solar plexus”), providing sympathetic innervation to the abdominal organs.
· Mesenteric nodes , which are part of the autonomic 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 parts
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 organ function and reduces metabolic rate.
The predominance of the parasympathetic nervous system creates conditions for the human body to rest. Parasympathetic nerves cause constriction of the pupils, reduce 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, secretion of saliva and digestive enzymes.
Divisions of the parasympathetic autonomic nervous system
As part of the parasympathetic part of the autonomic nervous system, there are central And peripheral sections .
Central department presented by:
brain stem;
Parasympathetic nuclei located in sacral part of the spinal cord.
Peripheral department includes parasympathetic nerves and parasympathetic ganglia.
Parasympathetic nodes are located next to organs or in their walls.
Parasympathetic nerves:
· Coming out brain stem as part of the following cranial nerves :
oculomotor nerve (3 a pair of cranial nerves), which penetrates the eyeball and innervates the muscle that constricts the pupil;
Facial nerve(7 a pair of cranial nerves), which innervates the lacrimal gland, submandibular and sublingual salivary glands;
Glossopharyngeal nerve(9 a 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).
Nuclei of the brainstem: a) Accessory nucleus of the oculomotor nerve (nucl. accessorius n. oculomotorii). Located on the ventral surface of the cerebral aqueduct in the midbrain. Preganglionic fibers leave the brain as part of the oculomotor nerve and leave it in the orbit, heading to the ciliary ganglion (gangl. ciliare) (Fig. 529).
The ciliary ganglion is located in the back of the orbit on the outer surface of the optic nerve. Sympathetic and sensory nerves pass through the node. After switching parasympathetic fibers in this node (II neuron), postganglionic fibers leave the node along with the sympathetic ones, forming nn. ciliares breves. These nerves enter the posterior pole of the eyeball to innervate the muscle that constricts the pupil, the ciliary muscle that causes accommodation (parasympathetic nerve), and the muscle that dilates the pupil (sympathetic nerve). Through gang. ciliare and sensory nerves. Sensory nerve receptors are found in all structures of the eye (except for the lens and vitreous body). Sensitive fibers leave the eye as part of the 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 pass gangl. ciliare and then only enter n. ophthalmicus.
b) Superior salivatory nucleus (nucl. salivatorius superior). Its fibers leave the pontine core along with the motor part of the facial nerve. In one portion, separated in the facial canal of the temporal bone near the hiatus canalis n. petrosi majoris, it lies in sulcus n. petrosi majoris, after which the nerve receives the same name. Then it passes through the connective tissue of the lacerated opening of the skull and connects with 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 switch to gangl. pterygopalatinum(). Postganglionic fibers in the branches of n. maxillaris (II branch of the trigeminal nerve) reach the mucous glands of the nasal cavity, the cells of the ethmoid bone, the mucous membrane of the air sinuses, cheeks, lips, oral cavity and nasopharynx, as well as the lacrimal gland, to which they pass along n. zygomaticus, then through an anastomosis into the lacrimal nerve.
The second portion of parasympathetic fibers of the facial nerve leaves it through the canaliculus chordae tympani under the name chorda tympani, connecting with n. lingualis. As part of the lingual nerve, parasympathetic fibers reach the submandibular salivary gland, first switching to the gangl. submandibular and gangl. sublinguale. Postganglionic fibers (axons of the second neuron) provide secretory innervation to the sublingual, submandibular salivary glands and mucous glands of the tongue (Fig. 529). Sympathetic fibers pass through the pterygopalatine ganglion, which, without switching, reach the innervation zones along with the parasympathetic nerves. Sensitive fibers from the receptors of the nasal cavity, oral cavity, soft palate and n. pass through this node. nasalis posterior and nn. palatini reach the node. They leave this node as part of nn. pterygopalatini, included in 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 ganglion of the glossopharyngeal nerve, which lies in the fossula petrosa on the inferior surface of the pyramid of the temporal bone, and penetrate the tympanic canal under the same name. The tympanic nerve enters the anterior surface of the pyramid of the temporal bone through the hiatus canalis n. petrosi minoris. The part of the tympanic nerve emerging from the tympanic canal is called n. petrosus minor, which follows the groove of the same name. Through the foramen lacerum, the nerve passes to the outer base of the skull, where about for. ovale switches in the parotid node (gangl. oticum). In the node, preganglionic fibers switch to postganglionic fibers, which are part of n. auriculotemporalis (branch of the third 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 tympanic-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 the 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 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 superior and inferior 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) Spinal 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 the 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 tract (motor innervation); blue - sensory nerves; green - sympathetic nerves; violet - parasympathetic fibers.
Acetylcholine. Acetylcholine serves as a neurotransmitter in all autonomic ganglia, in postganglionic parasympathetic nerve endings and in postganglionic sympathetic nerve endings innervating the exocrine sweat glands. The enzyme choline acetyltransferase catalyzes the synthesis of acetylcholine from acetyl CoA produced in nerve endings and from choline actively absorbed from the extracellular fluid. Within cholinergic nerve endings, acetylcholine is stored in discrete synaptic vesicles and is released in response to nerve impulses, depolarizing the nerve endings and increasing calcium entry into the cell.
Cholinergic receptors. Various receptors for acetylcholine exist on postganglionic neurons in the autonomic ganglia and in postsynaptic autonomic effectors. Receptors located in the autonomic ganglia and in the adrenal medulla are stimulated mainly by nicotine (nicotinic receptors), and those receptors located in the vegetative cells of the effector organs are stimulated by the alkaloid muscarine (muscarinic receptors). Ganglion blocking agents act against nicotinic receptors, while atropine blocks muscarinic receptors. Muscarinic (M) receptors are divided into two types. Mi receptors are localized in the central nervous system and possibly in the parasympathetic ganglia; M2 receptors are non-neural muscarinic receptors located on smooth muscle, myocardium and glandular epithelium. The selective agonist of M2 receptors is bnechol; Pirenzepine, currently being tested, is a selective M1 receptor antagonist. This drug causes a significant decrease in the secretion of gastric juice. Other mediators of muscarinic effects may include phosphatidylinositol and inhibition of adenylate cyclase activity.
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 is different from butyrocholinesterase (serum cholinesterase or pseudocholinesterase). The latter enzyme is present in blood plasma and non-neuronal tissues and does not play a primary role in terminating the action of acetylquinine in autonomic effectors. The pharmacological effects of anticholinesterase drugs are due to inhibition of neural (true) acetylcholinesterase.
Physiology of the parasympathetic nervous system. The parasympathetic nervous system is involved in regulating the functions of the cardiovascular system, digestive tract and genitourinary system. Tissues of organs such as the liver, kidneys, 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 is not 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 sinoatrial node and reduces the heart rate. Heart rate under various physiological conditions is the result of a coordinated interaction between sympathetic stimulation, parasympathetic inhibition, and automatic activity of the sinoatrial pacemaker. Acetylcholine also delays the conduction of excitation in the atrium muscles by 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 excitation, increases the duration of the effective refractory period, and thereby weakens the reaction of the ventricles of the heart during atrial flutter or fibrillation (Chapter 184). The weakening of the inotropic effect 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 influenced 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 peripheral vessels. However, the parasympathetic nervous system may influence peripheral resistance indirectly by inhibiting the release of norepinephrine from the sympathetic nerves.
Digestive tract. Parasympathetic innervation of the intestine is carried out through the vagus nerve and 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 by the epithelium of the glands of gastrin, secretin and insulin.
Genitourinary and respiratory systems. The sacral parasympathetic nerves innervate the bladder and genitals. Acetylcholine enhances ureteral peristalsis, causes contraction of the bladder muscles that empty it, and relaxes the urogenital diaphragm and bladder sphincter, thereby playing a major role in coordinating the process of urination. The respiratory tract is innervated by parasympathetic fibers arising 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 spread 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 and genitourinary tracts. with minimal impact 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 disorders of the digestive tract, 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 at 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 cessation of neuromuscular blockade that develops after anesthesia, and the reversal of intoxication caused by substances with central anticholinergic activity. Physostigmine, a tertiary amine, easily penetrates the central nervous system, while related quaternary amines [proserine, pyridostigmine bromide, oxazyl and Edrophonium] do not have this property. Organophosphorus cholinesterase inhibitors cause irreversible blockade of cholinesterase; these substances are used primarily as insecticides and are mainly of toxicological interest. With regard to the autonomic nervous system, cholinesterase inhibitors have limited use in the treatment of intestinal and bladder smooth muscle dysfunction (eg, paralytic ileus 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 has little effect on cholinergic neurotransmission in the autonomic ganglia and neuromuscular junctions. Many of the effects of atropine and atropine-like drugs on the central nervous system can be attributed to blockade of central muscarinic synapses. The homogeneous alkaloid scopolamine is similar in action to atropine, but causes drowsiness, euphoria and amnesia - effects that allow it to be used 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 increased vagal tone. 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 [eg, Propantheline, Isopropamide, and Glycopyrrolate] have been promoted as treatments for patients suffering from gastric ulcers or diarrheal syndromes, long-term use of these drugs is limited by such manifestations of parasympathetic depression such as dry mouth and urinary retention. Pirenzepine, a selective Mi-inhibitor under trial, 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 cause dilation of the bronchi; they were used in experiments to treat bronchial asthma.
CHAPTER 67. ADENYLATE CYCLASE SYSTEM
Henry R. Bourne
Cyclic 3'5'-monophosphate (cyclic AMP) acts as an intracellular secondary transmitter for a wide variety of peptide hormones and biogenic amines, drugs and toxins. Therefore, studying the adenylate cyclase system is essential for understanding the pathophysiology and treatment of many diseases. Research into the role of the secondary transmitter cyclic AMP has expanded our knowledge of endocrine, nervous and cardiovascular regulation. Conversely, studies aimed at unraveling the biochemical basis of certain diseases have contributed to the understanding of the molecular mechanisms regulating the synthesis of cyclic AMP.
Biochemistry. The sequence of action of enzymes involved in the implementation of the effects of hormones (primary mediators) carried out through cyclic AMP is presented in Fig. 67-1, and the 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. Activated protein kinase transfers the terminal phosphorus of 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 particular hormone on its target cell.
A second class of hormones acts by binding to membrane receptors that inhibit adenylate cyclase. The action of these hormones, designated Ni, in contrast to stimulating hormones (He), is described below in more detail. In Fig. 67-1 also shows additional biochemical mechanisms that limit the action of cyclic AMP. These mechanisms can also be regulated by hormones. This allows for fine-tuning of cell function using additional neural and endocrine mechanisms.
Biological role of cyclic AMP. Each of the protein molecules involved in the complex mechanisms of stimulation and 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 that occur during the course of the disease. Specific examples of such interactions are discussed in later sections of this chapter. To bring them together, it is necessary to consider the general biological functions of AMP as a secondary mediator, which can be done using the example of regulation of the process of glucose release from glycogen stores contained in the liver (the biochemical system in which cyclic AMP was discovered) with the help of 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 carried out through cyclic AMP. Black arrows indicate the path of information flow from the 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) the membrane enzyme adenylate cyclase (AC) (see 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 relationship 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 removal from the cell by energy-dependent transport system. The intracellular effects of cyclic AMP are mediated or regulated by proteins of at least five additional classes. The first of these, cAMP-dependent protein kinase (PK), consists of regulatory (P) and catalytic (K) subunits. In the PC holoenzyme, the K subunit is catalytically inactive ( inhibited by the P subunit. Cyclic AMP acts by binding to the P subunits, releasing the K subunits from the cAMP-P complex. The free catalytic subunits (K+) catalyze the transfer of the terminal phosphorus of ATP to specific protein substrates (C), such as phosphorylase kinase. In the phosphorylated state (C~P) these protein substrates (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 the kinase in the phosphorylated state (C~P) is regulated by proteins of two additional classes: the kinase inhibitory protein (KIP) reversibly binds to K^, making it catalytically inactive (KP-K) Phosphatases (P-ase) convert C~P back in C, removing covalently bound phosphorus.
Transmission 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 weaken their ability to penetrate cell membranes. Hormone-sensitive adenylate cyclase allows the information content of the hormonal signal to cross the membrane, although the hormone itself cannot cross it.
Table 67-1. Hormones for which cyclic AMP serves as a secondary transmitter
| Hormone | Target: organ/tissue | Typical action |
| Adrenocorticotropic hormone | Adrenal cortex | Cortisol production |
| Calcitonin | Bones | Serum calcium concentration |
| Catecholamines (b-adrenergic) | Heart | Heart rate, myocardial contractility |
| Chorionic gonadotropin | Ovaries, testes | Production of sex hormones |
| Follicle-stimulating hormone | Ovaries, testes | Gametogenesis |
| Glucagon | Liver | Glycogenolysis, release of glucose |
| 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-stimulating hormone releasing factor | Pituitary | f Release of thyroid-stimulating hormone |
| Vasopressin | Kidneys | f Urine concentration |
Note. Only the most convincingly documented effects mediated by cyclic AMP are listed here, although many of these hormones exhibit multiple actions in different target organs.
Gain. By binding to a small number of specific receptors (probably less than 1000 per cell), glucagon stimulates the synthesis of a much larger number of cyclic AMP molecules. These molecules in turn stimulate cyclic AMP-dependent protein kinase, which causes the activation of thousands of molecules of phosphorylase contained in the liver (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 single cell level. In addition to the fact that cyclic AMP-mediated protein phosphorylation 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 cause gluconeogenesis in the liver. Thus, a single chemical signal - glucagon - mobilizes energy reserves through several metabolic pathways.
Converting diverse signals into a single metabolic program. Since 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 there were no secondary transmitter, then each of the regulatory enzymes involved in the mobilization of liver carbohydrates would have to be able to recognize both glucagon and epinephrine.
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). Activation and inhibition of AC are mediated by formally identical systems shown in the left and right parts of the figure. In each of these systems, the G protein oscillates between an inactive state, being bound to GDP (G-GDP), and an active state, being bound to GTP (G 4 "-GTP); only proteins in the active state can stimulate ( Gs) or inhibit (Gi) AC activity. Each G-GTP complex has 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 with GTP at the site of binding of the G protein to guanine nucleotide. While the GiR complex is required for the initial stimulation or inhibition of AC by Gs or GC proteins, the hormone can detach from the receptor independently of the regulation of AC, which, on the contrary, depends on the duration of the binding state between GTP and the corresponding G protein, regulated by its internal GTPase.Two bacterial toxins regulate the activity of adenylate cyclase by catalyzing the ADP-ribosylation of G proteins (see. text). ADP-ribosylation of G with cholera toxin inhibits the activity of its GTPase, stabilizing G in its active state and thereby increasing the synthesis of cyclic AMP. In contrast, ADP-ribosylation of Gi by pertussis toxin prevents its interaction with the gnri complex and stabilizes Gi in a GDP-bound, inactive state; As a result, pertussis toxin prevents hormonal suppression of AC.
Coordinated regulation of various cells and tissues by a primary mediator. In the classic fight-or-flight stress response, catecholamines bind to beta-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, dilation of blood vessels supplying blood to skeletal muscles, mobilization of energy from carbohydrate and fat stores), then the combination of a huge number of individual enzymes in tissues would have to have specific binding sites for regulation by catecholamines.
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 transmitter for each of these hormones, indicating their presence on the cell surface. Like all effective neurotransmitters, cyclic AMP provides a simple, economical, and highly specialized pathway for the transmission of diverse 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 adipose bilayer plasma membrane (Fig. 67-2).
On the outer surface of the cell membrane, two classes of hormonal receptors, Pc and Pc, are found. They contain specific recognition sites for binding hormones that stimulate (Hc) or inhibit (Hi) 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. Two classes of guanine nucleotide-binding regulatory proteins are also present on the cytoplasmic surface. These proteins, Gs and Gi, mediate the stimulatory and inhibitory effects perceived by the Pc and Pu receptors, respectively.
Both the stimulatory and inhibitory 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 inhibition of AC is a constant process; instead, the terminal phosphorus of GTP in each G-GTP complex is eventually hydrolyzed, and Gs-GDP or Gi-GDP cannot regulate AC. For this reason, persistent processes of stimulation or inhibition of adenylate cyclase require the continuous conversion of G-GDP into G-GTP. In both pathways, hormone-receptor complexes (HcRc or NiRi) 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 cyclic AMP synthesis within a single cell. Since receptors differ in their physical characteristics from adenylate cyclase, the set of receptors located on the surface of the cell determines the specific pattern of its sensitivity to external chemical signals. A single cell may have three or more different inhibitory receptors and six or more different stimulatory receptors. In contrast, all cells appear to contain similar (possibly identical) G and AC components.
The molecular components of hormone-sensitive adenylate cyclase provide control points for changing 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 G proteins are considered to be the primary lesion occurring in the four diseases discussed below.
Regulation of sensitivity to hormones (see also Chapter 66). Repeated administration of a hormone or drug usually causes a gradual increase in resistance to its action. This phenomenon goes by different names: hyposensitization, refractoriness, tachyphylaxis or tolerance.
Hormones or mediators can cause the development of hyposensitization, which is receptor specific, or “homologous”. For example, the administration of b-adrenergic catecholamines causes specific refractoriness of the myocardium to repeated 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 quickly reversible upon removal of the injected hormone, functionally “uncouples” the receptors and the Gc protein and, therefore, reduces their ability to stimulate adenylate cyclase. The second process involves an actual decrease in the number of receptors on the cell membrane, a process called receptor downregulation. The process of receptor downregulation requires several hours to develop and is difficult to reverse.
Hyposensitization processes are part of normal regulation. Removal of normal physiological stimuli may result in increased sensitivity of the target tissue to pharmacological stimulation, as occurs in the development of denervation-induced hypersensitivity. A potentially important clinical correlation of this increase in the number of receptors may develop in patients with sudden cessation of treatment with anaprilin, which is a beta-blocking agent. Such patients often experience transient signs of increased sympathetic tone (tachycardia, increased blood pressure, headaches, tremors, etc.) and may develop symptoms of coronary insufficiency. In the peripheral blood leukocytes of patients receiving anaprilin, an increased number of b-adrenergic receptors is detected, and the number of these receptors slowly returns to normal values when the drug is stopped. Although the more numerous other leukocyte receptors do not mediate the cardiovascular symptoms and events that occur with anaprilin withdrawal, receptors in the myocardium and other tissues are likely to undergo similar changes.
The sensitivity of cells and tissues to hormones can also be regulated in a “heterologous” way, that is, when sensitivity to one hormone is regulated by another hormone acting through a different set of receptors. Regulation of the sensitivity of the cardiovascular system to b-adrenergic amines by thyroid hormones is the best known clinical example of heterologous regulation. Thyroid hormones cause the accumulation of an excess amount of b-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 beta-adrenergic receptors caused by the administration of thyroid hormones is not sufficient to attribute an increase in the sensitivity of the heart to catecholamines suggests that components of the response to hormones are also susceptible 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's control of uterine sensitivity to the relaxing effects of beta-adrenergic agonists and the increased reactivity of many tissues to epinephrine caused by glucocorticoids.
The second type of heterologous regulation is the inhibition of hormonal stimulation of adenylate cyclase by substances acting through Pu and Gi, as noted above. Acetylcholine, opiates, and α-adrenergic catecholamines act through distinct classes of inhibitory receptors (muscarinic, opiate, and α-adrenergic receptors), reducing the sensitivity of adenylate cyclase in certain tissues to the stimulating effects of other hormones. Although the clinical significance of heterologous regulation of this type has not been established, inhibition of cyclic AMP synthesis by morphine and other opiates could account for some aspects of tolerance to drugs of this class. Likewise, reversal of such inhibition may play a role in the development of the syndrome following opiate cessation.
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