? Vascular permeability

spasm Endocardial spasm Blood fibrosis

Blood pressure coagulation -



Eicosanoids are a large group of intracellular and intercellular mediators that are formed from arachidonic acid, a polyunsaturated fatty acid. They are rapidly inactivated in the blood and thus act mainly on their immediate environment.

Arachidonic acid is released from phospholipids of the cell membrane under the influence of the enzyme phospholipase A2 A1). This enzyme is activated by cell swelling and by an increase of intracellular Ca2+ concentration. It is stimulated by a number of mediators, such as histamine, serotonin, bradykinin, and norepinephrine (via a-receptors). Phopholi-pase A2 is inhibited by glucocorticoids (via li-pocortin) and epinephrine (via p-receptors). ^ Arachidonic acid can be transformed to leu-o kotrienes via the enzyme lipoxygenase and to £ prostacyclin (prostglandin G [PGG2]) via the X enzyme cyclo-oxygenase. Substances that can ci be formed from PGG2 include thromboxan A2 (TXA2) and the prostaglandins F2a (PGF2a), E2 (PGE2), and 12 (PG12 = prostacyclin) (^A3). The enzyme cyclo-oxygenase is inhibited by non-steroidal anti-inflammatory drugs (NSAlDs), for example, acetylsalicylic acid (aspirin). 1nflammations and tissue damage cause activation of both cyclo-oxygenase and lipoxygenase, and thus increase the formation of ei-cosanoids.

The leukotrienes (^ A2) cause the contraction of the smooth muscles in the bronchi, blood vessels, gut, and uterus. They are responsible for lasting bronchoconstriction in asthma; their action on the gut can cause diarrhea and their effects on the uterus can bring about abortion of the fetus. Leukotrienes indirectly increase vascular permeability and thus bring about edemas. They also promote adhesions and chemotaxis and stimulate the release of histamine, oxygen radicals, and lysosomal enzymes as well as ofinsulin.

TXA2 is formed largely in thrombocytes and is essential for blood clotting. An excess of TXA2 favors the formation of thrombi. Administration of small doses of the cyclo-oxygenase inhibitor acetylsalicylic acid can thus reduce the risk of myocardial infarction because of its 296 effect of reducing thrombocyte aggregation.

PGF2a stimulates the release of a series of hormones and the contraction of the smooth muscles of blood vessels, gut, bronchi, and uterus.

PGE2 inhibits the release of hormones and lipolysis, stimulates the contraction of smooth muscles of the gut and uterus; however, it inhibits the contraction of the vascular and bronchial muscles. Cyclo-oxygenase inhibitors can thus cause asthma in an atopic individual (so-called analgesic asthma). The vascular effect can cause persistence of the ductus arteriosus. Conversely, the administration of cyclo-oxy-genase inhibitors during the last trimester can cause the premature closure of the ductus ar-teriosus. PGE2 increases glomerular filtration rate. It raises vascular permeability and thus promotes the development of edemas.

PGE2 and PGI2 aid in the demineralization of the bones (osteolysis). They stimulate the renal formation of renin and, by inhibiting the tubular reabsorption of Na+ and water, they produce natriuresis and diuresis. They raise the target level of temperature regulation (fever) and cause pain. The effects of the prosta-glandins contribute to a large extent to the symptoms of infection.

PGE2 has an essential, protective role in the stomach by inhibiting the secretion of HCl and pepsin while promoting the secretion of HCO3-and mucus, which has a protective effect. 1t also causes vascular dilation. A reduction in PGE2 formation by cyclo-ogygenase inhibitors favors the development of gastric ulcers.

PGE2 also has a protective effect on the renal medulla. Via dilation of the vasa recta it improves O2 and substrate availability, and decreases the expenditure of energy by inhibiting NaCl reabsorption.

PGE2 is also of great importance in Bartter's syndrome, which is due to mutations of the Na+-K+-2Cl- cotransporter, the luminal K+ channels, or the basolateral Cl- channels in the loop of Henle. An excessive local formation of PGE2 is the consequence of the resulting transport defect. The inhibitory action of PGE2 on Na+ transport in more distal nephron segments adds to NaCl loss and its vasodilator action causes a profound drop in blood pressure. The affected children can be kept alive only with inhibitors of cyclo-oxygenase.


Bradykinin, Histamine Epinephrine (ß) epinephrine, Serotonin Ca etc.


Bradykinin, Histamine Epinephrine (ß) epinephrine, Serotonin Ca etc.

10 Neuromuscular and Sensory Systems f. lang


The nervous system receives stimuli from the surroundings and its own body, and also directs the body's functions by influencing muscle activity and autonomic nervous functions (e.g., vascular tone, sweat secretion).

The sensory signals influence motor and autonomic nervous functions in manifold ways by means of reflexes and complex connections. A few of the signals first reach the primary sensory cortex via the thalamus and there become conscious. These perceived signals are then analyzed, interpreted, evaluated (development of emotions), and in certain circumstances stored (memory) by secondary sensory cortical areas.

The emotions, which arise from current perceptions or items of memory, can bring about motor activity. It is the task of associated cortical areas to plan sensible motor responses. The motoneurons that stimulate the muscle fibers are ultimately activated via basal ganglia, cerebellum, thalamus, and the primary motor cortex.

The sensory, motor, and autonomic nervous systems are closely interconnected at every level, and thus the autonomic nervous system is also under the influence of sensory and motor activity and of the emotions.

Disorders of the nervous system can have many different causes, such as genetic defects, degenerative diseases, tumors, mechanical lesions (trauma), bleeding, ischemia, systemic metabolic disorders (hypoglycemia, hypergly-cemia, uremia, liver failure, endocrine disorders, etc.), and electrolyte abnormalities. Other possible causes include drugs, toxins (e.g., heavy metals, alcohol), radiation, inflammation, and infection (viruses, bacteria, prions, autoimmune diseases).

The functions of the effectors in the periphery (sensory receptors, muscles, and organs innervated by the autonomic nervous system; ^A1), peripheral nerve conduction (^A2), spinal cord function (^A3), and/or the supraspinal nervous system (^ A4) can be impaired as a consequence of nervous system disorders.

298 Damage to the peripheral effectors (^ A1)

leads to disturbance of the particular function, which may be localized (e.g., individual muscles) or generalized (e.g., the entire musculature). Such damage can result in overactivity (e.g., involuntary muscle cramps or inadequate activity of sensory receptors with faulty sensory perceptions), or functional deficits (muscle paralysis or sensory deficits). Even when the sensory receptors are intact, sensory perception, especially via the eyes and ears, may be impaired if the transmission apparatus is defective.

An interruption of peripheral nerve conduction (^ A2) impairs the signals that are propagated in this nerve, but different types of fibers (e.g., myelinated and nonmyelinated) may be affected differently. The result of complete disruption of nerve conduction is flaccid paralysis, loss of sensation and of autonomic regulation in the innervation area of the affected nerve. Analogously, lesions of a spinal nerve affect the corresponding dermatome. Diagnosis of nerve lesions thus requires an exact knowledge of the innervation area of individual nerves and dermatomes (cf. anatomy textbooks).

Lesions of the spinal cord (^ A3) can cause loss of sensory perception and/or autonomic functions as well as flaccid or spastic paralysis. Conversely, abnormal stimulation of neurons can lead to inadequate sensations and functions. The affected areas approximately follow the distribution of the dermatomes.

Lesions in supraspinal structures (^ A4) can also result in deficits or abnormal excitations that are circumscribed both as to function and to body region (e.g., in localized lesions in primary sensory cortical areas). However, more commonly they cause complex disorders of the sensory and motor systems and/ or autonomic regulation. Additionally, impairment of integrative cerebral functions such as memory, emotions, or cognition may occur in the course of a variety of diseases.

|— A. Pathophysiology of the Nervous System (Overview)

Primary motor cortex

Primary sensory cortex

Visual cortex

Primary motor cortex

Primary sensory cortex

Visual cortex

Vegetative system Motor system

Pathophysiology of Nerve Cells

T3 C ra

In order to fulfill their function, neurons must be able to receive information from other cells and then pass it on to yet other cells. As a rule the information is received via membrane receptors that are activated by neurotransmitters. The activity of ionic channels is influenced directly or via intracellular mechanisms of transmission. Thus, in suitable target cells acetylcholine (ACh) opens nonspecific cation channels that will then allow the passage of Na+ and K+. This will lead to depolarization of the cell membrane and thus to opening of the voltage-gated Na+ and Ca2+ channels. Ca2+ ions then mediate the release of neurotransmitters by the target cell. In the long term, cell metabolism and gene expression of the target cell, and thus the formation of synapses and the synthesis and storage of neurotransmitters are also regulated.

Abnormalities can interfere with each element of this cascade (^ A). For example, receptor density can be reduced by down-regulation. Also, certain mechanisms of intracellu-lar transmission can be blocked. An example is the blocking of G proteins by, among others, pertussis toxin (^A1). Ionic channels can be blocked by drugs, or their activity changed by Ca2+, Mg2+, or H+. Furthermore, their effect on the membrane potential can be distorted by a change in ionic gradients, such as an increase or a decrease in the intracellular or, more importantly, extracellular K+ concentration. Both occur when Na+/K+-ATPase is inhibited, for example, due to energy deficiency. Axonal transport as well as formation, storage, release, and inactivation of neurotransmitters (^A2) can be impaired, for example, by genetic defects or drugs. Functional abnormalities can be reversible once the damage is no longer effective.

Lesions may also lead to irreversible destruction of neurons. In addition to cell death by direct damage to it (necrosis, e.g., due to energy deficiency or mechanical destruction), so-called programmed cell death (apoptosis) may also play a role in this (^ A3 and p. 12). Neurons cannot be renewed in adults. Thus, the destruction of neurons will cause an irreversible impairment of function, even if other neu rons can partly take over the function of the dead cell.

Deleterious substances must pass the blood-brain barrier if they are to reach the neurons of the central nervous system (CNS) (^ B). An intact blood-brain barrier impedes the passage of most substances and prevents pathogens and immunocompetent cells entering (^ p. 356). However, some toxins (e.g., pertussis and botulinus toxins) reach neurons in the spinal cord through retrograde axonal transport via peripheral nerves, and thus avoid the blood-brain barrier (^p. 356). Some viruses also reach the CNS in this way.

If an axon is transected (^C), the distal parts of the axon die (Waller degeneration). Axons of central neurons as a rule do not grow outward again, rather the affected neuron dies by apoptosis. Causes include absence of the nerve growth factor (NGF), which is normally released by the innervated, postsynaptic cell and, via the axon, keeps the presynaptic cell alive. Interruption of the retrograde axonal transport in an otherwise intact axon also leads to death of the neuron. The proximal stump of the peripheral axon can grow out again (^C2). The proteins that are necessary for this to happen are formed within the cell body and are transported to the place of injury by axonal transport. A possible reason for survival of the affected cell is that macrophages migrating into the peripheral nerve, via the formation of interleukin 1, stimulate the Schwann cells to produce NGF. Macrophages are not, however, able to enter the CNS.

Transection of an axon not only causes death of the primarily damaged neuron (^ C1), the absence of innervation often leads to death of the target cell (anterograde transneuronal degeneration) and sometimes also of cells that innervate the damaged cell (retrograde transneuronal degeneration).

I— A. General Functional Disorders

Receptor density \ Receptor blockade

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