Sympathetic nervous system catecholamines

Enhanced automaticity occurs in hypoxia, hypokalemia, hypercarbia, excessive sympathetic nervous system stimulation, or high concentrations of catecholamines. These conditions may lead to arrhythmias. Decreased automaticity may also lead to production of arrhythmias by enhancing ectopic activity in latent pacemakers (ectopic foci) or by altering conductivity and refractoriness in conduction pathways of myocardium. 

Signs and symptoms of sympathetic nervous system activity are invariably found in MH. Levels of catecholamines are markedly increased in MH. Whether activation of the sympathetic nervous system is a primary or a secondary response in the syndrome has not been fully elucidated. Gronert reported that stress-induced sympathetic hyperactivity can initiate a malignant hyperthermic episode in susceptible swine without a triggering agent. Stress-induced MH in humans has been inferred because susceptible families have been shown to have an increased incidence of sudden death. Gronert s reasons that activation of the sympathetic... 

These are four monoamines synthesized and seereted within many mammalian tissues, ineluding various regions in the brain, sympathetic nervous system, enlero-chromafhn cells of the digestive tract, and adrenal mednlla. These biogenic amines (indoleamine and catecholamines — dopamine, norepinephrine, and epinephrine) are synthesized within the cell from their precursor amino acids and have been associated with many physiological and behavioral functions in animals and humans. 

The adrenal gland is located on the upper segment of the kidney (Fig. 42-1). It consists of an outer cortex and an inner medulla. The adrenal medulla secretes the catecholamines epinephrine (also called adrenaline) and norepineprhine (also called noradrenaline), which are involved in regulation of the sympathetic nervous system. The adrenal cortex consists of three histologically distinct zones zona glomerulosa, zona fasciculata, and an innermost layer called the zona reticularis. Each zone is responsible for production of different hormones (Fig. 42-2). 

Adrenal medulla. Derived from neural crest tissue, the adrenal medulla forms the inner portion of the adrenal gland. It is the site of production of the catecholamines, epinephrine and norepinephrine, which serve as a circulating counterpart to the sympathetic neurotransmitter, norepinephrine, released directly from sympathetic neurons to the tissues. As such, the adrenal medulla and its hormonal products play an important role in the activity of the sympathetic nervous system. This is fully discussed in Chapter 9, which deals with the autonomic nervous system. 

The sympathetic nervous system (SNS) and the hypothalamic-pituitary axis work together as important modulators of the immune system after exposure to stressors. Norepinephrine (NE) and epinephrine (EPI) (catecholamines from the SNS) and neuroendocrine hormones modulate a range of immune cell activities, including cell proliferation, cytokine and antibody production, lytic activity, and migration. This chapter will focus on these two major pathways of brain-immune signaling, briefly summarizing the evidence for SNS and hypothalamic-pituitary-adrenal (HPA) modulation of immune function, their influence on immune-mediated diseases, immune modulation in aging, and early life influences on these pathways. 

Known most famously for their part in the fight or flight response to a threat, challenge or anger, adrenaline (epinephrine) and dopamine from the adrenal medulla and noradrenaline (norepinephrine), mainly from neurones in the sympathetic nervous system are known collectively as catecholamines. Synthesis follows a relatively simple pathway starting with tyrosine (Figure 4.7). 

The hypothesis that is formulated on the basis of these properties is as follows. The signal for increased thermogenesis, when the body temperature falls, is an increase in the level of catecholamines, probably the local concentration of noradrenaline, which will be increased via stimulation of sympathetic nervous system. The catecholamine increases the activity of triacylglycerol lipase within the brown adipose tissue, by a similar mechanism to that which occurs in white adipose tissue (Chapter 7), i.e. by an... 

The examined drugs reversibly bind with 8-adrenergic receptive regions and competitively prevent activation of these receptors by catecholamines released by the sympathetic nervous system, or externally introduced sympathomimetics. 

The adrenal medulla synthesizes two catecholamine hormones, adrenaline (epinephrine) and noradrenaline (norepinephrine) (Figure 1.8). The ultimate biosynthetic precursor of both is the amino acid tyrosine. Subsequent to their synthesis, these hormones are stored in intracellular vesicles, and are released via exocytosis upon stimulation of the producer cells by neurons of the sympathetic nervous system. The catecholamine hormones induce their characteristic biological effects by binding to one of two classes of receptors, the a- and )S-adrenergic receptors. These receptors respond differently (often oppositely) to the catecholamines. 

The neurotransmitters of the sympathetic nervous system are the catecholamines noradrenaline (mainly in the nerve terminals of peripheral nerves and in the central nervous system), adrenaline (mainly in the adrenal medulla) which has to reach the target organs with the blood stream and dopamine. 

Noradrenaline and adrenaline are the classic catecholamines and neurotransmitters in the sympathetic nervous system. Noradrenaline stimulates the following subtypes of adrenoceptors P, a, U2. It has positive inotropic and chronotropic activities as a result of /3i-receptor stimulation. In addition, it is a potent vasoconstrictor agent as a result of the stimulation of both subtypes (ai,a2) of a-adrenoceptors. After intravenous infusion, its effects develop within a few minutes, and these actions disappear within 1-2 minutes after stopping the infusion. It may be used in conditions of acute hypotension and shock, especially in patients with very low vascular resistance. It is also frequently used as a vasoconstrictor, added to local anaesthetics. Adrenaline stimulates the following subtypes of adrenoceptors /3i, P2, oil, 0L2. Its pharmacological profile greatly resembles that of noradrenaline (see above), as well as its potential applications in shock and hypotension. Like noradrenaline, its onset and duration of action are very short, as a result of rapid inactivation in vivo. Both noradrenaline and adrenaline may be used for cardiac stimulation. Their vasoconstrictor activity should be kept in mind. A problem associated with the use of /3-adrenoceptor stimulants is the tachyphylaxis of their effects, explained by the /3-adrenoceptor downregulation, which is characteristic for heart failure. 

A unique property of bretylium as an antiarrhythmic agent is its positive inotropic action. This effect, related to its actions on the sympathetic nervous system, includes an initial release of neuronal stores of norepinephrine followed shortly by a prolonged period of inhibition of direct or reflex-associated neuronal norepinephrine release. The onset of bretylium-induced hypotension is delayed 1 to 2 hours because the initial catecholamine release maintains arterial pressure before this time. 

The myocardial response to exercise includes an increase in heart rate and myocardial contractility. These effects are mediated in part by the sympathetic nervous system. Propranolol and other p-adrenoceptor blockers antagonize the actions of catecholamines on the heart... 

There is good evidence that the facilitation of peripheral sympathetic nervous system transmission prcxluced by the amphetamines also occurs in the CNS.The possibihty that amphetamines act indirectly (i.e., by releasing monoamines) at monoaminergic synapses in the brain and spinal cord seems likely. However, amphetamine has effects beyond displacement of catecholamines these include inhibition of neuronal amine uptake, direct stimulation of dopamine and serotonin receptors, antagonism of catecholamine action at certain subtypes of adrenoceptors, and inhibition of monoamine oxidase. Interestingly, none of these actions explains the therapeutic benefit of the amphetamines in hyperkinetic children. 

Unlike isoflurane, desflurane may stimulate the sympathetic nervous system at concentrations above 1 MAC. Sudden and unexpected increases in arterial blood pressure and heart rate have been reported in some patients, accompanied by increases in plasma catecholamine and vasopressin concentrations and increased plasma renin activity. These pressor effects may increase morbidity or mortality in susceptible patients. The mechanism of sympathetic activation is unclear but does not appear to be baroreceptor-mediated. Clonidine, esmolol, fentanyl and propofol partially block the response but lignocaine (lignocaine) is ineffective. 

Many of the manifestations of thyroid hyperactivity resemble sympathetic nervous system overactivity (especially in the cardiovascular system), although catecholamine levels are not increased. Changes in catecholamine-stimulated adenylyl cyclase activity as measured by cAMP are found with changes in thyroid activity. Possible explanations include increased numbers of 13 receptors or enhanced amplification of the 13 receptor signal. Other clinical symptoms reminiscent of excessive epinephrine activity (and partially alleviated by adrenoceptor antagonists) include lid lag and retraction, tremor, excessive sweating, anxiety, and nervousness. The opposite constellation of effects is seen in hypothyroidism (Table 38-4). 

Drugs that block beta-1 receptors on the myocardium are one of the mainstays in arrhythmia treatment. Beta blockers are effective because they decrease the excitatory effects of the sympathetic nervous system and related catecholamines (norepinephrine and epinephrine) on the heart.5,28 This effect typically decreases cardiac automaticity and prolongs the effective refractory period, thus slowing heart rate.5 Beta blockers also slow down conduction through the myocardium, and are especially useful in controlling function of the atrioventricular node.21 Hence, these drugs are most effective in treating atrial tachycardias such as atrial fibrillation.23 Some ventricular arrhythmias may also respond to treatment with beta blockers. 

When injected intravenously, kinins produce a rapid fall in blood pressure that is due to their arteriolar vasodilator action. The hypotensive response to bradykinin is of very brief duration. Intravenous infusions of the peptide fail to produce a sustained decrease in blood pressure prolonged hypotension can only be produced by progressively increasing the rate of infusion. The rapid reversibility of the hypotensive response to kinins is due primarily to reflex increases in heart rate, myocardial contractility, and cardiac output. In some species, bradykinin produces a biphasic change in blood pressure—an initial hypotensive response followed by an increase above the preinjection level. The increase in blood pressure may be due to a reflex activation of the sympathetic nervous system, but under some conditions, bradykinin can directly release catecholamines from the adrenal medulla and stimulate sympathetic ganglia. Bradykinin also increases blood pressure when injected into the central nervous system, but the physiologic significance of this effect is not clear, since it is unlikely that kinins cross the blood-brain barrier. 

The brain and the immune system are accepted as the two major body s adaptive systems (Elenkov et al., 2000). The brain can modulate immune functions and the immune system also sends messages to the brain. The communication between these two systems is done mainly by the hypothalamic-pituitary-adrenal axis and the autonomic nervous system (ANS). The sympathetic nervous system (SNS), which is part of the ANS, innervates the lymphoid organs (Elenkov et al., 2000) (Flierl et al., 2007). Catecholamines, like dopamine, serotonin, epinephrine and norepinephrine, are the end products of the SNS. 

The most well known of the naturally occurring phenethylamine derivatives (Table I) are the transmitters of the sympathetic nervous system, epinephrine, norepinephrine, and dopamine. All these compounds are 3,4-dioxygenated in the aromatic nucleus and are collectively known as the catecholamines. Norepinephrine is the transmitter of most sympathetic postganglionic fibers, dopamine is the predominant transmitter of the mammalian extrapyramidal system and of several mesocortical and mesolimbic neuronal pathways, and epinephrine is the major hormone of the adrenal medulla (363). The literature that has accumulated on the action of these compounds in higher animals is enormous. Metanephrine and normetanephrine are known from animals as deactivated metabolites of epinephrine and norepinephrine that result from the action of the enzyme catechol O-methyltransferase (364). 

There are two kinds of catecholamine receptors, the a and fi receptors. The former respond best to norepinephrine, whereas the latter prefer epinephrine. Norepinephrine is normally associated with neurotransmission, and a-adrenergic receptors are indeed found in tissues serviced by the sympathetic nervous system. An example is the smooth muscle, which contracts in response to stimulation by... 

Cocaine may directly affect the fetal cardiovascular system or do so by increasing the concentrations of circulating catecholamines and activating the sympathetic nervous system. 

The activation of the stress systems affects all tissues of the organism, and the peripheral immune system is no exception. These effects are mediated through at least tw o pathways via the HPA axis and by virtue of the innervation of lymphatic tissues by autonomic nerve fibers, especially from the sympathetic nervous system. All lymphoid tissues, primary (bone marrow and thymus) as well as secondary (spleen, lymph nodes, and gut-associated lymphoid tissue) are innervated by sympathetic nerve fibers. As discussed above, most lymphoid cells express catecholamine receptors, including B-lymphocytes, CD4- and CD 8-positive T cells, dendritic cells, monocytes, and macrophages. 

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