STUDY - Technical - New Dacian's Medicine
Physiology
and Pharmacology of the Vegetative Nervous System (3)
Translation Draft
So, today we're talking about the physiology of the sympatoadrenergic system. Catecolamines influence all important organs and systems. Effects on them occur in seconds and can occur in anticipation of physiological needs. An increase in sympatoadrenergic activity, which precedes intense physical exertion, for example, decreases the impact of physical exertion on the internal environment.
Now let's see what's with the direct effects of catecholamines, starting with the cardiovascular system. Catecolamines stimulate vasoconstriction in the subcutaneous, mucous, renal and splahnic vascular territory, through mechanisms mediated by the alpha receptor. Although vasoconstriction was initially considered an alpha1 receptor response, vascular tone appears to be more complex controlled, and in some areas it also involves responses mediated by alpha2 receptors. Venous circulation, in particular, is endowed with alpha2 receptors.
Differentiated regulation of the two types of alpha receptors contributes, under certain circumstances, to an integrated physiological response. Because vasoconstriction is minimal in coronary and cerebral circulation, flow in these areas is maintained during sympathetic stimulation. The skeletal muscle vessels contain beta-receptors sensitive to low circulating levels of E, so that blood flow from skeletal muscles is increased during the activation of the medulloadrenal. The effects of catecholamines on the heart are mediated by beta1 receptors and consist of increasing heart rate, improving cardiac contractility and increasing driving speed. The increase in myocardial contractility is illustrated by a left-hand and upward shift of the ventricular function curve, which expresses the link between cardiac mechanical work and muscle fiber length in the diastole (at any initial length of the fiber, catecholamines increase cardiac mechanical work).
Catecholamines also increase cardiac output by stimulating venoconstriction, increasing venous return and increasing atrial contraction force, thereby increasing diastolic volume and thus muscle fiber length. Accelerating conduction in the junctional tissues leads to greater synchronization, thus more effective muscle contraction. Cardiac stimulation increases myocardial oxygen consumption, being a major factor in the pathogenicity and treatment of myocardial ischemia.
In terms of metabolism, catecholamines increase its rate. In small mammals, mitochondrial respiration in brown adipose tissue is not functionally coupled with NE. In a specific reaction, brown adipose tissue, NE stimulates the adrenergic beta3 receptor, which activates a specific mitochondrial decoupling protein, reducing the proton gradient between the internal mitochondrial matrix and the cytoplasm and thus decoupleting the use of the ATP synthesis substrate. In humans, a functional role of brown fat tissue has not been established with certainty, but an increased number of samples suggest a potential role in heat production, stimulated by catecholamines.
From the point of view of substrate mobilization, in different tissues, catecholamines stimulate the release of stored combustible material, with the production of the substrate necessary for local consumption (in the heart, for example, glycogenolysis provides the substrate for immediate metabolism at the myocardial level). Catecolamines also accelerate the mobilization of liver reserves, fat tissue and skeletal muscle, releasing into circulation substrates (glucose, free fatty acids, lactate) that will be used by the whole body. From the point of view of fluids and electrolytes, by direct action on the renal tubes, NE stimulates the reabsorption of sodium, thus maintaining the volume of extracellular fluid.
Dopamine, on the contrary, stimulates sodium excretion. NE and E also stimulate the penetration of potassium into the cell, thus helping to prevent hyperpotassium. Catecolamines influence the functions of the viscera, acting on the glandular epithelium and smooth muscles. The smooth muscles of the bladder and intestine are relaxed, while the corresponding sphincters are contracted. Empty gallbladder also involves sympathetic mechanisms. In women, the contraction of smooth muscles, mediated by catecholamines, helps ovulation and contributes to the transport of the egg along the fallopian tube, and in men provides the necessary propellant force for seminal fluid during ejaculation. Alpha2 inhibitor receptors on cholinergic neurons at the intestinal level contribute to bowel relaxation. Catecolamines cause bronchodilation by mechanism mediated by beta2 receptors.
Let's see what the indirect effects of catecholamines are. The fundamental physiological response to catecholamines involves changes in hormonal secretion and blood flow distribution, both supporting and amplifying the direct effects of catecholamines. Thus, we reach the level of the endocrine system. catecholamines influence the secretion of renin, insulin, glucagon, calcitonin, parathormon, thyroxine, gastrine, erythropietin, progesterone and probably testosterone. The secretion of each of these hormones is governed by complex feedback loops. With the exception of thyroxine and sex steroids, all other hormones are polypeptides that are not under the direct control of hypophysis.
The sympatoadrenergic intervention in the secretion of these hormones provides a regulating mechanism by the central nervous system and a coordinated hormonal response, in accordance with the homeostatic needs of the body. As for renin, sympathetic stimulation causes increased renin release, through a direct effect mediated by the beta receptor, independent of renal vascular changes. The response of the renin to the volume delet is sympatheticmediated and is initiated by the decrease in central venous pressure.
Because renin secretion activates the angiotensin-aldosterone system, vasoconstriction produced by angiotensin maintains the direct effects of catecholamines on blood vessels, while sodium reabsorption, mediated by aldosterone, complements the direct increase in sodium reabsorption caused by sympathetic stimulation. Beta receptor blockers suppress renin secretion. It's insulin and glucagon's turn. Stimulation of pancreatic sympathetic nerves or increased circulating catecholamines inhibits the release of insulin and increases the release of glucagon. Inhibition of insulin secretion is mediated by the alpha2 receptor, and stimulation of glucagon release is mediated by the beta receptor. This combination of effects contributes to the mobilization of energy substrates, reinforcing the direct effects of catecholamines on lipolysis and hepatic glucose release. Although the suppression of insulin release mediated by the alpha receptor usually prevails, under certain conditions, a mechanism mediated by the beta receptor may increase insulin secretion.
Let's move on to the sympatoadrenergic function in certain physiological and physiopathological states, starting with the presentation of the elements related to the support of blood circulation. The sympathetic nervous system works in order to maintain adequate blood circulation. During orthostatism and volemy depleties, the decrease in the related impulses at the level of venosand and arterial baroreceptors reduces inhibitory afferences to the vasomotor center, thus increasing sympathetic activity and decreasing the efferent vagal tone. As a result, the heart rate is increased and the heart rate is diverted from the territory of the skin, subcutaneous tissues, mucous membranes and viscera. Sympathetic stimulation of the kidneys increases sodium reabsorption, and sympathetically mediated venoconstriction increases venous return.
Accentuating hypotension stimulates the medulloadrenal, and E released strengthens the effects of the sympathetic nervous system. Intense sympathoadrenergic stimulation accompanying severe volemic depletion may contribute to ketoacidosis in alcoholics, as well as ketoacidosis sometimes observed in association with hyperemesis during pregnancy. In these circumstances, the suppression of insulin, mediated by catecholamines, and stimulation of glucagon potentiates marked the appearance of ketoacidosis. The restoration of volemia and adequate glucose supply quickly cancels ketoacidosis in most cases. The sympathetic nervous system also provides circulatory support during congestive heart failure.
Venoconstriction and sympathetic stimulation of the heart increase heart rate, while peripheral vasoconstriction directs blood flow to the heart and brain. The related signals are less clear than in simple volume demotion, since the venous pressure is usually increased. In severe heart failure, NE exhaustion in the heart may affect the effectiveness of sympathetic circulatory support. On the other hand, intense sympathetic stimulation may further hamper cardiac function, suggesting a possible benefit of beta-adrenergic blockage. The use of beta blockers in the treatment of congestive heart failure should however be considered as experimental and used with great caution. In the case of trauma and shock, in acute traumatic injuries or in shock, adrenal catecholamines support blood circulation and mobilize energy substrates.
In the chronic, reparative phase that follows the lesion, catecholamines also contribute to the mobilization of the energogen substrate and to increase the rate of metabolism. And finally, for physical exertion, sympathetic activation during physical exertion increases cardiac output and provides sufficient substrate for increased metabolic needs. Central nerve factors, such as anticipation, along with circulatory factors, such as decreased venous pressure, initiate the sympathetic response. Mild physical efforts exclusively stimulate the sympathetic nervous system (intense ones also activate the medulloadrenal). Physical training is associated with decreased activity of the sympathetic nervous system, both at rest and during physical exertion.
Hypoglycaemia causes a marked increase in E secretion by the adrenal medullo. When the increase in glucose levels drops below the nocturnal level, glucose-sensitive regulatory neurons in the central nervous system initiate a rapid, prompt increase in medulloadrenal secretion. The increase is particularly intense at glucose levels 25-50 times the basal level, stimulating hepatic glucose discharge and forming an alternative energy substrate in the form of free fatty acids, suppressing the release of endogenous insulin and inhibiting the insulin-mediated use of glucose from muscles.
Many clinical manifestations of hypoglycaemia, such as tachycardia, palpitations, nervousness, tremors and pulse amplification, are secondary to the increase in E secretion. In patients with old diabetes, the E response to hypoglycaemia may be diminished or absent, with an increased risk of severe hypoglycaemia.
In the case of exposure to cold, the sympathetic nervous system plays a decisive role in maintaining body temperature during exposure to a cold environment. The receptors and those in the central nervous system respond to the drop in temperature by activating the hypothalamic centers and the brain stem, which increase sympathetic activity. Sympathetic stimulation leads to vasoconstriction in superficial vascular beds, thereby lessidonating heat loss. The sympathetic response involves a complex interaction between the low temperature of the external environment and adrenergic alpha2 receptors. Acclimatization during prolonged exposure to cold increases the ability to produce metabolic heat in response to sympathetic stimulation.
The sympathetic nervous system is stimulated by overeating and inhibited by fasting. The reduction of sympathetic activity during fasting or inanition contributes to the decrease of metabolic rate, bradycardia and hypotension, which occur in these situations. Increased sympathetic activity during periods of increased caloric intake contributes to increased metabolic rate, associated with chronic increase in dietary intake.
Chronic hypoxia is associated with stimulation of the sympatoadrenergic system, and some cardiovascular changes that accompany hypoxia are dependent on catecholamines.
And at the end of this post, there's something else to be said for orthostatic hypotension. Maintaining arterial pressure during orthostatism depends on the presence of adequate blood volume, normal venous return and the integrity of the sympathetic nervous system. Therefore, significant postural hypotension often reflects a delet of the volume of extracellular fluid or a dysfunction of circulatory reflexes. Nervous system disorders, such as dorsal tabes, syringolilia or diabetes mellitus, can interrupt these sympathetic reflexes, resulting in orthostatic hypotension.
Although any antiadrenergic agent may affect the sympathetic postural response, orthostatic hypotension is more evident after taking drugs that block the transmission of impulses into the adrenergic ganglia or neurons. The term idiopathic orthostatic hypotension refers to a group of degenerative disorders involving sympathetic neurons, either pre or postganglionary. Treatment of orthostatic hypotension is usually unsatisfactory, except in mild cases. There is no way to restore the normal relationship between diminishing venous return and sympathetic neural activity. Volemic expansion obtained with fludrocortisone and a diet rich in salt, together with wearing suitable stockings, up to the waist, and lifting the head of the bed, to avoid a horizontal position, will maintain plasma volume and venous return, often causing an improvement in symptomatology.
Both for this post! Next time we'll talk about the pharmacology of the sympathoadrenergic system.
So, today we're talking about the physiology of the sympatoadrenergic system. Catecolamines influence all important organs and systems. Effects on them occur in seconds and can occur in anticipation of physiological needs. An increase in sympatoadrenergic activity, which precedes intense physical exertion, for example, decreases the impact of physical exertion on the internal environment.
Now let's see what's with the direct effects of catecholamines, starting with the cardiovascular system. Catecolamines stimulate vasoconstriction in the subcutaneous, mucous, renal and splahnic vascular territory, through mechanisms mediated by the alpha receptor. Although vasoconstriction was initially considered an alpha1 receptor response, vascular tone appears to be more complex controlled, and in some areas it also involves responses mediated by alpha2 receptors. Venous circulation, in particular, is endowed with alpha2 receptors.
Differentiated regulation of the two types of alpha receptors contributes, under certain circumstances, to an integrated physiological response. Because vasoconstriction is minimal in coronary and cerebral circulation, flow in these areas is maintained during sympathetic stimulation. The skeletal muscle vessels contain beta-receptors sensitive to low circulating levels of E, so that blood flow from skeletal muscles is increased during the activation of the medulloadrenal. The effects of catecholamines on the heart are mediated by beta1 receptors and consist of increasing heart rate, improving cardiac contractility and increasing driving speed. The increase in myocardial contractility is illustrated by a left-hand and upward shift of the ventricular function curve, which expresses the link between cardiac mechanical work and muscle fiber length in the diastole (at any initial length of the fiber, catecholamines increase cardiac mechanical work).
Catecholamines also increase cardiac output by stimulating venoconstriction, increasing venous return and increasing atrial contraction force, thereby increasing diastolic volume and thus muscle fiber length. Accelerating conduction in the junctional tissues leads to greater synchronization, thus more effective muscle contraction. Cardiac stimulation increases myocardial oxygen consumption, being a major factor in the pathogenicity and treatment of myocardial ischemia.
In terms of metabolism, catecholamines increase its rate. In small mammals, mitochondrial respiration in brown adipose tissue is not functionally coupled with NE. In a specific reaction, brown adipose tissue, NE stimulates the adrenergic beta3 receptor, which activates a specific mitochondrial decoupling protein, reducing the proton gradient between the internal mitochondrial matrix and the cytoplasm and thus decoupleting the use of the ATP synthesis substrate. In humans, a functional role of brown fat tissue has not been established with certainty, but an increased number of samples suggest a potential role in heat production, stimulated by catecholamines.
From the point of view of substrate mobilization, in different tissues, catecholamines stimulate the release of stored combustible material, with the production of the substrate necessary for local consumption (in the heart, for example, glycogenolysis provides the substrate for immediate metabolism at the myocardial level). Catecolamines also accelerate the mobilization of liver reserves, fat tissue and skeletal muscle, releasing into circulation substrates (glucose, free fatty acids, lactate) that will be used by the whole body. From the point of view of fluids and electrolytes, by direct action on the renal tubes, NE stimulates the reabsorption of sodium, thus maintaining the volume of extracellular fluid.
Dopamine, on the contrary, stimulates sodium excretion. NE and E also stimulate the penetration of potassium into the cell, thus helping to prevent hyperpotassium. Catecolamines influence the functions of the viscera, acting on the glandular epithelium and smooth muscles. The smooth muscles of the bladder and intestine are relaxed, while the corresponding sphincters are contracted. Empty gallbladder also involves sympathetic mechanisms. In women, the contraction of smooth muscles, mediated by catecholamines, helps ovulation and contributes to the transport of the egg along the fallopian tube, and in men provides the necessary propellant force for seminal fluid during ejaculation. Alpha2 inhibitor receptors on cholinergic neurons at the intestinal level contribute to bowel relaxation. Catecolamines cause bronchodilation by mechanism mediated by beta2 receptors.
Let's see what the indirect effects of catecholamines are. The fundamental physiological response to catecholamines involves changes in hormonal secretion and blood flow distribution, both supporting and amplifying the direct effects of catecholamines. Thus, we reach the level of the endocrine system. catecholamines influence the secretion of renin, insulin, glucagon, calcitonin, parathormon, thyroxine, gastrine, erythropietin, progesterone and probably testosterone. The secretion of each of these hormones is governed by complex feedback loops. With the exception of thyroxine and sex steroids, all other hormones are polypeptides that are not under the direct control of hypophysis.
The sympatoadrenergic intervention in the secretion of these hormones provides a regulating mechanism by the central nervous system and a coordinated hormonal response, in accordance with the homeostatic needs of the body. As for renin, sympathetic stimulation causes increased renin release, through a direct effect mediated by the beta receptor, independent of renal vascular changes. The response of the renin to the volume delet is sympatheticmediated and is initiated by the decrease in central venous pressure.
Because renin secretion activates the angiotensin-aldosterone system, vasoconstriction produced by angiotensin maintains the direct effects of catecholamines on blood vessels, while sodium reabsorption, mediated by aldosterone, complements the direct increase in sodium reabsorption caused by sympathetic stimulation. Beta receptor blockers suppress renin secretion. It's insulin and glucagon's turn. Stimulation of pancreatic sympathetic nerves or increased circulating catecholamines inhibits the release of insulin and increases the release of glucagon. Inhibition of insulin secretion is mediated by the alpha2 receptor, and stimulation of glucagon release is mediated by the beta receptor. This combination of effects contributes to the mobilization of energy substrates, reinforcing the direct effects of catecholamines on lipolysis and hepatic glucose release. Although the suppression of insulin release mediated by the alpha receptor usually prevails, under certain conditions, a mechanism mediated by the beta receptor may increase insulin secretion.
Let's move on to the sympatoadrenergic function in certain physiological and physiopathological states, starting with the presentation of the elements related to the support of blood circulation. The sympathetic nervous system works in order to maintain adequate blood circulation. During orthostatism and volemy depleties, the decrease in the related impulses at the level of venosand and arterial baroreceptors reduces inhibitory afferences to the vasomotor center, thus increasing sympathetic activity and decreasing the efferent vagal tone. As a result, the heart rate is increased and the heart rate is diverted from the territory of the skin, subcutaneous tissues, mucous membranes and viscera. Sympathetic stimulation of the kidneys increases sodium reabsorption, and sympathetically mediated venoconstriction increases venous return.
Accentuating hypotension stimulates the medulloadrenal, and E released strengthens the effects of the sympathetic nervous system. Intense sympathoadrenergic stimulation accompanying severe volemic depletion may contribute to ketoacidosis in alcoholics, as well as ketoacidosis sometimes observed in association with hyperemesis during pregnancy. In these circumstances, the suppression of insulin, mediated by catecholamines, and stimulation of glucagon potentiates marked the appearance of ketoacidosis. The restoration of volemia and adequate glucose supply quickly cancels ketoacidosis in most cases. The sympathetic nervous system also provides circulatory support during congestive heart failure.
Venoconstriction and sympathetic stimulation of the heart increase heart rate, while peripheral vasoconstriction directs blood flow to the heart and brain. The related signals are less clear than in simple volume demotion, since the venous pressure is usually increased. In severe heart failure, NE exhaustion in the heart may affect the effectiveness of sympathetic circulatory support. On the other hand, intense sympathetic stimulation may further hamper cardiac function, suggesting a possible benefit of beta-adrenergic blockage. The use of beta blockers in the treatment of congestive heart failure should however be considered as experimental and used with great caution. In the case of trauma and shock, in acute traumatic injuries or in shock, adrenal catecholamines support blood circulation and mobilize energy substrates.
In the chronic, reparative phase that follows the lesion, catecholamines also contribute to the mobilization of the energogen substrate and to increase the rate of metabolism. And finally, for physical exertion, sympathetic activation during physical exertion increases cardiac output and provides sufficient substrate for increased metabolic needs. Central nerve factors, such as anticipation, along with circulatory factors, such as decreased venous pressure, initiate the sympathetic response. Mild physical efforts exclusively stimulate the sympathetic nervous system (intense ones also activate the medulloadrenal). Physical training is associated with decreased activity of the sympathetic nervous system, both at rest and during physical exertion.
Hypoglycaemia causes a marked increase in E secretion by the adrenal medullo. When the increase in glucose levels drops below the nocturnal level, glucose-sensitive regulatory neurons in the central nervous system initiate a rapid, prompt increase in medulloadrenal secretion. The increase is particularly intense at glucose levels 25-50 times the basal level, stimulating hepatic glucose discharge and forming an alternative energy substrate in the form of free fatty acids, suppressing the release of endogenous insulin and inhibiting the insulin-mediated use of glucose from muscles.
Many clinical manifestations of hypoglycaemia, such as tachycardia, palpitations, nervousness, tremors and pulse amplification, are secondary to the increase in E secretion. In patients with old diabetes, the E response to hypoglycaemia may be diminished or absent, with an increased risk of severe hypoglycaemia.
In the case of exposure to cold, the sympathetic nervous system plays a decisive role in maintaining body temperature during exposure to a cold environment. The receptors and those in the central nervous system respond to the drop in temperature by activating the hypothalamic centers and the brain stem, which increase sympathetic activity. Sympathetic stimulation leads to vasoconstriction in superficial vascular beds, thereby lessidonating heat loss. The sympathetic response involves a complex interaction between the low temperature of the external environment and adrenergic alpha2 receptors. Acclimatization during prolonged exposure to cold increases the ability to produce metabolic heat in response to sympathetic stimulation.
The sympathetic nervous system is stimulated by overeating and inhibited by fasting. The reduction of sympathetic activity during fasting or inanition contributes to the decrease of metabolic rate, bradycardia and hypotension, which occur in these situations. Increased sympathetic activity during periods of increased caloric intake contributes to increased metabolic rate, associated with chronic increase in dietary intake.
Chronic hypoxia is associated with stimulation of the sympatoadrenergic system, and some cardiovascular changes that accompany hypoxia are dependent on catecholamines.
And at the end of this post, there's something else to be said for orthostatic hypotension. Maintaining arterial pressure during orthostatism depends on the presence of adequate blood volume, normal venous return and the integrity of the sympathetic nervous system. Therefore, significant postural hypotension often reflects a delet of the volume of extracellular fluid or a dysfunction of circulatory reflexes. Nervous system disorders, such as dorsal tabes, syringolilia or diabetes mellitus, can interrupt these sympathetic reflexes, resulting in orthostatic hypotension.
Although any antiadrenergic agent may affect the sympathetic postural response, orthostatic hypotension is more evident after taking drugs that block the transmission of impulses into the adrenergic ganglia or neurons. The term idiopathic orthostatic hypotension refers to a group of degenerative disorders involving sympathetic neurons, either pre or postganglionary. Treatment of orthostatic hypotension is usually unsatisfactory, except in mild cases. There is no way to restore the normal relationship between diminishing venous return and sympathetic neural activity. Volemic expansion obtained with fludrocortisone and a diet rich in salt, together with wearing suitable stockings, up to the waist, and lifting the head of the bed, to avoid a horizontal position, will maintain plasma volume and venous return, often causing an improvement in symptomatology.
Both for this post! Next time we'll talk about the pharmacology of the sympathoadrenergic system.
Love, Gratitude and
Understanding!
Dorin, Merticaru