The response of a given cell to circulating epinephrine and/or norepinephrine will depend on the type(s) of adrenergic receptors present, the relative number of each if there is more than one type, which is often the case, and the prevailing concentrations of the two catecholamines. All of the circulating epinephrine comes from the adrenal medulla and makes up 80% of the catecholamines released from the chromaffin cells, the remaining 20% being norepinephrine. Of the circulating nonepinephrine, about one third comes from the adrenal medulla and the remainder diffuses into the circulatory system from postganglionic sympathetic nerve terminals in which this catecholamine is the neurotransmitter. Thus, at any one time target cells are exposed to ligand derived from both glandular and neural sources.

Since the adrenal medulla receives signals directly from the autonomic nervous system, its response to change is very rapid and epinephrine levels, relative to norepinephrine, rise very quickly. This neural signal to the adrenal medulla conveys an emergency situation; the effects of the epinephrine secreted in response to this message are directed towards the dual goals of increasing fuel availability to the cardiac and skeletal muscles and to preserve the supply of glucose and oxygen for the brain. The many organs and pathways involved in this effort, and the receptors that mediate the responses, are summarized in Figure 1.

Fig1. Catecholamine-mediated responses to acute stress. Three types of responses are shown: On the left (pink) are effects of epinephrine on the heart and vasculature which allow increased blood flow to skeletal muscles and decreased flow to the GI tract. In the center (blue) is bronchodilation to allow increased gas exchange, thus maintaining the flow of oxygen to the muscles and brain. On the right (green) are the metabolic responses which increase the supply of fuel to the muscles and brain. In each box, the primary adrenergic receptor responsible for the actions is indicated.

1. Blood Flow

 Increased epinephrine from the adrenal medulla binds to the β1 receptor in the heart to increase the heartbeat rate (chronotropic effect) and strength (ionotropic effect). In addition, the rapid relaxation of the ventricle during diastole is facilitated (lusitropic effect). These actions contribute to an overall increase in cardiac output. At the same time, α2 receptors in the veins are constricted, increasing the rate of return of blood to the heart. Through the vasoconstriction of splanchnic arterioles leading to the GI tract as well as the skin and kidney, blood flow to these parts of the body is decreased. Vasodilation of skeletal and cardiac muscle arterioles, as well as those of the liver and lungs, is mediated by the β2 receptor and the increased blood flow to these organs completes the diversion of blood to the sites where it is most needed.

2. Gas Exchange

Interaction of epinephrine with the β2 receptors on the smooth muscle cells of the bronchioles (the smallest branches of the airway) increases the flow of gases to and from the alveoli of the lungs. This provides for a faster rate of removal of carbon dioxide from the blood and its replacement with oxygen.

3. Metabolic Changes

The many metabolic effects of epinephrine are summarized on the right side of Figure 1. Adipose tissue contributes to the increased availability of glucose in the blood through the increase of lipid breakdown and decreased glucose uptake. In the liver, glucose output is increased through elevated glycogen breakdown and gluconeogenesis.

The liver responds to epinephrine by increasing glycogen breakdown; increasing gluconeogenesis; and increasing its breakdown of free fatty acids (released from adipose tissue; see below). The pathway of epinephrine stimulation of glycogen breakdown in the liver and skeletal muscle is well known and in fact is the first instance of cyclic AMP as a second messenger to be elucidated and is presented in Chapter 1. Interaction of the occupied β2 receptor with Gs is followed by activation of adenyl cyclase and of cAMP dependent protein kinase (PKA). Phosphorylation and activation of phosphorylase b by PKA and phosphorylase a by phosphorylase b ensue. Phosphorylase a then phosphorylates glycogen, the first step in the removal of one glucose (as glucose-1-phosphate) molecule from the chain. The same pathway is used in the response of the skeletal muscle to epinephrine shown in Figure 1. The resulting rise in plasma glucose from this burst of hepatic glycogenolysis in the liver is followed by a sustained two fold rise in gluconeogenesis to augment and maintain the output of glucose from the liver. These effects of epinephrine on glucose metabolism in the liver are summarized in Figure 2. Also shown in Figure 2 is the output from the liver of ketone bodies, derived from increased fatty acid breakdown (see Figure 3). These fuels, acetoacetate and D-β-hydroxybutyrate, are important ones for the brain as well as kidney and lung (Figure 1), to maintain their function during a time of stress.

Fig2. Epinephrine and liver metabolism. When the hepatocyte is stimulated by epinephrine, the output of glucose is increased by increased glycogen breakdown and gluconeogenesis (pink pathways). Increased free fatty acids, from lipolysis adipose tissue, are available for β-oxidation, resulting in increased ketone bodies, acetoacetate and D-β-hydroxybutyrate (blue pathway). Both the increased glucose and ketone bodies are released into the circulation to maintain the fuel supply to the brain and other tissues.

Fig3. Effect of epinephrine on adipose cell fatty acid mobilization. When adipose cells are stimulated by epinephrine, the fatty acids stored as triglycerides are released by the action of three lipases (blue ovals). Triacylglycerides (TAG) are the substrates for acetyl triglyceride lipase (ATGL; also known as desnitrin); diacylglycerides (DAG) are the substrates for hormone sensitive lipase (HSL); and monacylglycerides (MAG) are the substrates for monoglyceride lipase (MGL). Activation of the β-adrenergic receptor leads to increased intracellular cyclic AMP and activation of protein kinase A (PKA) which phosphorylates hormone sensitive lipase, increasing its activity. The result is the release of fatty acids into the circulation.

The details of action of epinephrine to mobilize free fatty acids in adipose tissue are shown in Figure 3. Interaction of epinephrine with a β-adrenergic receptor increases intracellular cyclic AMP, which activates cyclic AMP-dependent protein kinase. PKA phosphorylates hormone sensitive lipase (HSL), one of three enzymes that removes fatty acids from storage as triglycerides. Epinephrine also results in the cyclic AMP-mediated phosphorylation and activation of perilipin, a protein that coats lipid droplets. In its phosphorylated state, perilipin allows HSL greater access to the glycerides within the droplet. HSL can remove fatty acids from triacylglycerides, but its most important regulatory role is as the rate-limiting step in their removal from diacylglycerides. As its name suggests, HSL is also sensitive to regulation by other hormones including insulin (inhibitory) and glucagon (stimulatory).

In addition to the above direct effect on liver, adipose, and skeletal muscle cells, epinephrine also increases glucagon secretion and decreases insulin secretion from the α and β cells of the pancreas, respectively (Figure 1). The resulting change in the ratio of glucagon to insulin in the blood reinforces the effects of epinephrine to increase blood glucose and mobilize fatty acids. Taken together, the effects of epinephrine on intermediary metabolism, in combination with those of the flow of blood and gases, prepare the organism to meet an emergency with increased muscular capacity for action, while maintaining the fuel supply to the brain so that these actions can be coordinated and directed to a desirable outcome.

اخر الاخبار

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طاقم أرتميس 2 يحطم رقما قياسيا ويستعرض الجانب البعيد للقمر

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مواضيع ذات صلة

Clinical Aspects of Hormones of the Adrenal Medulla: Chronic Stress

Adrenergic Receptors

Pharmacology of Catecholamines

Regulation of Catecholamine Synthesis and Secretion

Feedback Effects of Glucocorticoids

Glucocorticoids and Stress

Transport of Glucocorticoids in the Blood (CBG)

Integrated Actions of 1α,25(OH)2D3, PTH, Calcitonin, and FGF23 on Bone Remodeling and Calcium Homeostasis

Calcitonin Receptor and Biological Actions

Parathyroid Hormone-Related Protein Receptor and Biological Actions

Parathyroid Hormone Receptor and Biological Actions

T3 Inhibition of TSH and TRH Gene Expression