Metabolic effects of catecholamines

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Adrenaline and noradrenaline are both amines derived from the catechol nucleus, and the term catecholamines is often used to cover them both (see Fig. 5.10). It will be appreciated that the catecholamines have indirect effects on metabolism which are mediated through 'physiological' changes - heart rate, blood flow, etc. They also have indirect effects mediated through changes in hormone secretion, as well as direct effects in some tissues.

7.3.3.1 Glycogenolysis

In the liver, the catecholamines stimulate glycogen breakdown (glycogenolysis) through P2 (adenylyl cyclase-linked) receptors and the 'cascade' mechanism discussed earlier (see Box 2.4). In addition, they can activate glycogenolysis through a second mechanism, via the a1 (phospholipase C-linked) receptors (see Table 5.1) and elevation of the cytoplasmic Ca2+ concentration. (This was mentioned in Box 2.4; one particular situation in which elevation of intracellular Ca2+ concentration stimulates glycogenolysis will be covered in Section 8.4.3 and Fig. 8.8.) The degradation of glycogen, via glucose 1-phosphate, leads to production of glucose, which can be released into the bloodstream. This is a major response to hypoglycaemia (a fall in the blood glucose concentration) and leads to rapid restoration of the glucose concentration provided there is adequate glycogen stored in the liver. There is much experimental evidence that the liver is supplied with sympathetic nerves and that these can activate glycogenolysis directly, although adrenaline from the adrenal medulla is also released under such conditions and will certainly play a role. In humans, it has been very difficult to show directly that the sympathetic nerves are involved, but people whose adrenals have been removed can respond fairly normally to glucose deprivation, implying that at least in that situation the sympathetic nerves to the liver can play a role.

In skeletal muscle, the catecholamines are undoubtedly important for stimulation of glycogenolysis; but they are not in themselves sufficient to activate it. The activation of skeletal muscle glycogen breakdown is intimately linked with the stimulation of muscle contraction, which, as we have seen, is brought about by the cholinergic fibres of the somatic nervous system. (The links between contraction and glycogenolysis will be fully discussed in Chapter 8; see Fig. 8.8.) Glycogenolysis seems to be 'primed' by catecholamines, perhaps released in response to anticipation of the exercise. Circulating adrenaline is likely to be more important in this respect than noradrenaline from sympathetic nerve terminals, since the main (possibly the only) sympathetic supply to muscle is to the smooth muscle of the blood vessels and is responsible for regulation of blood flow.

7.3.3.2 Lipolysis

Human fat cells have both a2- and P1-adrenergic receptors. There are also P3 ('atypical') receptors that are responsible for stimulation of lipolysis in rodent fat cells, although their role in humans is presently unclear.

The a2 receptors are linked, via inhibitory G; proteins, to adenylyl cyclase, and reduce its activity. The P1 receptors are linked to it through Gs proteins and stimulate its activity. Activation of adenylyl cyclase will increase the cellular concentration of cAMP and activate hormone-sensitive lipase (see Box 2.4), bringing about a breakdown of the triacylglycerol stores and the release of non-esterified fatty acids into the plasma.

There is usually a balance between stimulatory and inhibitory effects, and in normal sedentary daily life it is probable that regulation of hormonesensitive lipase by insulin predominates. However, in response to any kind of stress, including exercise, there is activation of the P1 receptors so that lipolysis is stimulated. Blockade of the P receptors with the P-antagonist propranolol reduces, or may completely suppress, the liberation of non-esterified fatty acids into the plasma in response to exercise (Fig. 7.7). Activation of hormone-sensitive lipase can be brought about purely by mental stress. Stimulation of lipolysis is an important feature of the response to physical stresses such as surgical operations or injury. Again, it is not certain to what extent the direct innervation of adipose tissue is involved, or whether circulating adrenaline plays the major role. But, as with glycogenolysis, people without adrenals can raise their plasma non-esterified fatty acid concentration in response to lack of glucose, so the sympathetic nerves must play a role in that situation.

Not only is the rate of lipolysis regulated by the nervous system, but also the rate of blood flow through adipose tissue. This can have indirect effects on the release of non-esterified fatty acids. In very severe stress states, typified by physical injury with major blood loss, a-adrenergic effects predominate in the blood vessels of adipose tissue and cause it to constrict. Presumably the body is trying to preserve blood for more vital organs and tissues. This reduces the ability of adipose tissue to liberate fatty acids into the plasma, since the binding

Catecholamine Effects Urine

Fig. 7.7 Propranolol (a ^-adrenergic blocker) inhibits lipolysis in response to exercise. The figure shows changes in the concentration of glycerol (released in fat mobilisation) in the interstitial fluid in adipose tissue, measured with a small probe. During exercise (0-30 min) the glycerol concentration rises, indicating lipolysis. When propranolol is introduced (via the probe) the rise is inhibited. In separate experiments, when phentolamine (an a-adrenergic blocker) was introduced, glycerol release was not affected. Based on Arner, P., Kriegholm, E., Engfeldt, P. & Bolinder, J. (1990) Adrenergic regulation of lipolysis in situ at rest and during exercise. J Clin Invest 85: 893-898. Reproduced with permission.

Fig. 7.7 Propranolol (a ^-adrenergic blocker) inhibits lipolysis in response to exercise. The figure shows changes in the concentration of glycerol (released in fat mobilisation) in the interstitial fluid in adipose tissue, measured with a small probe. During exercise (0-30 min) the glycerol concentration rises, indicating lipolysis. When propranolol is introduced (via the probe) the rise is inhibited. In separate experiments, when phentolamine (an a-adrenergic blocker) was introduced, glycerol release was not affected. Based on Arner, P., Kriegholm, E., Engfeldt, P. & Bolinder, J. (1990) Adrenergic regulation of lipolysis in situ at rest and during exercise. J Clin Invest 85: 893-898. Reproduced with permission.

sites on the albumin become saturated, and fatty acids may accumulate within the tissue. Thus, after moderately severe injuries or during surgical operations, the level of non-esterified fatty acids in the plasma is usually very high, but after very severe injuries the level may be relatively normal. Although there is no doubt that lipolysis is activated, the fatty acids are unable to leave the adipose tissue as rapidly as they are released from triacylglycerol (Table 7.1). The same phenomenon may come into play to some extent during strenuous exercise (see Chapter 8).

7.3.3.3 Glucose utilisation

There is consistent evidence that elevated plasma adrenaline concentrations impair glucose utilisation by skeletal muscle. One plausible mechanism is that adrenaline stimulates glycogenolysis, so there is an accumulation of glucose 6-phosphate, which will inhibit hexokinase and reduce the entry of further glucose into the cell. This might seem odd during exercise, but in that situation other mechanisms operate to stimulate glucose entry, mainly exercise-induced translocation of GLUT4 to the cell membrane. Also, during exercise glycolysis will be rapid and so any build-up of glucose 6-phosphate probably minimised. But we can see that during hypoglycaemia, inhibition of muscle glucose utilisation by adrenaline would spare glucose for use by the brain.

However, there is also evidence for P-adrenergic receptor-stimulation of glucose uptake into muscle. This seems to be mediated by the sympathetic nervous system rather than by circulating adrenaline: effects of hypothalamic

Table 7.1 Plasma glycerol and non-esterified fatty acid (NEFA) concentrations after physical injury.

Measurement

Non-injured

Minor

Moderate

Severe

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  • uta
    What best describes the metabolic effects of catecholamines?
    12 months ago

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