Responses to Adrenergic Stimulation

Adrenergic stimulation—by epinephrine in the blood and by norepinephrine released from sympathetic nerve endings—has both excitatory and inhibitory effects. The heart, dilatory muscles of the iris, and the smooth muscles of many blood vessels are stimulated to contract. The smooth muscles of the bronchioles and of some blood vessels, however, are inhibited from contracting; adrenergic chemicals, therefore, cause these structures to dilate.

Since excitatory and inhibitory effects can be produced in different tissues by the same neurotransmitter, the responses must depend on the characteristics of the cells. To some degree, this is due to the presence of different membrane receptor proteins for the catecholamine neurotransmitters. (The interaction of neurotransmitters and receptor proteins in the postsynaptic membrane was described in chapter 7.) The two major classes of these receptor proteins are designated alpha- (a) and beta- (P) adrenergic receptors.

Experiments have revealed that each class of adrenergic receptor has two major subtypes. These are designated by subscripts: ai and a2; Pi and p2. Compounds have been developed that selectively bind to one or the other type of adrenergic receptor and, by this means, either promote or inhibit the normal action produced when epinephrine or norepinephrine binds to the receptor. As a result of its binding to an adrenergic receptor, a drug may either promote or inhibit the adrenergic effect. Also, by using these selective compounds, it has been possible to determine which subtype of adrenergic receptor is present in each organ (table 9.5). An additional subtype of adrenergic receptor, designated P3, has been demonstrated in adipose tissue, but its physiological significance has not yet been established.

Chapter Nine

All adrenergic receptors act via G-proteins. The action of G-proteins was described in chapter 7, and can be reviewed by reference to fig. 7.28 and table 7.7. In short, the binding of epi-nephrine and norepinephrine to their receptors causes the group of three G-proteins (designated a, P, and y) to dissociate into an a subunit and a Py complex. In different cases, either the a subunit or the Py complex causes the opening or closing of an ion channel in the plasma membrane, or the activation of an enzyme in the membrane. This begins the sequence of events that culminates in the effects of epinephrine and norepinephrine on the target cells.

All subtypes of beta receptors produce their effects by stimulating the production of cyclic AMP (discussed in chapter 7) within the target cells. The response of a target cell when nor-epinephrine binds to the a1 receptors is mediated by a different second-messenger system—a rise in the cytoplasmic concentration of Ca2+. This Ca2+ second-messenger system is similar, in many ways, to the cAMP system and is discussed together with endocrine regulation in chapter 11. It should be remembered that each of the intracellular changes following the binding of norepinephrine to its receptor ultimately results in the characteristic response of the tissue to the neurotransmitter.

The physiology of a2-adrenergic receptors is complex. These receptors are located on presynaptic axon terminals, and when stimulated, cause a decreased release of norepinephrine. This may represent a form of negative feedback control. On the other hand, vascular smooth muscle cells also have a2-adrenergic receptors on the postsynaptic membrane, where they can be activated to produce vasoconstriction. This action would cause a rise in blood pressure. However, drugs that activate a2-adrenergic receptors are used to lower blood pressure. This is because they stimulate a2-adrenergic receptors in the

Table 9.5 Selected Adrenergic Effects in Different Organs

Organ

Adrenergic Effects of Sympathoadrenal System

Adrenergic Receptor

Eye

Contraction of radial fibers of the iris dilates the pupils

ai

Heart

Increase in heart rate and contraction strength

Pi primarily

Skin and visceral vessels

Arterioles constrict due to smooth muscle contraction

ai

Skeletal muscle vessels

Arterioles constrict due to sympathetic nerve activity

ai

Arterioles dilate due to hormone epinephrine

P2

Lungs

Bronchioles (airways) dilate due to smooth muscle relaxation

P2

Stomach and intestine

Contraction of sphincters slows passage of food

ai

Liver

Glycogenolysis and secretion of glucose

ai, P2

Source: Simplified from table 6-l, pp. ll0-lll of Goodman and Gilman's The Pharmacological Basis of Therapeutics. Ninth edition. J.E. Hardman et al., eds. 1996. McGraw-Hill.

Source: Simplified from table 6-l, pp. ll0-lll of Goodman and Gilman's The Pharmacological Basis of Therapeutics. Ninth edition. J.E. Hardman et al., eds. 1996. McGraw-Hill.

Fox: Human Physiology, Eighth Edition

9. The Autonomic Nervous System

Text

© The McGraw-H Companies, 2003

The Autonomic Nervous System brain, and this somehow reduces the activity of the entire sympathetic nervous system!

A review of table 9.5 reveals certain generalities about the actions of adrenergic receptors. The stimulation of aj-adrenergic receptors consistently causes contraction of smooth muscles. We can thus state that the vasoconstrictor effect of sympathetic nerves always results from the activation of alpha-adrenergic receptors. The effects of beta-adrenergic activation are more complex; stimulation of beta-adrenergic receptors promotes the relaxation of smooth muscles (in the digestive tract, bronchioles, and uterus, for example) but increases the force of contraction of cardiac muscle and promotes an increase in cardiac rate.

The diverse effects of epinephrine and norepinephrine can be understood in terms of the "fight-or-flight" theme.

Adrenergic stimulation wrought by activation of the sympathetic division produces an increase in cardiac pumping (a Pi effect), vasoconstriction and thus reduced blood flow to the visceral organs (an aj effect), dilation of pulmonary bronchioles (a p2 effect), and so on, preparing the body for physical exertion (fig. 9.10).

A drug that binds to the receptors for a neurotransmitter and that promotes the processes that are stimulated by that neuro-transmitter is said to be an agonist of that neurotransmitter. A drug that blocks the action of a neurotransmitter, by contrast, is said to be an antagonist. The use of specific drugs that selectively stimulate or block aj, a2, pj, and p2 receptors has proven extremely useful in many medical applications (see the boxed information).

Parasympathetic division

Nicotinic ACh receptors

Nicotinic ACh receptors

Norepinephrine^

Sympathetic division

Parasympathetic nerve effects

Vasoconstriction in Increased viscera and skin heart rate and contractility i '1 >

Jssis.

Preganglionic neurons

Postganglionic neurons

Parasympathetic nerve effects

Vasoconstriction in Increased viscera and skin heart rate and contractility

Dilation of bronchioles of lung

Dilation of bronchioles of lung

■ Figure 9.10 Receptors involved in autonomic regulation. Acetylcholine released by all preganglionic neurons stimulates the postganglionic neurons by means of nicotinic ACh receptors. Postganglionic parasympathetic axons regulate their target organs using muscarinic ACh receptors. Postganglionic sympathetic axons provide adrenergic regulation of their target organs by binding of norepinephrine to ai, Pi, and p2.-adrenergic receptors.

Bft Many people with hypertension were once treated with a beta-blocking drug known as propranolol. This drug ^ blocks |3| receptors, which are located in the heart, and thus produces the desired effect of lowering the cardiac rate and blood pressure. Propranolol, however, also blocks p2 receptors, which are located in the bronchioles of the lungs. This reduces the bronchodilation effect of epinephrine, producing bronchoconstriction and asthma in susceptible people. A more selective p1 antagonist, atenolol, is now used instead to slow the cardiac rate and lower blood pressure. At one time, asthmatics inhaled an epinephrine spray, which stimulates p1 receptors in the heart as well as p2 receptors in the airways. Now, drugs such as terbutaline that selectively function as p2 agonists are more commonly used.

Drugs such as phenylephrine, which function as a| agonists, are often included in nasal sprays because they promote vasoconstriction in the nasal mucosa. Clonidine is a drug that selectively stimulates a2 receptors located on neurons in the brain. As a consequence of its action, clonidine suppresses the activation of the sympathoadrenal system and thereby helps to lower the blood pressure. For reasons that are poorly understood, this drug is also helpful in treating patients with an addiction to opiates who are experiencing withdrawal symptoms.

Clinical Investigation Clues

Remember that Cathy had a rapid pulse and higher than usual blood pressure after staying up studying for an exam and taking her asthma inhaler.

■ Why did Cathy have a rapid pulse and higher blood pressure than usual?

■ Was there more than one factor that contributed to these symptoms?

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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