β-ADRENERGIC AGONISTS

Synthetic compounds called β-adrenergic agonists exhibit profound effects on growth and metabolism of skeletal muscle and adipose tissue. They share some similarity in structure and function with the naturally occurring catecholamines. Three major catecholamines (dopamine, norepinephrine, and epinephrine) are found in mammals. They circulate in the blood plasma, can act at sites removed from their origin (a relationship that is used to define a hormone), and regulate a wide range of physiological responses in many tissues. Epinephrine in particular, but also norepinephrine, are major regulators of metabolism. Examples of the various physiological actions of catecholamines include the following: regulation of the speed and force of heart contractility, motility and secretory responses of various portions of the gastrointestinal tract, bronchodilation, salivary gland and pancreatic insulin secretion, blood vessel constriction and dilation, uterine contraction, and spleen capsule contraction.

The three endogenous catecholamines are related in structure, biosynthetic sequence, and function. General information regarding catecholamine structure, biosynthesis, metabolism, and adrenergic control of physiological and metabolic function has been reviewed (Martin, 1985; Norman and Litwack, 1987; Timmerman, 1987; Mersmann, 1989b; Weiner and Molinoff, 1989; Hoffman and Lefkowitz, 1990). The chemical structures of dopamine, norepinephrine, and epinephrine are presented in Figure 2-3. Epinephrine is the primary hormone secreted by the adrenal medulla.

External stimuli cause the adrenal medulla to release epinephrine and rapidly elevate the peripheral concentration. Stimulation can cause the release of some norepinephrine from the adrenal medulla as well. The relative plasma concentration of these two naturally occurring catecholamines varies among different species. Norepinephrine is usually present at two-to-five times the concentration of epinephrine under resting conditions, whereas dopamine is present at similar or lower concentrations than epinephrine in most mammalian species (Buhler et al., 1978).

All three catecholamines, but particularly norepinephrine and epinephrine, precipitate an extremely large spectrum of physiological functions either by stimulating central nervous system synaptic activity or direct innervation of an organ by the sympathetic nervous system or by acting as plasma hormones. Response to catecholamines requires the presence of a receptor that will bind the particular neurotransmitter or hormone whose concentration has been increased and then couple the receptor binding to an effective intracellular response system. Because most organs of the mammalian body possess receptors for catecholamines, these substances have a major role in regulating many metabolic processes. For example, catecholamines are instrumental in stimulation of glycogen phosphorylase and inhibition of glycogen synthase to stimulate the production

FIGURE 2-3

Chemical structures of the endogenous catecholamines dopamine, norepinephrine, and epinephrine and of select synthetic β-adrenergic agonists.

of glucose from glycogen stores. Catecholamines also stimulate lipolysis to cause the release of free fatty acids from adipose tissue triacylglycerol stores. Thus, catecholamines have a role in control of plasma concentrations of two primary oxidative substrates—glucose and free fatty acids.

Adrenergic Receptors

The many and sometimes antipodal functions regulated by the naturally occurring catecholamines lead to the concept that different receptors must exist in different organs. For example, norepinephrine stimulates mammalian heart contractility at a lower concentration than epinephrine, whereas epinephrine is more potent for stimulation of spleen capsule contraction. Observations such as this led to the concept of distinct α- and α-adrenergic receptors that control various physiological and metabolic functions. This type



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