of classification was aided by the synthesis of a large number of analogs of norepinephrine. As the number of analogs increased, compounds became available that would preferentially stimulate (or inhibit) a particular function. With an increased spectrum of norepinephrine analogs and continued investigation of the adrenergic control of additional biological functions, it became appropriate to divide the β-adrenergic receptor class into β-1 and β-2 subclasses. Eventually, the β-adrenergic receptor class was divided into β-1 and β-2 subclasses. These classification schemes for adrenergic receptors are attempts to codify biological responses so that the complex functions and plethora of chemical structures can be integrated into a rational pattern.

There have been attempts to establish additional subclasses of receptors based on pharmacological properties and distribution of both α- and α-receptors (Martin, 1985; Norman and Litwack, 1987; Timmerman, 1987; Mersmann, 1989a; Weiner and Molinoff, 1989; Hoffman and Lefkowitz, 1990). Protein purification techniques (Lefkowitz and Caron, 1988) and molecular biology techniques using nucleotide sequences of cDNAs have definitively established the existence of distinct α-1- (Cotecchia et al., 1988), α-2-(Kobilka et al., 1987b), α-1- (Machida et al., 1990), and α-2-(Kobilka et al., 1987a) adrenergic receptors. Molecular characterization of the human α-3-receptor has also been reported (Emorine et al., 1989). It is too early to know the extent of homology between receptor types purported to be α-1- (or α-2- and α-3-) adrenergic receptors when examined in the same tissue in a number of species or in a variety of tissues within a single species.

It is important to note that earlier attempts to classify adrenergic receptors, agonists, and antagonists was confounded by arbitrary selection of ligands, choice of variable biochemical or physiological events, and use of discrete ''all-or-none" response criteria. These physiological data are complemented by ligand binding studies in some but not all cases. In addition, ligand binding can be affected by subtle differences among the same cell type across species or in different cell types within a given species. Receptor classification becomes extremely confounded by use of a variety of species, a multiplicity of analogs, several diverse cell types, and numerous experimental approaches (McGonigle et al., 1986; Neve et al., 1986; Timmerman, 1987; Mersmann, 1989b; Lafontan et al., 1990). Although most of the synthetic adrenergic agonists found to exhibit repartitioning effects on growth of mammalian species have been characterized as β-agonists; whether their effects are directly mediated through the β-receptors is equivocal.

Distribution of adrenergic receptor types is of equal importance in determining the nature or magnitude of a response. It has become apparent that many or even most mammalian organs, tissues, or cell types do not have a pure population of α- or α-adrenergic receptors; rather a mixture of subtypes of these receptors is usually present, albeit at different levels (Minneman et al., 1979). For example, heart contractility usually is considered to be stimulated by α-1-adrenergic receptors, although mammalian heart muscle appears to have both α-1-and α-2-adrenergic receptors. The proportion may vary from essentially 100 percent α-1-adrenergic receptors in the guinea pig ventricle (Hedberg et al., 1980) to 35 percent α-2-adrenergic receptors in the human ventricle (Heitz et al., 1983).

Skeletal muscle has β-adrenergic receptors as evidenced by the stimulation of glycogenolysis and the production of lactate by epinephrine, norepinephrine, and the analog isoproterenol both in vitro and in vivo. The antagonist propranolol inhibits this response. More direct measurement of β-adrenergic receptors by ligand binding techniques also indicates the presence of β-receptors, with the β-2 subtype predominating over the β-1 subtype (Liggett et al., 1988). Expression of β-3-receptor mRNA has been demonstrated in rat skeletal muscle (soleus), as well as adipose, liver, and ileum, but was not observed in brain, skin, heart, and lung (Emorine et al., 1989). Two β-adrenergic agonists that dramatically enhance skeletal muscle deposition, clenbuterol and cimaterol, are purportedly specific for the β-2-receptor subtype (O'Donnell, 1976; Kim and Sainz, 1990), whereas ractopamine is primarily a β-1-agonist (Anderson et al., 1991).

Mammalian adipose tissue cells contain β-adrenergic receptors as indicated by stimulation of lipid breakdown (lipolysis) by epinephrine, norepinephrine, and isoproterenol as well as a number of other norepinephrine analogs both in vitro and in vivo. These effects can be antagonized by propranolol or other β-adrenergic antagonists. Lipogenesis, both fatty acid and triacylglycerol biosynthesis in the adipocyte, is inhibited by β-adrenergic agonists and such effects can be antagonized by β-adrenergic antagonists (Fain and Garcia-Sainz, 1983; Buttery and Dawson, 1987; Timmerman, 1987; Mersmann, 1989a; Yang and McElligott, 1989). Establishment of the β-adrenergic receptor subtypes on the mammalian adipocyte has not been particularly successful. Some studies have indicated the receptor is of the β-1-adrenergic subtype, others indicate a mixture of β-1- and β-2-adrenergic receptors, and yet others indicate that a totally different receptor, the β-3-adrenergic receptor, is also present (Emorine et al., 1989; Lafontan et al., 1990). How much of the diversity in description of the adipose tissue adrenergic receptor subtypes is the result of studies in different species, use of different agonists and antagonists, or use of different methodologies, including ligand binding compared to measurement of cellular function, is not yet understood.

Since the early 1980s, several synthetic analogs of epinephrine and norepinephrine have been investigated for their

Front Matter (R1-R12)

Executive Summary (1-2)

1. Introduction (3-4)

2. Mechanisms of Action of Metabolic Modifiers (5-22)

3. Effect of Somatotropin on Nutrient Requirements of Dairy Cattle (23-29)

4. Effect of Metabolic Modifiers on Nutrient Requirements of Growing Ruminants (30-37)

5. Effect of Metabolic Modifiers on Nutrient Requirements of Growing Swine (38-51)

6. Effect of Metabolic Modifiers on Nutrient Requirements of Poultry (52-58)

References (59-73)

Authors (74-74)

Index (75-82)