Tjele, Denmark, personal communication, 1990) with acute administration of cimaterol, but chronic treatment reduces insulin concentrations 25 to 50 percent (Beermann et al., 1987; O'Connor et al., 1988). Circulating levels of ST are not elevated with acute or chronic exposure of growing lambs to cimaterol (O'Connor et al., 1988), and no difference was observed in plasma concentrations of prolactin, cortisol, or thyroid hormones at 6 or 12 weeks. Similar results have been reported for growing steers fed cimaterol (Chikhou et al., 1991).

Cimaterol evokes similar stimulation of skeletal muscle growth and reduction in lipid accretion in animals surgically manipulated to remove the source of somatotrophic and metabolic hormone secretion. Cimaterol administration causes marked muscle hypertrophy in hypophysectomized rats (Thiel et al., 1987) and thyroidectomized rats (Forsberg and Wehr, 1990), and muscle hypertrophy is stimulated in severely diabetic rats and diabetic rats given a daily fixed dose of insulin (McElligott et al., 1987). These data suggest that ST, the thyroid hormones, and insulin, all important metabolic hormones required for normal muscle growth, are not involved to any great extent in the mediation of β-agonist-induced skeletal muscle hypertrophy. These results and the lack of significant changes in circulating metabolic hormone concentrations in response to β-agonist administration suggest that the β-agonist's mode of action involves direct, receptor-mediated stimulation of skeletal muscle growth.

It is generally accepted that β-agonists act directly on adipose tissue via the β-receptor to stimulate lipolysis. This is supported by the consistent observation of elevated plasma free fatty acids in treated animals (Beermann et al., 1987; Eisemann et al., 1988). Results from in vitro studies have not yielded such clear-cut results. For example, clenbuterol has been shown to stimulate lipolysis in adipose tissue from rats (Duquette and Muir, 1985) and chickens (Campbell and Scanes, 1985) but not pigs (Rule et al., 1987) or cattle (Miller et al., 1988; Dawson et al., 1989). However, isoproterenol, cimaterol, and ractopamine all stimulate lipolysis in pig adipose tissue in vitro (Liu et al., 1989; Peterla and Scanes, 1990). Several reports have shown that β-agonists can also affect the in vitro rate of lipogenesis (Mersmann, 1989a,b; Mills and Liu, 1990; Peterla and Scanes, 1990). In the absence of any effect on lipolysis, some reports have concluded that the reduction in lipogenesis is a very important component in the mechanism whereby total body fat is reduced (Miller et al., 1988). It is becoming clear that the incubation conditions used for these in vitro incubations is critical (Liu et al., 1989; Mersmann, 1989a,b; Mills and Liu, 1990). Liu and Mills (1990) have subsequently shown that clenbuterol and ractopamine reduce insulin binding to porcine adipocytes presumably through reduced insulin receptor number, thereby antagonizing insulin action on porcine adipocytes.

A major deterrent to conclusively identifying the mode of action is that it is difficult to measure rates of lipogenesis in vivo. It is also very likely that potencies differ among β-agonists, especially in terms of their relative effects on lipolysis and lipogenesis as well as the response between different species.

The ability of many β-agonists to induce a decrease in adipose tissue and at the same time an increase in skeletal muscle is a very useful attribute for animal production. However, there are agonists developed for other purposes that reduce adipose tissue without increasing lean mass, for example BRL 35135 (Arch and Ainsworth, 1983; Arch et al., 1984). It therefore seems that the increase in lean mass seen with many β-2-selective agonists is not simply a consequence of the reduced amount of energy stored in adipose tissue.

There have been relatively few reports in which the interaction between response to β-agonists and dietary protein and/or energy intake was investigated. Dry-matter intake is commonly reduced on initial exposure to the β-agonists but most often returns to normal within a short time and remains unchanged thereafter. The repartitioning effects of β-agonists are reported to occur in both adequate and restricted feeding conditions in lambs (Hovell et al., 1989; Kim et al., 1989) and pigs (Bracher-Jakob and Blum, 1990; Bracher-Jakob et al., 1990; Dunshea et al., 1991). However, significant increases in growth rate tend to occur only in well-fed animals. Even these effects can be lost if the animals become refractory to the compound or if the dose rate is increased (see, e.g., the data assembled by Williams, 1987; Beermann, 1993).

Providing adequate supplies of amino acids and energy is prerequisite to optimizing rate and efficiency of protein use for growth in normal management systems and may be particularly important when protein deposition rates are enhanced by β-agonist administration. Increased skeletal muscle protein deposition will increase the requirement for individual amino acids unless there is an increase in the efficiency with which dietary protein (amino acids) is used for growth. Inadequate protein intake constrains the magnitude of improvement in growth performance, nitrogen balance, or the degree to which protein accretion rate or skeletal muscle growth is enhanced by ractopamine in pigs (Anderson et al., 1987; Adeola et al., 1990; Dunshea et al., 1991; Mitchell et al., 1991). Anderson et al. (1987) observed that nitrogen retention in swine fed ractopamine is enhanced with an 18 percent crude protein diet, but nitrogen retention was reduced with a 12 percent protein diet.

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)