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The mechanisms that mediate the effects of muscarinic agonists on the actions of beta1- and beta2-adrenergic receptors were analyzed in neonatal rat ventricular myocytes. The administration of isotoproterenol enhanced inotropic and lusitropic vasorelaxation and increased the accumulation of cyclic adenosine 3',5'-monophosphate (cAMP). However, the inotropic and lusitropic effects of the beta-receptor agonist/beta2-receptor agonist was inhibited by carbachol via a mechanism that was mediated by M2-muscarinic receptor and a pertussis toxin-sensitive pathway.

The mechanisms that mediate the beta-adrenergic stimulation of gastric somatostatin and gastrin were characterized by utilizing beta-adrenoceptor (AR) agonists and antagonists such as SR-58611A and SR-59230A. Administration of SR-59611A beta-AR agonists stimulated the release of somatostatin and gastrin in isolated rat gastric antral epithelial cells in a concentration-dependent manner. However, the effects of SR-58611A were inhibited by the administration of the selective beta-AR antagonists such as SR-59230A and ICI-118551.

The bronchoscopy model was utilized to evaluate the effects of airway inflammation drug treatment on beta2-adrenergic (beta2-AR) receptor regulation in allergic asthmatic subjects. Albuterol inhalation in allergic asthmatics led to the desentization of beta2-AR indicating the potential interactive effect of beta-agonists and airway inflammation on beta2-AR. Chronic inflammation also impaired beta2-agonist function during the treatment of asthmatic symptoms.

A study was conducted to determine whether lung cell beta2-adrenergic receptors (beta2-AR) in humans become desensitized after agonist administration. Bronchial epithelial cells and alveolar macrophages were given six doses of the beta-agonist metaproterenol over a 24-hour period and were examined by radioligand binding. Beta2-AR expression decreased on both cell types. Agonist inhalation also resulted to impaired beta2-AR function and decreased cAMP accumulation. These results suggest that exposure to beta-agonists results to the desensitization of lung cells.

Beta-adrenergic agonists have been fed to avian and mammalian species to modulate growth. Such treatment produces increased rate of gain, decreased feed consumption, increased skeletal muscle and decreased fat accretion. There is good evidence for the inhibition of adipose tissue lipogenesis and stimulation of lipolysis as well as stimulation of skeletal muscle protein synthesis and inhibition of degradation. Other effects include increased blood flow and modulation of plasma concentration of various hormones. The degree to which each of these effects is observed varies considerably between experiments. Some of the diversity may be explained by species and/or tissue differences in distribution of beta-adrenergic receptor subtypes, in structure and, consequently, in response of receptors and in the pharmacodynamics of the agonist. In addition, several different agonists have been used, adding further complexity. Oversimplification by extrapolation of research observations across species and agonists may confuse attempts to derive mechanisms for the growth modulation effects of beta-adrenergic agonists in vivo. INDEXING KEY WORDS: skeletal muscle; adipose tissue; beta-adrenergic receptors; beta-adrenergic; agonists

The affinities (K(sub i)) with which ractopamine (RA), clenbuterol (CB), and L-644,969 (L6) bind the Beta-adrenoceptor populations of adipose tissue (middle and outer subcutaneous (SQ) layers) and longissimus (LM) and semitendinosus (ST) muscle were determined. Within a given agonist, K(sub i) values (nanomolar) were similar among tissues, except for RA, which had a higher (P is less than or equal to .05) affinity (lower K(sub i)) for middle SQ adipose tissue than for outer SQ adipose and both muscles. For all tissues, binding affinities were greatest for CB (126), followed by L6 (350) and RA (856, exclusive of middle SQ adipose). The data indicate that both adipose and muscle tissues are targets of CB, RA, and L6 in vivo, and that tissue preferences of the agonists cannot be established from affinity data alone. The relatively constant affinity of the agonists for the various tissues examined implies that if tissue preferences exist, the efficiency with which postreceptor events are invoked by these agonists is the determining factor.

The influence of the beta-adrenoreceptor agonist climaterol on the beta-adrenoreceptor density in the soleus, gastrocnemius and plantaris muscles of the rat was evaluated. Rats were fed with climaterol, and muscle samples were collected and analyzed. Results indicated that climaterol decreases the receptor density of the different skeletal muscles. This might be the reason for the short-term effect of climaterol on muscle hypertrophy, since the reduction in the number of receptors diminishes the adrenoreceptor agonist's effect on muscle growth.