CIMATEROL REDUCES BETA-ADRENERGIC-RECEPTOR DENSITY IN RAT SKELETAL-MUSCLES

Interactions between the beta-adrenoceptor agonist cimaterol and beta-adrenoceptors on rat skeletal muscle membranes were examined in two studies. In Exp. 1, muscle samples from eight Sprague-Dawley rats (female, approximately 200 g) were used for competition binding and autoradiographic studies using [I-125]cyanopindolol (ICYP) as a radioligand. The affinities or dissociation constants for binding (K(D) values) for cimaterol in plantaris and soleus muscles were .68 and .92-mu-M, respectively. Muscle areas stained for succinic dehydrogenase had propranolol-resistant ICYP binding sites; cimaterol did not seem to compete for these sites. In Exp. 2, 60 Sprague-Dawley rats (female, approximately 218 g) were fed 0 or 10 ppm of cimaterol in rat diet that was ground. Groups were killed after 1, 3, 7, 14, or 28 d of treatment. Cimaterol increased BW gain up to 14 d after commencement of treatment, with little or no improvement thereafter. Enhanced weight gain in skeletal muscles also occurred up to 14 d of cimaterol treatment. Densities of beta-adrenoceptors in plantaris and soleus muscle membrane homogenates were estimated using a radioligand binding assay with ICYP. A significant reduction in the number of binding sites (B(max)) was observed after 3 d of cimaterol treatment in plantaris muscle without a change in the K(D) of ICYP binding. The percentage reductions in B(max) were 26.8, 42.2, 37.7, and 37.8% at 3, 7, 14, and 28 d after cimaterol administration, respectively. In the soleus muscle, significant reductions (44.1 and 29.8%) in B(max) were observed after 3 and 14 d of cimaterol treatment. Because the reduction in receptor density preceded the attenuation of muscle weight gain, it is suggested that the decrease in growth-promoting effect of beta-adrenoceptor agonists is at least partly due to alterations in the number of beta-adrenoceptor binding sites.