Biphasic effects of the beta-adrenoceptor agonist, BRL 37344, on glucose utilization in rat isolated skeletal muscle

1 The effects of the selective beta(3)-adrenoceptor agonist, BRL 37344 (BRL) on glucose uptake and phosphorylation (i.e. glucose utilization; GU) and glycogen synthesis in rat isolated soleus and extensor digitorium longus (EDL) muscle preparations in vitro were investigated by use of 2-deoxy-[H-3]- glucose (GU) and [U-C-14]-glucose (glycogen synthesis). 2 Low concentrations of BRL (10(-11)-10(-9)M) significantly increased GU, with maximal increases of 30% in soleus and 24% in EDL at 10(-11)M. Neither the selective beta(1)-adrenoceptor antagonist, atenolol (10(-8)-10(-6)M), nor the selective beta(2)-adrenoceptor antagonist, ICI 118551 (10(-8)-10(-6)M) had any effect on the stimulation of GU induced by 10(-11)M BRL. 3 High concentrations of BRL (10(-6)-10(-5)M) caused significant inhibition (up to 30%) of GU in both soleus and EDL muscles. The inhibition at 10(-6)M BRL was blocked completely by 10(-6) and 10(-7)M ICI 118551 in soleus, and by 10(-6)-10(-8)M ICI 118551 in EDL; atenolol (10(-8)-10(6)M) had no effect. 4 Another selective beta(3)-adrenoceptor agonist, CL 316,243, also caused a significant stimulation of muscle GU, with maximal increases of 43% at 10(-9)M in soleus and 45% at 10(-10)M in EDL. The stimulation of GU declined with further increases in the concentration of CL 316,243, but no inhibition of GU was seen, even at the highest concentration (10(-5)M) tested. 5 BRL at 10(-5)M inhibited completely insulin-stimulated glycogen synthesis in both soleus and EDL, but this inhibitory effect of BRL was abolished by 10(-6)M ICI 118551. BRL at 10(-11)M (with or without 10(-6)M ICI 118551) had no effect on insulin-stimulated glycogen synthesis. 6 It is concluded that: (i) low (<nM) concentrations of BRL stimulate GU via an atypical beta-adrenoceptor that is resistant to conventional beta(1)-adrenoceptor and beta(2)-adrenoceptor antagonists; (ii) the stimulation of GU is negated by the activation of beta(2)-adrenoceptors that occurs at higher (>nM) concentrations of BRL; (iii) inhibition of GU via beta(2)-adrenoceptor activation is associated with inhibition of glycogen synthesis, possibly due to activation of glycogenolysis; (iv) the opposing effects of beta(2)-adrenoceptor and atypical beta-adrenoceptor activation on GU suggest that in skeletal muscle these adrenoceptors are linked to different post-receptor pathways.