Beta2-adrenoceptors and non-beta-adrenoceptors mediate effects of BRL37344 and clenbuterol on glucose uptake in soleus muscle: studies using knockout mice.

background and purposeIn previous work, 10 pM BRL37344 and 10 pM clenbuterol stimulated glucose uptake in mouse soleus muscle. Ten nM BRL37344 also stimulated uptake but 100 nM clenbuterol inhibited uptake. Antagonist studies suggested that the opposite effects of 10 nM BRL37344 and 100 nM clenbuterol are mediated by the beta(2)-adrenoceptor. BRL37344 and clenbuterol have been studied in muscles that lack beta(3)-, beta(2)- or all three beta-adrenoceptors. Effects of beta-adrenoceptor antagonists on responses to the agonists have been studied further using muscles from wild-type mice. EXPERIMENTAL APPROACH: Soleus muscles of wild-type or beta-adrenoceptor knockout mice were incubated with 2-deoxy[1-(14)C]-glucose, and beta-adrenoceptor ligands. Formation of 2-deoxy[1-(14)C]-glucose-6-phosphate was measured. KEY

resultsConcentration-response relationships were similar for BRL37344 and clenbuterol in normal muscle and muscle lacking beta(3)-adrenoceptors. Ten pM BRL37344 and clenbuterol stimulated glucose uptake in muscle lacking beta(2)-adrenoceptors or all three beta-adrenoceptors, but 10 nM BRL37344 did not stimulate uptake in either case, and 100 nM clenbuterol stimulated, rather than inhibited, uptake in muscle lacking beta(2)-adrenoceptors. One hundred nM clenbuterol also stimulated glucose uptake in normal muscle when beta(2)-adrenoceptors were blocked with ICI118551, and this was not prevented by antagonism of beta(1)- or beta(3)-adrenoceptors. CONCLUSIONS AND IMPLICATIONS: Ten nM BRL37344 and 100 nM clenbuterol have opposite effects on glucose uptake but both effects are mediated by the beta(2)-adrenoceptor - apparently an example of agonist-directed signalling. Ten pM BRL37344, 10 pM clenbuterol and 100 nM clenbuterol in the presence of ICI118551 stimulate glucose uptake via beta-adrenoceptor-independent mechanisms, demonstrating unknown properties for the agonists.