SELECTIVITY PROFILE OF THE ALPHA-2-ADRENOCEPTOR ANTAGONIST EFAROXAN IN RELATION TO PLASMA-GLUCOSE AND INSULIN LEVELS IN THE RAT

The effects of efaroxan (RX 821037A; 2-[2-(2-ethyl-2,3-dihydrobenzofuranyl)]-2-imidazoline HCl) at alpha-1- and alpha-2-adrenoceptors were investigated in isolated tissues, pithed rats and conscious rats. In isolated tissues, efaroxan competitively antagonised the inhibitory effects of p-aminoclonidine in the electrically stimulated (0.1 Hz) rat vas deferens (pA2 = 8.89) and the contractile effects of phenylephrine on the rat anococcygeus muscle (pA2 = 6.03). Efaroxan had a selectivity ratio (alpha-2/alpha-1) of 724 compared to a value of 182 for idazoxan. In pithed rats, the i.v. doses of efaroxan (mu-mol/kg) producing 2-fold shifts in dose-response curves for UK-14,304 at prejunctional cardiac alpha-2-adrenoceptors and postjunctional vascular alpha-2-adrenoceptors, and for cirazoline at postjunctional vascular alpha-1-adrenoceptors, were 0.05, 0.13 and 2.96, respectively. In conscious fasted rats, prazosin (5 mg/kg p.o.) increased resting glucose levels and exacerbated the hyperglycaemic effects of UK-14,304 and adrenaline. In contrast, efaroxan (1-5 mg/kg p.o.) had little effect on resting plasma glucose but markedly antagonised the hyperglycaemic actions of UK-14,304 and adrenaline. Efaroxan increased resting plasma insulin levels and markedly potentiated the rise in insulin levels produced by adrenaline; this latter effect was prevented by the co-administration of propranolol. These results demonstrate that efaroxan is a potent and selective alpha-2-adrenoceptor antagonist and provide further support for the involvement of alpha-2-adrenoceptors in glucose homeostasis.