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 (mumol/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.
Research and Development Laboratories, Reckitt and Colman Pharmaceuticals, Kingston-upon-Hull, U.K.
T L
TL
Berridge
J C
JC
Doxey
A G
AG
Roach
C F
CF
Smith
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects*; D000068438:Brimonidine Tartrate; D003000:Clonidine / Q000031:analogs & derivatives / Q000494:pharmacology; D003655:Decerebrate State; D004146:Dioxanes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000494:pharmacology; D019329:Idazoxan; D007093:Imidazoles / Q000494:pharmacology*; D007328:Insulin / Q000097:blood*; D008297:Male; D009132:Muscles / Q000187:drug effects; D011224:Prazosin / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D014649:Vas Deferens / Q000187:drug effects
D000317:Adrenergic alpha-Antagonists; D001572:Benzofurans; D001786:Blood Glucose; D004146:Dioxanes; D007093:Imidazoles; D007328:Insulin; D011810:Quinoxalines; D000068438:Brimonidine Tartrate; C016986:apraclonidine; C062597:efaroxan; D003000:Clonidine; D011224:Prazosin; D019329:Idazoxan; D004837:Epinephrine