α 2 ‐Adrenoceptor subtypes involved in the regulation of catecholamine release from the adrenal medulla of mice

Background and purpose: This study was carried out to elucidate which α 2 ‐adrenoceptor subtypes mediated the inhibition of noradrenaline and adrenaline release from the adrenal medulla of mice. Experimental approach: Isolated adrenal medullae from wild‐type and α 2A , α 2B and α 2C ‐adrenoceptor knockout (KO) mice were placed in superfusion chambers. Catecholamine overflow was evoked by 1,1‐dimethyl‐4‐phenylpiperazinium (500 μM) in absence or in presence of the α 2 ‐adrenoceptor agonist medetomidine. The effect of medetomidine was tested in presence of the α‐adrenoceptor antagonists rauwolscine, WB 4101, spiroxatrine, phentolamine and prazosin. Key results: In wild‐type mice, medetomidine reduced noradrenaline and adrenaline overflow in a concentration‐dependent manner (EC 50 in nM: 1.54 and 1.92; E max in % of inhibition: 91 and 94, for noradrenaline and adrenaline, respectively). The p K D values of the antagonists for noradrenaline overflow did not correlate with pK D values at α 2A , α 2B , or α 2C binding sites. The p K D values of the antagonists for adrenaline overflow correlated positively with pK D values at α 2C binding sites (opossum kidney cells). The effect of medetomidine (100 nM) on noradrenaline overflow was significantly reduced in all three α 2 KO mice (57, 54, 44 % inhibition, for α 2A , α 2B , and α 2C , respectively), whereas the effect of medetomidine on adrenaline overflow was greatly reduced in α 2C KO mice (14 % inhibition). Conclusions and implications: In the adrenal medulla of mice, all three α 2 ‐adrenoceptor subtypes (α 2A , α 2B , and α 2C ) play an equal role in the inhibition of noradrenaline overflow, whereas the α 2C ‐adrenoceptor is the predominant α 2 ‐adrenoceptor subtype involved in the inhibitory mechanism controlling adrenaline overflow. British Journal of Pharmacology (2006) 149 , 1049–1058. doi: 10.1038/sj.bjp.0706950 Published online 30 October 2006