Phenoxybenzamine partially inhibits α2-adrenoceptors without affecting their presynaptic function

Abstract

The turnover of α-adrenoceptors was assessed by administering phenoxybenzamine (PBZ) intraperitoneally to rats in order to block the receptors irreversibly. The reappearance of the binding of [ 3H]prazosin, [ 3H]clonidine and [ 3H]rauwolscine in membranes from cerebral cortices was then measured. Maximum inhibition of binding occurred 3 hr after administration of phenoxybenzamine. The binding of [ 3H]prazosin was inhibited by 95% after administration of phenoxybenzamine (2 × 4 mg/kg, i.p.), and the half life ( t 1 2 ) for the α 1-adrenoceptor was 1.87 days. The “turnover” of binding for the α 2-adrenoceptor ligands ([ 3H]clonidine and [ 3H]rauwolscine) was similar: with doses of phenoxybenzamine up to 15 mg/kg (i.p.), the binding of both ligands was inhibited to a maximum of 30%. Maximum recovery occurred 3 days after treatment with phenoxybenzamine and the α 2-adrenoceptor has an apparent half life for recovery of 12hr. Since only partial blockade of α 2-adrenoceptors was possible with phenoxybenzamine the possibility that these blocked sites included functional presynaptic autoreceptors was investigated. Clonidine (1 μM) attenuated K +-induced release of preloaded [ 3H]noradrenaline from cortical synaptosomes prepared from control rats by some 35%. Clonidine inhibited this release of [ 3H]noradrenaline to the same extent in synaptosomes prepared from rats treated with phenoxybenzamine 3 hr prior to sacrifice. This indicates that the α 2-adrenoceptors which are blocked by phenoxybenzamine are not part of the functional receptor population.