The effects of phenoxybenzamine on specific binding and function of central alpha-adrenoceptors in the rabbit.

We have studied the effects of phenoxybenzamine, an irreversible alpha-adrenoceptor antagonist on the binding of the alpha-adrenoceptor ligands [3H]prazosin and [3H]clonidine to rabbit brain membranes. Where possible changes in binding were related to changes in central alpha-adrenoceptor function. Phenoxybenzamine showed a similar alpha 1/alpha 2-adrenoceptor selectivity in the brain to that previously reported in the periphery. Much higher doses were required to reduce specific clonidine binding and to interfere with the hypotensive response to intracisternal clonidine than to reduce specific prazosin binding. Recovery of binding site number of both alpha 1- and alpha 2-adrenoceptor selective ligands was slower than in peripheral tissues (heart and spleen). Recovery was log linear and the half time (t1/2) for recovery of the maximum number of specific prazosin and clonidine binding sites in forebrain was 10.8 +/- 2.6 days and 6.1 +/- 0.1 days and in hindbrain 13.3 +/- 3.1 days and 4.6 +/- 1.8 days, respectively. t1/2 for recovery of the in vivo hypotensive response to intracisternal clonidine was 2.7 +/- 1.0 days. Recovery of this response was attenuated by treatment with the inhibitor of protein synthesis, 5-fluorouracil. This suggests that recovery after phenoxybenzamine in brain, as in the periphery, may depend at least in part on synthesis of new receptor protein. The recovery of brain adrenoceptor number after phenoxybenzamine may be an index of receptor turnover and is much slower in brain than in heart and spleen.