Insights into the unusual alpha adrenoceptor subtype in dog saphenous veinusing phenoxybenzamine

In the dog saphenous vein (DSV), phenylephrine (PE) responses through alpha -1 adrenoceptors receptors are antagonized by both alpha-1 and alpha-2 rece ptor antagonists. Furthermore, pretreatment with chloroethylclonidine (CEC) eliminates prazosin binding but reduces rauwolscine binding by half (Danie l et al., 1996). in new functional experiments, the effects of preincubatio n with phenoxybenzamine (PBZ), an irreversible alpha adrenoceptor antagonis t, on responses to PE and two selective alpha-2 adrenoceptor agonists were evaluated. Also, the ability of prazosin or rauwolscine to prevent irrevers ible losses of responses to these agonists when coincubated with PBZ was de termined. Preincubation in PBZ (10-300 nM) concentration dependently reduce d PE E-max and the calculated fraction of residual receptors (q). Preincuba tion in PBZ (10-300 nM) increased K-B values for prazosin (30 and 100 nM) b ut did not alter the K-B value for rauwolscine (50 nM) acting at the residu al receptors from control values. Coincubation of PBZ with prazosin partial ly prevented these PBZ actions (E-max partly restored) on responses to PE, but coincubation of rauwolscine (less than or equal to 1 mu M) With PBZ, di d not. Rauwolscine competitively inhibited responses to two alpha-2 adrenoc eptor agonists (Schild plot pA(2) values near 9). Preincubation with PBZ co ncentrations of greater than or equal to 300 nM caused >50% reduction in E- max values of responses but did not alter the EC50 values for either agonis t. Coincubation of rauwolscine with PBZ protected responses to alpha-2 agon ists against PBZ(1 mu M) effects. This study shows that PE initiates contra ctions at atypical alpha-1 adrenoceptors represented by all sites of PE act ion. Rauwolscine antagonizes PE actions but does not protect against PBZ in activation. Typical alpha-2 adrenoceptors are distinguished from the unusua l alpha-1 adrenoceptors by their lesser sensitivity to PBZ and their protec tion by rauwolscine from PBZ.