Abstract

In the dog saphenous vein (DSV), phenylephrine (PE) responses throughalpha-1 adrenoceptors receptors are antagonized by bothalpha-1 and alpha-2 receptor antagonists. Furthermore, pretreatment with chloroethylclonidine (CEC) eliminates prazosin binding but reduces rauwolscine binding by half (Daniel et al.,1996). In new functional experiments, the effects of preincubation with phenoxybenzamine (PBZ), an irreversible alphaadrenoceptor antagonist, on responses to PE and two selectivealpha-2 adrenoceptor agonists were evaluated. Also, the ability of prazosin or rauwolscine to prevent irreversible losses of responses to these agonists when coincubated with PBZ was determined. Preincubation in PBZ (10–300 nM) concentration dependently reduced PEE_max and the calculated fraction of residual receptors (q). Preincubation in PBZ (10–300 nM) increasedK_B values for prazosin (30 and 100 nM) but did not alter the K_B value for rauwolscine (50 nM) acting at the residual receptors from control values. Coincubation of PBZ with prazosin partially prevented these PBZ actions (E_max partly restored) on responses to PE, but coincubation of rauwolscine (≤1 μM) with PBZ, did not. Rauwolscine competitively inhibited responses to twoalpha-2 adrenoceptor agonists (Schild plot pA₂ values near 9). Preincubation with PBZ concentrations of ≥300 nM caused >50% reduction in E_maxvalues of responses but did not alter the EC₅₀ values for either agonist. Coincubation of rauwolscine with PBZ protected responses to alpha-2 agonists against PBZ (1 μM) effects. This study shows that PE initiates contractions at atypicalalpha-1 adrenoceptors represented by all sites of PE action. Rauwolscine antagonizes PE actions but does not protect against PBZ inactivation. Typical alpha-2 adrenoceptors are distinguished from the unusual alpha-1 adrenoceptors by their lesser sensitivity to PBZ and their protection by rauwolscine from PBZ.