Low A M, Lu-Chao H, Loke J C, Kwan C Y, Daniel E E
Department of Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
J Pharmacol Exp Ther. 1999 Jan;288(1):148-56.
In the dog saphenous vein (DSV), phenylephrine (PE) responses through alpha-1 adrenoceptors receptors are antagonized by both alpha-1 and alpha-2 receptor antagonists. Furthermore, pretreatment with chloroethylclonidine (CEC) eliminates prazosin binding but reduces rauwolscine binding by half (). In new functional experiments, the effects of preincubation with phenoxybenzamine (PBZ), an irreversible alpha adrenoceptor antagonist, on responses to PE and two selective alpha-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 PE Emax and the calculated fraction of residual receptors (q). Preincubation in PBZ (10-300 nM) increased KB values for prazosin (30 and 100 nM) but did not alter the KB value for rauwolscine (50 nM) acting at the residual receptors from control values. Coincubation of PBZ with prazosin partially prevented these PBZ actions (Emax partly restored) on responses to PE, but coincubation of rauwolscine (</=1 microM) with PBZ, did not. Rauwolscine competitively inhibited responses to two alpha-2 adrenoceptor agonists (Schild plot pA2 values near 9). Preincubation with PBZ concentrations of >/=300 nM caused >50% reduction in Emax values 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 microM) effects. This study shows that PE initiates contractions at atypical alpha-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.
在犬隐静脉（DSV）中，苯肾上腺素（PE）通过α-1肾上腺素能受体产生的反应受到α-1和α-2受体拮抗剂的拮抗。此外，用氯乙可乐定（CEC）预处理可消除哌唑嗪结合，但使育亨宾结合减少一半（）。在新的功能实验中，评估了用不可逆的α肾上腺素能受体拮抗剂苯氧苄胺（PBZ）预孵育对PE反应以及两种选择性α-2肾上腺素能受体激动剂反应的影响。此外，还测定了哌唑嗪或育亨宾与PBZ共同孵育时防止对这些激动剂反应不可逆丧失的能力。用PBZ（10 - 300 nM）预孵育浓度依赖性地降低了PE的最大效应（Emax）和计算得出的残余受体分数（q）。用PBZ（10 - 300 nM）预孵育增加了哌唑嗪（30和100 nM）的平衡解离常数（KB）值，但未改变育亨宾（50 nM）作用于对照值的残余受体时的KB值。PBZ与哌唑嗪共同孵育部分阻止了PBZ对PE反应的这些作用（Emax部分恢复），但育亨宾（≤1 μM）与PBZ共同孵育则没有。育亨宾竞争性抑制对两种α-2肾上腺素能受体激动剂的反应（希尔德图pA2值接近9）。用≥300 nM浓度的PBZ预孵育导致反应的Emax值降低> >50%，但未改变两种激动剂的半数有效浓度（EC50）值。育亨宾与PBZ共同孵育可保护对α-2激动剂的反应免受PBZ（1 μM）的影响。本研究表明，PE在由PE作用的所有位点所代表的非典型α-1肾上腺素能受体处引发收缩。育亨宾拮抗PE的作用，但不能防止PBZ失活。典型的α-2肾上腺素能受体与异常的α-1肾上腺素能受体的区别在于它们对PBZ的敏感性较低以及育亨宾可使其免受PBZ的影响。
