Development Research, R&D, Kissei Pharmaceutical, Co., Ltd., Nagano, Japan.
Urology. 2012 Aug;80(2):486.e9-16. doi: 10.1016/j.urology.2012.01.039. Epub 2012 Jun 5.
To compare the effects of four α(1)-adrenoceptor (AR) subtype-selective antagonists on ejaculatory function in rats to investigate whether the differences in their modes of action-based on their selectivities for the α(1A)-AR subtype-would be related to the prevalence of ejaculation disorder (EjD).
The effects of α(1)-AR antagonists on noradrenaline-induced contractions were studied in rat isolated seminal vesicles, vas deferens, bladder trigone, and prostate. Male rats were given α(1)-AR antagonists orally and, 1 hour after the drug administration they were cohoused in pairs for 1 hour with untreated female rats certified to be in estrus. The number of copulatory plugs (NP) present after mating was measured as a marker of EjD. Drug effects on ejaculatory function (ie, on NP) were compared with those on the prostatic urethra (ie, phenylephrine-induced increase in intraurethral pressure [IUP]).
All α(1)-AR antagonists concentration-dependently inhibited noradrenaline-induced contraction in all 4 tissues, and there were no differences in the rank order of potencies (tamsulosin > silodosin > alfuzosin > naftopidil) among the tissues. All α(1)-AR antagonists dose-dependently decreased NP and inhibited the phenylephrine-induced increase in IUP. There was little difference in the dose ratio ID(50) value (dose required to produce 50% inhibition) for NP/ID(50) value for IUP response among the four drugs. Drug potencies associated NP and IUP correlated closely with affinities for the human α(1A)-AR.
α(1)-AR antagonists cause EjD as a class effect that depends on affinity for α(1A)-AR. Differences in α(1A)-AR selectivity would be unlikely to be related to the incidence of EjD.
比较四种 α(1)-肾上腺素能受体（AR）亚型选择性拮抗剂对大鼠射精功能的影响，以探讨它们基于对 α(1A)-AR 亚型的选择性的作用模式的差异是否与射精功能障碍（EjD）的发生率有关。
研究了 α(1)-AR 拮抗剂对大鼠离体精囊、输精管、膀胱三角和前列腺中去甲肾上腺素诱导收缩的影响。雄性大鼠口服给予 α(1)-AR 拮抗剂，给药 1 小时后，与未经处理的处于发情期的雌性大鼠成对共居 1 小时。交配后存在的交配插塞（NP）数量作为 EjD 的标志物进行测量。将药物对射精功能（即 NP）的影响与对前列腺尿道（即，苯肾上腺素诱导的尿道内压[IUP]增加）的影响进行比较。
所有 α(1)-AR 拮抗剂均浓度依赖性地抑制了 4 种组织中去甲肾上腺素诱导的收缩，并且在组织中的效力（坦索罗辛>西洛多辛>阿夫唑嗪>萘哌地尔）没有差异。所有 α(1)-AR 拮抗剂均剂量依赖性地降低 NP，并抑制苯肾上腺素诱导的 IUP 增加。四种药物中，NP/ID(50)值（产生 50%抑制所需的剂量）与 IUP 反应的 ID(50)值的比值（ID(50)值）差异不大。与 NP 相关的药物效力和 IUP 与对人 α(1A)-AR 的亲和力密切相关。
α(1)-AR 拮抗剂作为一种依赖于对 α(1A)-AR 的亲和力的类效应导致 EjD。α(1A)-AR 选择性的差异不太可能与 EjD 的发生率有关。
