Martin D J, Lluel P, Guillot E, Coste A, Jammes D, Angel I
Synthélabo Recherche, Department of Internal Medicine, Rueil-Malmaison, France.
J Pharmacol Exp Ther. 1997 Jul;282(1):228-35.
We investigated the relevance of selectivity for a given alpha-1-adrenoceptor subtype for in vivo uroselectivity of several alpha-1-adrenoceptor antagonists (alfuzosin, doxazosin, prazosin, tamsulosin, terazosin and 5-Me-urapidil). Comparison of the affinities of these alpha-1-adrenoceptor antagonists at the cloned alpha-1a, alpha-1b and alpha-1d-adrenoceptor subtypes revealed that tamsulosin and 5-Me-urapidil showed selectivity for the alpha-1a subtype. No significant correlations were found between the affinities for alpha-1b or alpha-1d-adrenoceptors and the pK(B) values obtained against phenylephrine-induced contraction of the rabbit prostate in vitro. In contrast, the antagonist potencies in rabbit prostate were correlated (r = 0.89, P < .05) with the pKi values for the alpha-1a-adrenoceptor subtype. However, the pK(B) values were consistently smaller (by 0.6 to 1.9 log unit) than the pKi values for the alpha-1a-adrenoceptor subtype, a result that suggests that the alpha-1-adrenoceptor mediating urethral contractions does not have all the characteristics of the alpha-1a-adrenoceptor. The simultaneous measurement of urethral and arterial pressures in the same conscious male rat allows evaluation of the functional uroselectivity of these antagonists based on their respective effects on both pressures. Dose ranges were selected according to effects on urethral pressure and most antagonists were found effective within the 3 to 100 microg/kg i.v. range. Alfuzosin markedly decreased urethral pressure and either did not decrease blood pressure (10-30 microg/kg) or slightly decreased it at the highest dose tested (100 microg/kg). Doxazosin did not produce sustained reductions in urethral pressure until a dose of 30 microg/kg. Blood pressure was not reduced until 100 microg/kg. Prazosin reduced urethral pressure and blood pressure within the same dose-range whereas terazosin did not decrease urethral pressure at doses that significantly decreased blood pressure (30 and 100 microg/kg). 5-Me-urapidil, an alpha-1a-selective compound did not significantly modify urethral and blood pressure whereas tamsulosin, another alpha-1a-selective compound reduced urethral pressure and blood pressure within the same dose range. In conclusion, in the conscious male rat the functional uroselectivity is not correlated with a selective affinity for the alpha-1a-adrenoceptor subtype.
我们研究了几种α1肾上腺素能受体拮抗剂（阿夫唑嗪、多沙唑嗪、哌唑嗪、坦索罗辛、特拉唑嗪和5-甲基乌拉地尔）对特定α1肾上腺素能受体亚型的选择性与体内尿道选择性之间的相关性。比较这些α1肾上腺素能受体拮抗剂对克隆的α1a、α1b和α1d肾上腺素能受体亚型的亲和力发现，坦索罗辛和5-甲基乌拉地尔对α1a亚型具有选择性。在α1b或α1d肾上腺素能受体的亲和力与体外针对苯肾上腺素诱导的兔前列腺收缩所获得的pK(B)值之间未发现显著相关性。相反，兔前列腺中的拮抗剂效力与α1a肾上腺素能受体亚型的pKi值相关（r = 0.89，P <.05）。然而，pK(B)值始终比α1a肾上腺素能受体亚型的pKi值小（相差0.6至1.9个对数单位），这一结果表明介导尿道收缩的α1肾上腺素能受体并不具备α1a肾上腺素能受体的所有特征。在同一清醒雄性大鼠中同时测量尿道和动脉压力，可以根据这些拮抗剂对两种压力的各自影响来评估其功能尿道选择性。根据对尿道压力的影响选择剂量范围，发现大多数拮抗剂在静脉注射3至100μg/kg范围内有效。阿夫唑嗪显著降低尿道压力，在10 - 30μg/kg时不降低血压，在最高测试剂量（100μg/kg）时略有降低。多沙唑嗪直到30μg/kg剂量时才持续降低尿道压力。直到100μg/kg时血压才降低。哌唑嗪在相同剂量范围内降低尿道压力和血压，而特拉唑嗪在显著降低血压的剂量（30和100μg/kg）下未降低尿道压力。5-甲基乌拉地尔，一种α1a选择性化合物，对尿道和血压没有显著影响，而另一种α1a选择性化合物坦索罗辛在相同剂量范围内降低尿道压力和血压。总之，在清醒雄性大鼠中，功能尿道选择性与对α1a肾上腺素能受体亚型的选择性亲和力无关。
