Pharmacologically distinct phenotypes of α1B-adrenoceptors: variation in binding and functional affinities for antagonists
Pharmacologically distinct phenotypes of α1B-adrenoceptors: variation in binding and functional affinities for antagonists
复制标题
α1B-肾上腺素受体的药理学不同表型：拮抗剂的结合和功能亲和力的变化
DOI：
10.1111/bph.12813
复制
发表时间：
2014
影响因子：
7.3
通讯作者：
and Muramatsu I.
中科院分区：
文献类型：
--
作者：
Yoshiki H;Uwada J;Anisuzzaman ASM;Umada H;Hayashi R;Kainoh M;and Muramatsu I.
背景和目的近年来研究表明，特定受体的药理学特性在不同条件下会发生变化。我们比较了不同组织制备物和不同条件下α1B-肾上腺素受体亚型的药理学特性。实验方法[3 H]-哌唑嗪与大鼠肝脏α1B-肾上腺素受体的结合（片段，分散的肝细胞和匀浆）的药理学特征进行了评估，并与大鼠颈动脉和重组α1B-肾上腺素受体的功能和结合特征进行了比较。大鼠肝脏中，不同制备物对[3 H]-哌唑嗪的结合亲和力差异显著（片段中的KD值约为匀浆中的10倍）。各种药物在肝段中的结合特征也偏离了在肝匀浆和重组受体中观察到的代表性α1B-肾上腺素受体特征。L-765，314和ALS-77是α1B-肾上腺素受体的选择性拮抗剂，在肝匀浆和重组α1B-肾上腺素受体中显示出高结合和拮抗剂亲和力。然而，在大鼠肝脏和颈动脉的节段中，两种配体的结合亲和力低10倍，并且在α1B-肾上腺素受体介导的颈动脉收缩中的拮抗剂效力比代表性的α1B-肾上腺素受体谱低100倍以上。大鼠肝脏和颈动脉的天然α1B-肾上腺素受体的药理学特征在不同的受体环境下显著不同，显示出完整组织和匀浆之间显著不同的结合特性，以及功能亲和力和结合亲和力之间的分离。除了传统的“亚型”表征，“表型”药理学必须考虑在体内天然受体评估和未来的药物治疗。
Background and PurposeThe pharmacological properties of particular receptors have recently been suggested to vary under different conditions. We compared the pharmacological properties of the α1B‐adrenoceptor subtype in various tissue preparations and under various conditions.Experimental Approach[3H]‐prazosin binding to α1B‐adrenoceptors in rat liver (segments, dispersed hepatocytes and homogenates) was assessed and the pharmacological profiles were compared with the functional and binding profiles in rat carotid artery and recombinant α1B‐adrenoceptors.Key ResultsIn association and saturation‐binding experiments with rat liver, binding affinity for [3H]‐prazosin varied significantly between preparations (KDvalue approximately ten times higher in segments than in homogenates). The binding profile for various drugs in liver segments also deviated from the representative α1B‐adrenoceptor profile observed in liver homogenates and recombinant receptors. L‐765,314 and ALS‐77, selective antagonists of α1B‐adrenoceptors, showed high binding and antagonist affinities in liver homogenates and recombinant α1B‐adrenoceptors. However, binding affinities for both ligands in the segments of rat liver and carotid artery were 10 times lower, and the antagonist potencies in α1B‐adrenoceptor‐mediated contractions of carotid artery were more than 100 times lower than the representative α1B‐adrenoceptor profile.Conclusions and ImplicationsIn contrast to the consistent profile of recombinant α1B‐adrenoceptors, the pharmacological profile of native α1B‐adrenoceptors of rat liver and carotid artery varied markedly under various receptor environments, showing significantly different binding properties between intact tissues and homogenates, and dissociation between functional and binding affinities. In addition to conventional ‘subtype’ characterization, ‘phenotype’ pharmacology must be considered in native receptor evaluationsin vivoand in future pharmacotherapy.