Vauquelin Georges, Fierens Frederik, Van Liefde Isabelle
Department of Molecular and Biochemical Pharmacology, Free University of Brussels (VUB), Brussels, Belgium.
J Hypertens Suppl. 2006 Mar;24(1):S23-30. doi: 10.1097/01.hjh.0000220403.61493.18.
The ability of biphenyl-tetrazole angiotensin type 1 (AT1) receptor antagonists (BTsartans) to block angiotensin II (Ang II)-mediated responses has been extensively investigated in vascular tissues and, more recently, in cell lines expressing the human AT1-receptor. When pre-incubated, BTsartans acted surmountably (shifting the Ang II concentration-response curve to the right) or insurmountably (also decreasing the maximal response). It was shown that their insurmountable behaviour is due to the formation of tight, long-lasting complexes with the receptor. Partial insurmountable antagonism is due to the co-existence of tight and loose complexes. The proportion of insurmountable antagonism, the potency and the dissociation rate of the BTsartans decreases in the order: candesartan > EXP3174 (losartan's active metabolite) > valsartan > irbesartan >> losartan.
It is of interest to explore how tight AT1-receptor binding of BTsartans such as candesartan might contribute to their long-lasting clinical effect.
Computer-assisted simulations (COPASI program) were performed to follow the receptor-occupation and protection by different antagonists as a function of time. Free antagonist concentrations were allowed to decrease exponentially with time.
The simulations suggest that slow dissociation does not tangibly prolong receptor occupancy if the free antagonist is eliminated at a slower pace (as is the case for BTsartans). Yet when surmountable and insurmountable antagonists occupy the same amount of receptors, insurmountable antagonists offer appreciably better protection against fluctuations in natural messenger concentration.
Slow receptor dissociation and slow antagonist elimination are likely to act in synergy to produce long-lasting receptor protection.
联苯四氮唑血管紧张素1（AT1）受体拮抗剂（BT类沙坦）阻断血管紧张素II（Ang II）介导反应的能力已在血管组织中得到广泛研究，最近在表达人AT1受体的细胞系中也有研究。预孵育时，BT类沙坦表现为可克服性（将Ang II浓度-反应曲线右移）或不可克服性（也降低最大反应）。结果表明，它们的不可克服行为是由于与受体形成紧密、持久的复合物。部分不可克服性拮抗作用是由于紧密和松散复合物共存。BT类沙坦的不可克服性拮抗作用比例、效价和解离速率按以下顺序降低：坎地沙坦>EXP3174（氯沙坦的活性代谢物）>缬沙坦>厄贝沙坦>>氯沙坦。
探究坎地沙坦等BT类沙坦与AT1受体的紧密结合如何有助于其持久的临床效果，这很有意义。
进行计算机辅助模拟（COPASI程序），以跟踪不同拮抗剂随时间对受体的占据和保护情况。允许游离拮抗剂浓度随时间呈指数下降。
模拟结果表明，如果游离拮抗剂以较慢速度消除（BT类沙坦就是这种情况），缓慢解离并不会显著延长受体占据时间。然而，当可克服性和不可克服性拮抗剂占据相同数量的受体时，不可克服性拮抗剂能更好地抵御天然信使浓度的波动。
受体缓慢解离和拮抗剂缓慢消除可能协同作用，产生持久的受体保护作用。
