Inada Y, Ojima M, Kanagawa R, Misumi Y, Nishikawa K, Naka T
Pharmaceutical Research Division, Takeda Chemical Industries Ltd, Osaka, Japan.
J Hum Hypertens. 1999 Jan;13 Suppl 1:S75-80. doi: 10.1038/sj.jhh.1000749.
Candesartan cilexetil has shown potent and long-lasting antihypertensive effects in clinical trials and in several animal models of hypertension. In spontaneously hypertensive rats, the duration of the antihypertensive effect of candesartan cilexetil was compared to those of losartan, valsartan, eprosartan, and irbesartan at the same degree of maximal blood pressure reduction. A single oral dose of candesartan cilexetil at 0.3 mg/kg reduced maximal blood pressure by about 25 mm Hg, and the antihypertensive effect of candesartan cilexetil lasted the longest, continuing for more than 1 week, without an effect on circadian rhythm. In a rabbit aortic preparation, candesartan, active form of candesartan cilexetil, decreased the maximal contractile response of angiotensin II. This inhibitory mode was different from that of other angiotensin II-receptor antagonists, and showed a shift to the right in the angiotensin II-induced contraction curve and/or a small depression of the maximal response. In kinetic studies using bovine adrenal cortical membrane and tritiated candesartan, both receptor association and dissociation were found to be slow. The dissociation rate of tritiated candesartan binding (t1/2 = 66 min) was five times slower than that of radiolabelled angiotensin II binding (t1/2 = 12 min). The insurmountable inhibition of candesartan in vascular contraction is the result of its tight binding and slow dissociation from angiotensin II AT1 receptors. These characteristics are related to the potency and long duration of action in candesartan cilexetil.
坎地沙坦酯在临床试验和多种高血压动物模型中均显示出强效且持久的降压作用。在自发性高血压大鼠中，在最大血压降低程度相同的情况下，比较了坎地沙坦酯与氯沙坦、缬沙坦、依普罗沙坦和厄贝沙坦的降压作用持续时间。以0.3mg/kg的剂量单次口服坎地沙坦酯可使最大血压降低约25mmHg，且坎地沙坦酯的降压作用持续时间最长，持续超过1周，对昼夜节律无影响。在兔主动脉制剂中，坎地沙坦酯的活性形式坎地沙坦可降低血管紧张素II的最大收缩反应。这种抑制模式与其他血管紧张素II受体拮抗剂不同，表现为血管紧张素II诱导的收缩曲线向右移位和/或最大反应略有降低。在使用牛肾上腺皮质膜和氚标记坎地沙坦的动力学研究中，发现受体结合和解离均缓慢。氚标记坎地沙坦结合的解离速率（t1/2 = 66分钟）比放射性标记血管紧张素II结合的解离速率（t1/2 = 12分钟）慢五倍。坎地沙坦在血管收缩中不可克服的抑制作用是其与血管紧张素II AT1受体紧密结合和解离缓慢的结果。这些特性与坎地沙坦酯的效力和长效作用有关。
