Nozawa Y, Miyake H, Yamada S, Kimura R
Pharmacology Research Laboratory, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan.
Pharm Res. 1998 Jun;15(6):911-7. doi: 10.1023/a:1011932800729.
To study the relationship between angiotensin II (AII) receptor occupancy ex vivo in tissues plasma concentration and hypotensive effect of a novel AII receptor antagonist, TH-142177 and losartan in rats.
At 2, 8 and 24 hr after oral administration of TH-142177 and losartan in rats, AII receptors in myocardium, adrenal cortex and cerebral cortex were determined by radioligand binding assay using [125I]Sar1,Ile8-AII. Plasma concentrations of both drugs and metabolite in rats were also measured using validated HPLC assays. Further, systolic blood pressure (SBP) in conscious renal hypertensive rats treated orally with TH-142177 and losartan were measured by using a tail cuff plethysmographic method.
Oral administration of TH-142177 (1.8 and 5.5 micromol/kg) and losartan (6.5 and 21.7 micromol/kg) in rats brought about dose-dependent decreases in [125I]Sar1,Ile8-AII binding sites (Bmax) in myocardium and adrenal cortex. The extent of receptor occupancy by both drugs in adrenal cortex was maximal at 2 hr later but that in myocardium at 8 hr later. Further, the receptor occupancy was more sustained in myocardium than adrenal cortex. The ex vivo binding affinity of TH-142177 for AII receptors in these tissues was roughly three times higher than that of losartan. Also, cerebral cortical [125I]Sar1,Ile8-AII binding was significantly reduced by oral administration of losartan but not by TH-142177. The time course of AII receptor occupancy by both drugs in adrenal cortex appeared to be in parallel with that of their plasma concentrations, while the time course in myocardium correlated with that of their hypotensive effects rather than plasma concentrations.
TH-142177 produced a relatively selective and sustained occupancy ex vivo of AII receptors in myocardium and adrenal cortex of rats with approximately three times greater potency than losartan. Its time course of myocardial receptor occupancy was in parallel with that of hypotensive effect rather than plasma concentration.
研究新型血管紧张素II（AII）受体拮抗剂TH - 142177和氯沙坦在大鼠体内组织中AII受体占有率与血浆浓度及降压作用之间的关系。
在大鼠口服TH - 142177和氯沙坦后2、8和24小时，采用[125I]Sar1，Ile8 - AII放射性配体结合试验测定心肌、肾上腺皮质和大脑皮质中的AII受体。同时，使用经过验证的高效液相色谱法测定大鼠体内两种药物及其代谢物的血浆浓度。此外，通过尾袖体积描记法测量口服TH - 142177和氯沙坦的清醒肾性高血压大鼠的收缩压（SBP）。
大鼠口服TH - 142177（1.8和5.5微摩尔/千克）和氯沙坦（6.5和21.7微摩尔/千克）后，心肌和肾上腺皮质中[125I]Sar1，Ile8 - AII结合位点（Bmax）呈剂量依赖性降低。两种药物在肾上腺皮质中的受体占有率在2小时后达到最大值，而在心肌中则在8小时后达到最大值。此外，心肌中的受体占有率比肾上腺皮质更持久。TH - 142177对这些组织中AII受体的体外结合亲和力约为氯沙坦的三倍。而且，口服氯沙坦可显著降低大脑皮质[125I]Sar1，Ile8 - AII结合，而TH - 142177则无此作用。两种药物在肾上腺皮质中AII受体占有率的时间进程似乎与其血浆浓度的时间进程平行，而在心肌中的时间进程与其降压作用相关，而非血浆浓度。
TH - 142177在大鼠心肌和肾上腺皮质中产生了相对选择性和持久的体外AII受体占有率，其效力约为氯沙坦的三倍。其心肌受体占有率的时间进程与降压作用平行，而非血浆浓度。
