Receptor occupancy in myocardium, adrenal cortex, and brain by TH-142177, a novel AT1 receptor antagonist in rats, in relation to its plasma concentration and hypotensive effect.

PURPOSE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.