Assessment of angiotensin II receptor blockade in humans using a standardized angiotensin II receptor-binding assay

Abstract

An in vitro angiotensin II (AngII) receptor-binding assay was developed to monitor the degree of receptor blockade in standardized conditions. This in vitro method was validated by comparing its results with those obtained in vivo with the injection of exogenous AngII and the measurement of the AngII-induced changes in systolic blood pressure. For this purpose, 12 normotensive subjects were enrolled in a double-blind, four-way cross-over study comparing the AngII receptor blockade induced by a single oral dose of losartan (50 mg), valsartan (80 mg), irbesartan (150 mg), and placebo. A significant linear relationship between the two methods was found (r = 0.723, n = 191, P<.001). However, there exists a wide scatter of the in vivo data in the absence of active AngII receptor blockade. Thus, the relationship between the two methods is markedly improved (r = 0.87, n = 47, P<.001) when only measurements done 4 h after administration of the drugs are considered (maximal antagonist activity observed in vivo) suggesting that the two methods are equally effective in assessing the degree of AT-1 receptor blockade, but with a greatly reduced variability in the in vitro assay. In addition, the pharmacokinetic/pharmacodynamic analysis performed with the three antagonists suggest that the AT-1 receptor-binding assay works as a bioassay that integrates the antagonistic property of all active drug components of the plasma. This standardized in vitro-binding assay represents a simple, reproducible, and precise tool to characterize the pharmacodynamic profile of AngII receptor antagonists in humans.

Drug and Diabetic Nephropathy

“…Previous studies with ACEI and angiotensin II receptor antagonists have shown that increasing the dose once daily has little effect on the peak inhibition but tends to prolong the duration of the inhibition. In accordance with this observation increasing the dose of Losartan to 200mg (2 times higher than maximal recommended dose) once daily and that of Telmisartan to 160mg once daily significantly improved the trough blockade 68,69,70 . Another study with a total of 23 hypertensive patients with type 2 diabetes and nephropathy was carried out with four treatment periods, each lasting 2 months.…”

Integrating Drug Pharmacokinetics for Phenotyping Individual Renin Response to Angiotensin II Blockade in Humans

“…BP, plasma Ang II concentration, plasma active renin concentration measurements, and neutralization of BP response to challenges with exogenous Ang I or Ang II 11 coupled with an in vitro Ang II radioreceptor binding assay quantifying the displacement of Ang II by RAS blockers 12 can be used to assess the intensity and duration of a RAS blockade. Even in controlled conditions, it is difficult to demonstrate small changes in BP in sodium-depleted normotensive subjects, especially 24 hours after drug intake, as shown in this experiment and in a previous study.…”

A Systematic Comparison of the Properties of Clinically Used Angiotensin II Type 1 Receptor Antagonists

“…Antagonism of AT1R by various ARBs has also been tested in vivo in humans, mostly healthy volunteers, and, similar to the above animal studies, this was largely done for ANGinduced blood pressure elevations. Following the original study with losartan (Christen et al, 1991), such studies have been performed with candesartan (Delacretaz et al, 1995;Ogihara et al, 1995;Belz et al, 1997Belz et al, , 2000Malerczyk et al, 1998;Fuchs et al, 2000;Gleiter et al, 2004), irbesartan (Belz et al, 1999Maillard et al, 1999;Mazzolai et al, 1999), losartan (Munafo et al, 1992;Belz et al, 1997Belz et al, , 1999Belz et al, , 2000Maillard et al, 1999;Mazzolai et al, 1999;Fuchs et al, 2000;Gleiter et al, 2004), telmisartan Stangier et al, 2001), and valsartan (Müller et al, 1994;Morgan et al, 1997;Belz et al, 1999Belz et al, , 2000Maillard et al, 1999;Mazzolai et al, 1999).…”