Inhibitory Effect of Telmisartan on the Blood Pressure Response to Angiotensin II Challenge

Abstract

Telmisartan is a new angiotensin receptor antagonist possessing potent, selective, and insurmountable inhibitory activity specific to the angiotensin II type 1 (AT 1 ) receptor. The current study was performed to determine the inhibition of the angiotensin II pressor response by telmisartan in 48 healthy volunteers challenged with hypertension-inducing doses of i.v. angiotensin II. Subjects were challenged with this dose of angiotensin II at intervals between 0.25 and 48 h after double-blind single-dose oral administration of telmisartan 20 mg (n = 12), 40 mg (n = 12), or 80 mg (n = 12) or placebo (n = 12) in parallel groups. Diastolic and systolic blood pressure and pulse rate were recorded continuously using a servophotoplethysmograph. Urine samples were collected during the study for urinalysis. Tolerability of telmisartan, in comparison with placebo, was also monitored throughout the study. Telmisartan 20-80 mg dose dependently inhibited the increase in diastolic and systolic blood pressure induced by angiotensin II. Telmisartan 40 mg produced 80.1% maximum inhibition, and with 80 mg 89.6% maximum inhibition of diastolic blood pressure was achieved. Inhibition was apparent after 0.3-1.1 h and was still observed 48 h after administration for all telmisartan doses. The inhibitory effect of telmisartan 20, 40, and 80 mg, 48 h after dosing was significantly greater than that of placebo. A > 25% inhibition of the angiotensin II response on diastolic blood pressure was detected until 26.9, 35.4, and 40.5 h, respectively, after telmisartan 20 mg, 40 mg, and 80 mg. Anti-clockwise hysteresis was observed, indicating a delay and longer persistence of effect than to be expected from the plasma concentration-time course. The slow dissociation of telmisartan from the receptor probably contributed to this hysteresis. The incidence of adverse events was comparable in telmisartan-and placebo-treated subjects and was not dose dependent. In conclusion, telmisartan 40 mg provides rapid-onset, well-tolerated, and near-maximal inhibition of angiotensin II-induced hypertension, with maintenance of the inhibitory effect for 48 h.

Acute effects of renin-angiotensin system blockade on arterial function in hypertensive patients

“…In other studies that observed acute drug effects on arterial function, these effects occurred almost simultaneously with the BP change. 16,50 However, because the vascular effects observed in our study were largely BP independent, we cannot preclude possible delayed effects.…”

“…8,50 We used telmisartan 80 mg, since this dose may result in a greater arterial effect compared with lower doses. 50 On the other hand, studies that compared the acute endothelial effects of different ACEIs showed that increasing the dose of the low-tissue affinity ACEI does not modify the effect on arterial function. 25,26 Furthermore, even a higher dose of captopril (50 mg) does not improve FMD in hypertensive patients.…”

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).…”

Telmisartan Inhibits CD4-Positive Lymphocyte Migration Independent of the Angiotensin Type 1 Receptor via Peroxisome Proliferator-Activated Receptor-γ

“…25,26 Still, the concentrations used here correspond with the concentrations used in previous experiments investigating PPAR␥-activating properties of telmisartan. In addition, telmisartan is a very lipophilic agent, and the biological action in the tissue does not necessarily correlate with plasma concentrations.…”