In Vitro and in Vivo Characterization of the Activity of Telmisartan: An Insurmountable Angiotensin II Receptor Antagonist

Abstract

In vitro studies have shown that telmisartan is an insurmountable angiotensin II subtype-1 (AT1) receptor antagonist. Herein, the molecular basis of this insurmountable antagonism has been investigated in vitro, and the effect of telmisartan has been compared in vivo with that of irbesartan and candesartan. Association and dissociation kinetics of telmisartan to AT1 receptors have been characterized in vitro on rat vascular smooth muscle cells (RVSMC) expressing solely the AT1 receptor subtype. In a second set of experiments, the antagonistic efficacy of single intravenous doses (0.1, 0.3, and 1 mg/kg) of telmisartan was compared with that of irbesartan (0.3, 1.0, 3.0, and 10.0 mg/kg) and candesartan (0.3 and 1 mg/kg) in conscious, normotensive, male Wistar rats. The results show that the specific binding of [ 3 H]telmisartan to the surface of living RVSMC is saturable and increases quickly to reach equilibrium within 1 h. Telmisartan dissociates very slowly from the receptor with a dissociation half-life (t 1/2 ) of 75 min, which is comparable with candesartan and almost 5 times slower than angiotensin II (AngII). In vivo, telmisartan blunts the blood pressure response to exogenous AngII dose dependently. The blockade is long lasting and remains significant at 24 h at doses Ͼ0.1 mg/kg. Ex vivo assessment of the AT1 receptor blockade using an in vitro AngII receptor binding assay shows similar results. When administered intravenously in rats, telmisartan is 10-fold more potent than irbesartan and comparable to candesartan. Taken together, our in vitro data show that the insurmountable antagonism of telmisartan is due at least in part to its very slow dissociation from AT1 receptors.

Cardiovascular reactivity after blockade of angiotensin AT1 receptors in the experimental model of tilting test in conscious rats

“…In contrast, the present data in conscious rats reveal that the effect produced by losartan on the cardiovascular reactivity to orthostatic stress exhibits a profile similar to that of a highly specific AT 1 antagonist (Maillard et al, 2002). Therefore, it is likely that the more pronounced orthostatic hypotensive response described specifically for losartan in the orthostatic stress models reported previously was a consequence of the use of anaesthesia (Ohlstein et al, 1992;Hashimoto et al, 1999;de Moura et al, 2005).…”

Freehand three-dimensional echocardiographic evaluation of the effect of telmisartan compared with hydrochlorothiazide on left ventricular mass in hypertensive patients with mild-to-moderate hypertension: a multicentre study

“…8,9 The ARB telmisartan binds insurmountably to and dissociates slowly from the AT 1 receptor. 10 Other distinguishing features of telmisartan are its almost exclusive biliary excretion and terminal elimination half-life of about 24 h. 11 Clinical studies have shown the ability of once-daily telmisartan to provide effective control of blood pressure. 11 Preclinical studies suggest that telmisartan is highly effective in reducing LVH, [12][13][14][15] and preliminary observations provide evidence for the clinical efficacy of telmisartan in the treatment of LVH at doses that confer effective blood pressure control.…”

Angiotensin II-induced inotropism requires an endocardial endothelium-nitric oxide mechanism in the in-vitro heart of Anguilla anguilla

“…AJ05132; Tran van Chuoi et al 1999) that in the eel does not contain residues associated with losartan binding (Russell et al, 2000). For this reason we used as AT1 antagonist CV11974, which blocks the vascular ANG II-mediated effects in vivo and in vitro (Maillard et al, 2002) and also binds cardiac ANG II receptors in an elasmobranch (Cerra et al, 2001). CV11974, but not GCP42112, abolished the negative inotropism elicited by ANG II, suggesting that it may be mediated by an AT1-like receptor.…”