Pharmacological characterization of the novel nonpeptide angiotensin II receptor antagonist, BIBR 277

Abstract

The pharmacological profile of BIBR 277, 4′‐[(1,4′‐dimethyl‐2′‐propyl[2,6′‐bi‐1H‐benzimidazol]‐1′‐yl)methyl]‐[1,1′‐biphenyl]‐2‐carboxylic acid, a novel, nonpeptide angiotensin II receptor antagonist has been investigated by use of receptor binding studies, enzymatic assays, functional in vitro assays in rabbit aorta as well as in vivo experiments in pithed, anaesthetized and conscious rats. BIBR 277 potently interacted with rat AT1 receptors (Ki 3.7 nm). Competitive receptor interaction was shown by radioligand saturation experiments performed in the presence of BIBR 277. The failure to inhibit radioligand binding to AT2 sites demonstrates the selectivity of BIBR 277 for AT1 receptors. This is further substantiated by the findings that BIBR 277 neither interacted with other receptor systems investigated nor affected the activity of components of the human renin‐angiotensin system, such as plasma renin or serum converting enzyme. In rabbit aorta, BIBR 277 had no agonistic properties and was shown to be an insurmountable antagonist of angiotensin II‐induced contractions (KB 0.33 nm). The antagonistic effect persisted even after several wash‐out procedures. However, this interaction was not irreversible since the insurmountable antagonism was concentration‐dependently reversed when BIBR 277 (0.1 μm) and the surmountable antagonist, losartan (0.1 and 1.0 μm) were incubated simultaneously. The specificity of BIBR 277 for the AT1 receptor was further substantiated in this preparation since micromolar concentrations of BIBR 277 neither affected potassium chloride and noradrenaline‐induced contractions nor acetylcholine‐mediated tissue relaxation. In pithed rats, i.v. administration of BIBR 277 (0.1, 0.3 and 1.0 mg kg−1) shifted the dose‐pressor response curve to angiotensin II dose‐dependently to the right with ED50 values of 0.23 μg kg−1 (control) and 1.4 μg kg−1, 4.7 μg kg−1 and 20 μg kg−1, respectively. As observed in the in vitro experiments no agonistic effect was detected and the maximum of the blood pressure response to angiotensin II at the highest dose of BIBR 277 was decreased by 29%. In anaesthetized rats, bolus i.v. administration of 0.1, 0.3 and 1.0 mg kg−1 BIBR 277 attenuated the blood pressure response to bolus i.v. injections of angiotensin II (0.1 μg kg−1). At the highest dose an almost complete blockade was observed even after 2 h. Single oral administration of BIBR 277 (0.3 and 1.0 mg kg−1) to conscious, chronically instrumented renovascular hypertensive rats dose‐dependently decreased the mean arterial blood pressure by 15 and 30 mmHg, respectively. At the higher dose a significant antihypertensive effect was maintained for more than 24 h. Moreover, consecutive daily dosing of 1 mg kg−1 orally resulted in a sustained reduction in blood pressure over the 4 day observation period. It is concluded that BIBR 277 is an effective and selective angiotensin II antagonist with antihypertensive activity after oral administration.

Putting the efficacy of candesartan cilexetil into perspective: a review of new comparative data

“…[10][11][12][13][14][15] These studies have found that while candesartan (0.01-1 nM) produces a clear dose-dependent reduction in the maximal contractile response to angiotensin II (characteristic of insurmountable or non-competitive antagonism), 15 losartan and eprosartan are displaced from the AT 1 receptor with increasing doses of angiotensin II and cause parallel shifts of the dose response without affecting the maximal effect of angiotensin II (competitive or surmountable antagonism). 10,11,14 Valsartan, irbesartan and EXP-3174 (the active metabolite of losartan) exhibit mixed-type competitive (or surmountable) and non-competitive (insurmountable) antagonism at the AT 1 receptor; 11,12 telmisartan exhibits insurmountable (non-competitive) but reversible inhibition to angiotensin II-induced contractions in isolated rabbit aortic tissue.…”

“…10,11,14 Valsartan, irbesartan and EXP-3174 (the active metabolite of losartan) exhibit mixed-type competitive (or surmountable) and non-competitive (insurmountable) antagonism at the AT 1 receptor; 11,12 telmisartan exhibits insurmountable (non-competitive) but reversible inhibition to angiotensin II-induced contractions in isolated rabbit aortic tissue. 13 The antagonistic properties of candesartan, irbesartan, losartan and its active metabolite EXP-3174 were compared by Morsing and colleagues ( Figure 2). 16 The investigations were conducted in isolated preparations of rat portal vein and rabbit thoracic aortic strips using concentrations of antagonists equivalent to the (non-protein-bound) plasma concentrations achieved with oral dosing.…”

Angiotensin receptor blockers for the reduction of proteinuria in diabetic patients with overt nephropathy: results from the AMADEO study

“…The compound is not metabolized by cytochrome P450 isoenzymes and has a low risk for P450-based drug interactions. 37,38 A relevant fact to be noted is that unlike other ARBs, where up to 50% of the dose is excreted by the kidney, only 1% of a telmisartan dose in excreted by the kidney. Therefore renal impairment is unlikely to affect the pharmacokinetics of telmisartan.…”

Telmisartan — skuteczny lek w zapobieganiu i leczeniu chorób układu sercowo-naczyniowego

“…Sprawia to, że redukcja zarówno wartości skurczowego (SBP), jak i rozkurczowego (DBP) ciśnienia tętniczego powodowana podaniem telmisartanu nie koreluje ze spadkiem częstotliwości rytmu serca. Obserwuje się natomiast wywołany zastosowaniem leku rozkurcz mięśniówki gładkiej naczyń krwionośnych (w tym także aorty), wzrost przepływu krwi przez nerki i zwiększenie natriurezy [12,13]. U pacjentów z uprzednio nieleczonym nadciśnieniem tętniczym, którzy stosowali ściśle monitorowaną dietę, obejmującą spożycie sodu w ilości 100 mmol/d., wydalanie sodu z moczem dzięki podawaniu telmisartanu było znacznie zwiększone.…”