Insurmountable angiotensin AT1 receptor antagonists: the role of tight antagonist binding

Fierens, Frederik; Vanderheyden, Patrick; Backer, Jean‐Paul De; Vauquelin, Georges

doi:10.1016/s0014-2999(99)00205-8

Cited by 84 publications

(85 citation statements)

References 28 publications

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“…Similarly, losartan, irbesartan, valsartan, EXP3174 and candesartan were all competitive when measuring the Ang II-mediated inositol triphosphate production in CHO-hAT 1 cells. [29][30][31][32] The same profile also emerges when comparing radioligand binding studies on cell membranes involving pre and coincubation experiments. 22,[33][34] The ability of certain antagonists to decrease the maximal effect of Ang II is therefore the result of the experimental set-up (i.e., antagonist preincubation) and should not be ascribed to non-competitive behaviour (Figure 1).…”

Section: At 1 -Receptor Antagonists (Aiias) Are Competitivementioning

confidence: 91%

Distinctions between non-peptide angiotensin II AT1-receptor antagonists

Vauquelin¹,

Fierens²,

Verheijen³

et al. 2001

J Renin Angiotensin Aldosterone Syst

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A far-reaching understanding of the molecular action mechanism of AT 1 -receptor antagonists (AIIAs) was obtained by using CHO cells expressing transfected human AT 1 -receptors. In this model, direct [ 3 H]-antagonist binding and inhibition of agonistinduced responses (inositol phosphate accumulation) can be measured under identical experimental conditions. Whereas preincubation with a surmountable AIIA (losartan) causes parallel shifts of the angiotensin II (Ang II) concentration-response curve, insurmountable antagonists also cause partial (i.e., 30% for irbesartan, 50% for valsartan, 70% for EXP3174,) to almost complete (95% for candesartan) reductions of the maximal response. The main conclusions are that all investigated antagonists are competitive with respect to Ang II. They bind to a common or overlapping site on the receptor in a mutually exclusive way. Insurmountable inhibition is related to the slow dissociation rate of the antagonist-receptor complex (t 1/2 of 7 minutes for irbesartan, 17 minutes for valsartan, 30 minutes for EXP3174 and 120 minutes for candesartan). Antagonistbound AT 1 -receptors can adopt a fast and a slow reversible state. This is responsible for the partial nature of the insurmountable inhibition. The long-lasting effect of candesartan, the active metabolite of candesartan cilexetil, in vascular smooth muscle contraction studies, as well as in in vivo experiments on rat and in clinical studies, is compatible with its slow dissociation from, and continuous recycling between AT 1 -receptors. This recycling, or 'rebinding' takes place because of the very high affinity of candesartan for the AT 1 -receptor. IntroductionAngiotensin II (Ang II), the major peptide hormone of the renin-angiotensin-aldosterone system (RAAS) exerts most of its biological actions by stimulating Ang II receptors of the AT 1 subtype. Among these actions, the increased growth and contractility of vascular smooth muscle cells and cardiac myocytes 1,2 and the secretion of aldosterone by adrenal glomerulosa cells play a central role in the hypertensive effect of Ang II. AT 2 -receptors constitute the other major Ang II receptor subtype.3-5 They are expressed in foetal tissues and, in adulthood, they may also participate in blood pressure (BP) regulation albeit to a lesser extent than the AT 1 -receptors.During the last decade, much effort has been spent in developing non-peptide antagonists for the AT 1 -receptor for the clinical treatment of hypertension and congestive heart failure.

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Section: At 1 -Receptor Antagonists (Aiias) Are Competitivementioning

confidence: 91%

Distinctions between non-peptide angiotensin II AT1-receptor antagonists

Vauquelin¹,

Fierens²,

Verheijen³

et al. 2001

J Renin Angiotensin Aldosterone Syst

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“…These differences in affinity and duration of binding probably reflect the nature of the receptor-antagonist complex formed following binding of the antagonist to the receptor. Further evidence for this comes from the studies in transfected CHO cells, which suggest that with candesartan a higher proportion of this complex exists in a particularly tightly bound form than with losartan, EXP3174, or irbesartan; 15,16 more than 90% of candesartan is present in this form, compared with 70% for EXP3174 and 44% for irbesartan, whereas no tight binding is detectable with losartan. 16 This prolonged binding of candesartan to the AT 1 -receptor is associated with a long duration of biological activity in vivo.…”

Section: Nature Of Angiotensin II Antagonism: Surmountable Vs Insurmomentioning

confidence: 99%

“…Further evidence for this comes from the studies in transfected CHO cells, which suggest that with candesartan a higher proportion of this complex exists in a particularly tightly bound form than with losartan, EXP3174, or irbesartan; 15,16 more than 90% of candesartan is present in this form, compared with 70% for EXP3174 and 44% for irbesartan, whereas no tight binding is detectable with losartan. 16 This prolonged binding of candesartan to the AT 1 -receptor is associated with a long duration of biological activity in vivo. In studies in conscious rats, treatment with candesartan inhibited the increase in blood pressure induced by angiotensin II by approximately 80%; this effect was maintained for at least 24 h after dosing, despite the fact that plasma concentrations of candesartan declined rapidly and were undetectable at 24 h. 10 In other studies, increases in plasma renin were measured as a marker of inhibition of the renin-angiotensin system after administration of candesartan and other AT 1 -receptor blockers to healthy, salt-depleted, volunteers.…”

Section: Nature Of Angiotensin II Antagonism: Surmountable Vs Insurmomentioning

confidence: 99%

AT1-receptor blockers: differences that matter

Gradman

2002

J Hum Hypertens

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The available angiotensin II type 1 (AT 1 )-receptor blockers differ markedly in their pharmacological properties and clinical efficacy. Losartan shifts the dose-response curve for angiotensin II to the right without affecting the maximal response; this antagonism can be overcome by increasing concentrations of angiotensin II and thus losartan acts as a surmountable antagonist. By contrast, other agents suppress the maximal response to angiotensin II to varying extents; this can not be overcome by increasing angiotensin concentrations and hence these agents are insurmountable antagonists. Receptor binding studies have shown that candesartan has the highest affinity for the AT 1 -receptor, followed by irbesartan, valsartan and losartan, and that candesartan dissociates from the receptor more slowly than other antagonists. A meta-analysis using an E Max model has shown that differences in receptor binding activity are reflected in differences in maximal antihypertensive

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“…75,76 It has recently been shown that, in fact, all AT 1 -receptor antagonists are competitive antagonists, with tight-binding and very slow dissociation from the receptor. 77 This is especially true for candesartan, 78 which has demonstrated higher direct angiotensin II antagonistic activity in vivo than irbesartan, valsartan and losartan. 79,80 Thus, the effects of candesartan are likely to be long lasting and less easily overcome by increased endogeneous angiotensin II.…”

Section: Pharmacological Properties Of Candesartan Cilexetilmentioning

confidence: 99%

Blocking the tissue renin-angiotensin system: the future cornerstone of therapy

Unger

Azizi

Gg³

2000

J Hum Hypertens

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The development of angiotensin-converting enzyme inhibitors and selective angiotensin type 1 (AT 1 )-receptor antagonists has provided new insights into understanding the mechanism of the renin-angiotensin system (RAS) in the pathophysiology of cardiovascular disease. There is good evidence from meta-analyses that shows that inhibition of the RAS achieves organ protection features that go beyond blood pressure control. Candesartan cilexetil, a new angiotensin II receptor

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Insurmountable angiotensin AT1 receptor antagonists: the role of tight antagonist binding

Cited by 84 publications

References 28 publications

Distinctions between non-peptide angiotensin II AT1-receptor antagonists

Distinctions between non-peptide angiotensin II AT1-receptor antagonists

AT1-receptor blockers: differences that matter

Blocking the tissue renin-angiotensin system: the future cornerstone of therapy

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