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AT1-Receptor Blockers: Differences That Matter

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AT1-Receptor Blockers: Differences That Matter Journal of Human Hypertension (2002) 16, S9–S16 2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh AT1-receptor blockers: differences that matter AH Gradman Division of Cardiovascular Diseases, The Western Pennsylvania Hospital, Pittsburgh, Pennsylvania, USA The available angiotensin II type 1 (AT1)-receptor block- effect, and this finding is supported by the results of ers differ markedly in their pharmacological properties comparative clinical trials. Moreover, the prolonged and clinical efficacy. Losartan shifts the dose-response binding of candesartan to the receptor is reflected in a curve for angiotensin II to the right without affecting the longer duration of action, compared with losartan; the maximal response; this antagonism can be overcome by antihypertensive effect of candesartan persists for 48 h increasing concentrations of angiotensin II and thus los- after dosing, compared with approximately 24 h with artan acts as a surmountable antagonist. By contrast, losartan. Candesartan thus offers extended therapeutic other agents suppress the maximal response to angio- coverage, an important consideration since a majority tensin II to varying extents; this can not be overcome by of patients miss occasional doses of antihypertensive increasing angiotensin concentrations and hence these medication. There is currently no evidence that differ- agents are insurmountable antagonists. Receptor bind- ences in receptor binding between AT1-receptor block- ing studies have shown that candesartan has the high- ers translate into differences in tolerability. In summary, est affinity for the AT1-receptor, followed by irbesartan, therefore, pharmacological differences between AT1- valsartan and losartan, and that candesartan dis- receptor blockers are reflected in clinically important sociates from the receptor more slowly than other differences in maximal antihypertensive effect, antagonists. A meta-analysis using an EMax model has response rate, and duration of action. shown that differences in receptor binding activity are Journal of Human Hypertension (2002) 16, S9–S16. reflected in differences in maximal antihypertensive doi:10.1038/sj.jhh.1001434 Keywords: AT1-receptor blockers; blood pressure control; candesartan; irbesartan; losartan; receptor binding studies; valsartan Introduction ment. Each of these compounds selectively blocks the AT1-receptor, and as a class these agents have Angiotensin II is the principal effector peptide of the been shown to be at least as effective in lowering renin-angiotensin system and has a variety of bio- blood pressure as other antihypertensive agents and logical effects, including vasoconstriction, pro- to offer a tolerability profile comparable with that of motion of growth in vascular smooth muscle and placebo.6 There are, however, marked differences in cardiac myocytes, stimulation of aldosterone the pharmacological properties of these agents, and release, thrombosis, myocardial fibrosis, and pro- these may be reflected in important differences in motion of vascular inflammation.1 The deleterious clinical performance. effects of angiotensin II on blood pressure and car- diovascular remodelling are mediated via angioten- 1,2 sin II type 1 (AT1) receptors. The AT2-receptor subtype is also activated by angiotensin II, and has Pharmacological differences between been shown in experimental studies to counteract AT1-receptor blockers the detrimental effects of AT1-receptor stimu- 3,4 lation. Selective blockade of the AT1 receptor thus represents a rational therapeutic target in hyperten- AT1-receptor blockers bind selectively to AT1- sion and cardiovascular disease.5 receptors and thus inhibit the deleterious effects of angiotensin II, irrespective of whether angiotensin II Since the introduction of the prototype AT1- receptor blocker, losartan, in 1994 five others have is produced via angiotensin converting enzyme 2 been introduced into clinical practice: candesartan, (ACE) or by non-ACE pathways. As a result, they eprosartan, irbesartan, telmisartan and valsartan; a produce more complete blockade of the renin-angio- number of others are currently undergoing develop- tensin system than ACE inhibitors. However, the binding kinetics of AT1-receptor blockers vary con- siderably, both in terms of the type of antagonism Correspondence: Professor AH Gradman MD, The Western seen at the receptor and the affinity of the antagonist Pennsylvania Hospital, 4800 Friendship Avenue, Pittsburgh, for the receptor (Figure 1). Pennsylvania 15224, USA Pharmacology of AT1-receptor blockers AH Gradman S10 Affinity of AT1-receptor blockers for the receptor and duration of binding AT1-receptor blockers differ markedly in their affinity for the receptor. Experiments in animals have shown that the affinity of candesartan for the AT1-receptor is 10 and 80 times greater than that of EXP3174 and los- artan, respectively, and that candesartan dissociates more slowly from the receptor than other AT1-receptor blockers.11–13 In other experiments, rat portal vein preparations were incubated with various concen- trations of AT1-receptor blocker, which was washed out after different times to determine the duration of AT1 receptor blockade. The inhibition with candesar- tan persisted despite repeated washing for 2 h, whereas the effects of losartan, EXP3174 and irbesar- tan were significantly reduced 30–60 min after wash- ing.10 These findings are supported by studies with Chinese hamster ovary (CHO) cells transfected with Figure 1 Differences in receptor (R) binding kinetics of AT1- 14 receptor blockers, exemplified by losartan and candesartan.7 the human AT1-receptor. In these experiments, cells Reproduced with permission from Morsing P, Vauquelin G. How were preincubated with unlabelled candesartan, irbes- can the differences among AT1-receptor antagonists be explained? artan, EXP3174, or losartan and subsequently incu- Cell Biochem Biophys 2001; 35: 89–102. bated with [3H]-candesartan to determine the rate at which the unlabelled AT1-receptor blockers dis- sociated from the receptor and were replaced by [3H]- candesartan. The dissociation rate constant for candes- artan was markedly lower than that of other AT1- receptor blockers, and the half life for dissociation of Nature of angiotensin II antagonism: candesartan from the receptor was several-fold longer surmountable vs insurmountable (Table 1). Some agents, such as losartan, only produce a paral- Together, therefore, these studies show that candes- lel shift of the dose-response curve to the right with- artan binds to the AT1-receptor with greater affinity out reducing the maximal response to angiotensin than other AT1-receptor blockers, and dissociates from II. This inhibition can therefore be overcome by the receptor more slowly. These differences in affinity increasing concentrations of angiotensin II, and and duration of binding probably reflect the nature of hence these agents are described as surmountable the receptor-antagonist complex formed following antagonists. By contrast, other agents also depress binding of the antagonist to the receptor. Further evi- the maximal response to angiotensin II; the extent dence for this comes from the studies in transfected to which these agents depress the response ranges CHO cells, which suggest that with candesartan a from a partial decrease with irbesartan, valsartan higher proportion of this complex exists in a parti- and EXP3174 (the active metabolite of losartan) to cularly tightly bound form than with losartan, almost complete suppression with candesartan. This EXP3174, or irbesartan;15,16 more than 90% of candes- inhibition can not be overcome by increasing con- artan is present in this form, compared with 70% for centrations of angiotensin II and hence is described EXP3174 and 44% for irbesartan, whereas no tight as insurmountable antagonism.8,9 binding is detectable with losartan.16 These differences in the antagonist properties of This prolonged binding of candesartan to the AT1- different AT1-receptor blockers have been demon- receptor is associated with a long duration of bio- strated in a series of studies with isolated blood logical activity in vivo. In studies in conscious rats, vessel preparations.10 In one set of experiments, treatment with candesartan inhibited the increase in for example, rabbit aortic strips were preincubated blood pressure induced by angiotensin II by with various concentrations of candesartan, irbes- approximately 80%; this effect was maintained for artan, losartan and EXP3174, and the contractile at least 24 h after dosing, despite the fact that plasma response to increasing concentrations of angioten- concentrations of candesartan declined rapidly and sin II was assessed (Figure 2). Candesartan pro- were undetectable at 24 h.10 In other studies, duced a progressive reduction in the response to increases in plasma renin were measured as a angiotensin II, with a concentration of 1 nmol/L marker of inhibition of the renin-angiotensin system producing complete inhibition. Irbesartan and after administration of candesartan and other AT1- EXP3174 produced less marked reductions in the receptor blockers to healthy, salt-depleted, volun- maximal response, while losartan had no effect on teers. Candesartan, 16 mg, produced greater the maximal response at concentrations of up to increases in plasma renin over 24 h than losartan, 100 nmol/L. 50 mg, or valsartan, 80 or 160 mg.17,18 Journal of Human Hypertension Pharmacology of AT1-receptor blockers AH Gradman S11 Figure 2 Response
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