Evidence that the apparent complexity of receptor antagonism by angiotensin II analogues is due to a reversible and syntopic action

Liu, Y.J.; Shankley, Nigel P.; Welsh, N J; Black, J.W.

doi:10.1111/j.1476-5381.1992.tb14322.x

Cited by 66 publications

(35 citation statements)

References 27 publications

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“…Yet, similar to the experiments on rabbit aortic strips by Liu et al (1992) and Ojima et al (1997), we found that in CHO-AT 1 cells the insurmountable antagonism by candesartan of angiotensin II-mediated IP accumulation is attenuated in the presence of a high concentration of the surmountable antagonist losartan. This result rather suggests that candesartan antagonism is due to a syntopic action at the AT 1 receptor.…”

Section: Discussionsupporting

confidence: 64%

“…Insurmountable antagonists are able to depress the maximal response. The extent of this decline varies considerably from one antagonist to another and it seems to be unrelated to the potency of the antagonist to produce rightward shifts of the concentration-response curve (Liu et al 1992;Cazaubon et al, 1993;Noda et al, 1993;Mochizuki et al, 1995). The molecular basis for insurmountable antagonism is still a matter of debate.…”

Section: Introductionmentioning

confidence: 99%

“…The molecular basis for insurmountable antagonism is still a matter of debate. Although the longevity of the antagonist-receptor complex is retained as the cause in many studies, insurmountable antagonism has also been explained by the presence of allosteric binding sites on the receptor (Timmermans et al, 1991); slowly interconverting receptor conformations (de Cha oy de Courcelles et al, 1986;Robertson et al, 1994); slow removal of the antagonist from tissue compartments, cells or matrix surrounding the receptor (Robertson et al, 1992;Panek et al, 1995) and even by the ability of the antagonist to modulate the amount of internalized receptors (Liu et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

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Distinction between surmountable and insurmountable selective AT₁ receptor antagonists by use of CHO‐K1 cells expressing human angiotensin II AT₁ receptors

Vanderheyden¹,

Fierens²,

Backer³

et al. 1999

British J Pharmacology

146

106

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1 CHO-K1 cells that were stably transfected with the gene for the human AT 1 receptor (CHO-AT 1 cells) were used for pharmacological studies of non-peptide AT 1 receptor antagonists. 2 In the presence of 10 mM LiCl, angiotensin II caused a concentration-dependent and long-lasting increase of inositol phosphates accumulation with an EC 50 of 3.4 nM. No angiotensin II responses are seen in wild-type CHO-K1 cells. 5 Preincubation with the insurmountable antagonist candesartan decreased the maximal angiotensin II induced inositol phosphate accumulation up to 94% and, concomitantly, decreased the maximal binding capacity of the cell surface receptors. These inhibitory e ects were halfmaximal for 0.6 nM candesartan and were attenuated by simultaneous preincubation with 1 mM losartan indicating a syntopic action of both antagonists. 6 Losartan caused a parallel rightward shift of the angiotensin II concentration-response curves and did not a ect the maximal binding capacity. EXP3174 (the active metabolite of losartan) and irbesartan showed a mixed-type behavior in both functional and binding studies. 7 Reversal of the inhibitory e ect was slower for candesartan as compared with EXP3174 and irbesartan and it was almost instantaneous for losartan, suggesting that the insurmountable nature of selective AT 1 receptor antagonists in functional studies was related to their long-lasting inhibition.

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Section: Discussionsupporting

confidence: 64%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Distinction between surmountable and insurmountable selective AT₁ receptor antagonists by use of CHO‐K1 cells expressing human angiotensin II AT₁ receptors

Vanderheyden¹,

Fierens²,

Backer³

et al. 1999

British J Pharmacology

146

106

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“…The extent by which these antagonists depress the maximal response to Ang II is highly variable; it is almost complete for candesartan, but only partial for other antagonists such as irbesartan, valsartan and EXP3174 (the active metabolite of losartan). [9][10][11][12][13] Several theories have been proposed to explain the differences in behaviour of the AIIAs at the molecular level. These include noncompetitive antagonist action owing to the presence of allosteric antagonist binding sites on the receptor, 14 antagonist-mediated conformational changes of the receptor that render them refractory to stimulation, 15,16 slow dissociation of the antagonist-receptor complex or even irreversible antagonist binding, [17][18][19][20][21][22][23] slow removal of the antagonist from tissue compartments, cells or matrix surrounding the receptor, 24,25 co-existence of different receptor subpopulations, 7 and the ability of the antagonist to affect the internalisation of AT 1 -receptors within the cell.…”

Section: Introductionmentioning

confidence: 99%

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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“…The molecular basis for insurmountable antagonism is still a matter of debate and several potential mechanisms have been proposed including the presence of allosteric binding sites on the AT1 receptor Wienen et al, 1992), a possible modification of the receptor or change in its conformation (De Chaffoy de Courcelles et al, 1986;Robertson et al, 1994), two antagonist-induced receptor states with fast and slow dissociation (Fierens et al, 1999b), the slow removal of the antagonist from tissue compartments, cells, or matrices surrounding the receptor (Panek et al, 1995), the coexistence of different subtypes of the AT1 receptor, or the ability of antagonists to modulate the amount of internalized receptors (Liu et al, 1992). Recently increasing evidence has been provided suggesting that a slow dissociation from the receptor resulting in an increased longevity of the antagonist-receptor complex is one of the leading mechanism of the insurmountable characteristic of angiotensin II receptor antagonists (Fierens et al, 1999a;Vanderheyden et al, 2000a,b).…”

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confidence: 99%

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

Maillard¹,

Perregaux²,

Centeno³

et al. 2002

J Pharmacol Exp Ther

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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.

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Evidence that the apparent complexity of receptor antagonism by angiotensin II analogues is due to a reversible and syntopic action

Cited by 66 publications

References 27 publications

Distinction between surmountable and insurmountable selective AT₁ receptor antagonists by use of CHO‐K1 cells expressing human angiotensin II AT₁ receptors

Distinction between surmountable and insurmountable selective AT₁ receptor antagonists by use of CHO‐K1 cells expressing human angiotensin II AT₁ receptors

Distinctions between non-peptide angiotensin II AT1-receptor antagonists

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

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Evidence that the apparent complexity of receptor antagonism by angiotensin II analogues is due to a reversible and syntopic action

Cited by 66 publications

References 27 publications

Distinction between surmountable and insurmountable selective AT1 receptor antagonists by use of CHO‐K1 cells expressing human angiotensin II AT1 receptors

Distinction between surmountable and insurmountable selective AT1 receptor antagonists by use of CHO‐K1 cells expressing human angiotensin II AT1 receptors

Distinctions between non-peptide angiotensin II AT1-receptor antagonists

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

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Product

Resources

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Distinction between surmountable and insurmountable selective AT₁ receptor antagonists by use of CHO‐K1 cells expressing human angiotensin II AT₁ receptors

Distinction between surmountable and insurmountable selective AT₁ receptor antagonists by use of CHO‐K1 cells expressing human angiotensin II AT₁ receptors