Antagonist effect of losartan on angiotensin II induced contraction in five isolated smooth muscle assays

doi:10.1016/0014-2999(93)90892-L

European Journal of Pharmacology

Volume 240, Issues 2–3, 24 August 1993, Pages 147-154

https://doi.org/10.1016/0014-2999(93)90892-L Get rights and content

Abstract

Antagonist effect of losartan, a nonpeptide antagonist of angiotensin II, on angiotensin II induced contractile response was studied in five isolated smooth muscle assays. In the rabbit aorta and guinea-pig stomach assays, losartan competed with angiotensin II for the angiotensin receptors in an apparently simple manner, that is compliance with the basic criteria of Schild analysis for simple competition. Noncompliance, however, was observed in the guinea-pig ileum, rat ileum and guinea-pig trachea assays where losartan induced nonparallel rightward shifts of angiotensin II E/log[A] curved and the Schild plots were found to have slopes greater than unity. The observed deviations from simple competitive antagonism appeared to be different from those reported earlier, and a possible explanation involving tissue-dependent noncompetitive factor(s) is discussed.

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Angiotensin II type 1 receptor antagonists in animal models of vascular, cardiac, metabolic and renal disease
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Citation Excerpt :
All ARBs have been tested for their quantitative ability to inhibit acute ANG-induced vasoconstriction in vitro. This work has mostly been performed in isolated rabbit aorta (Wong et al., 1990c, 1990e; Buhlmayer et al., 1991; Lin et al., 1992; Wienen et al., 1992; Edwards et al., 1992a; Liu et al., 1992b; Bernhart et al., 1993; Cazaubon et al., 1993; Criscione et al., 1993; Liu, 1993; Noda et al., 1993; Shibouta et al., 1993; Wienen et al., 1993; Dickinson et al., 1994; Schambye et al., 1994; Keiser et al., 1995; Jin et al., 1997; Ojima et al., 1997; Tamura et al., 1997a; Inada et al., 1999; Morsing et al., 1999; Ojima et al., 2011). However, antagonism of ANG-induced contraction of isolated blood vessels was also shown in many other preparations including rabbit mesenteric artery (Balt et al., 2002), rabbit renal artery (Zhang et al., 1994; Li et al., 2001), rat aorta (Inada et al., 1994; Fortuno et al., 1999), rat coronaries (Tschudi & Lüscher, 1995), rat carotid artery (Inoue et al., 1999), rat portal vein (Zhang et al., 1993c; Morsing et al., 1999), guinea pig aorta (Leung et al., 1993; Mizuno et al., 1995; Hashimoto et al., 1997), hamster aorta (Nakamura et al., 1994a; Inoue et al., 1999), dog pulmonary artery (Guimaraes et al., 2011), pig and human coronary artery (Maassen van den Brink et al., 1999) and human gastroepiploic artery (Jin et al., 1997) and human subcutaneous microvessels (Garcha et al., 1999).
We have reviewed the effects of angiotensin II type 1 receptor antagonists (ARBs) in various animal models of hypertension, atherosclerosis, cardiac function, hypertrophy and fibrosis, glucose and lipid metabolism, and renal function and morphology. Those of azilsartan and telmisartan have been included comprehensively whereas those of other ARBs have been included systematically but without intention of completeness. ARBs as a class lower blood pressure in established hypertension and prevent hypertension development in all applicable animal models except those with a markedly suppressed renin–angiotensin system; blood pressure lowering even persists for a considerable time after discontinuation of treatment. This translates into a reduced mortality, particularly in models exhibiting marked hypertension. The retrieved data on vascular, cardiac and renal function and morphology as well as on glucose and lipid metabolism are discussed to address three main questions: 1. Can ARB effects on blood vessels, heart, kidney and metabolic function be explained by blood pressure lowering alone or are they additionally directly related to blockade of the renin–angiotensin system? 2. Are they shared by other inhibitors of the renin–angiotensin system, e.g. angiotensin converting enzyme inhibitors? 3. Are some effects specific for one or more compounds within the ARB class? Taken together these data profile ARBs as a drug class with unique properties that have beneficial effects far beyond those on blood pressure reduction and, in some cases distinct from those of angiotensin converting enzyme inhibitors. The clinical relevance of angiotensin receptor-independent effects of some ARBs remains to be determined.
Synthesis and antagonistic activity of four new 2-alkyl-N-biphenyl fused imidazoles on angiotensin II receptors
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In the current study, four new 2-alkyl-N-biphenyl fused imidazoles were synthesized and the pharmacological properties of these compounds as angiotensin II antagonists were studied. First, the potency of the synthesized compounds on guinea-pig ileum was evaluated and the vasopressor effect of the most potent compound 6a was compared with losartan on isolated perfused rat kidney. The antagonistic activity of compound 6a (sodium 2-propyl-5-carbomethoxy-1-[(biphenyl-4-yl)methyl]pyrrolo[3,2-d]imidazole-2′-carboxylate) on angiotensin II receptors was greater than the other synthesized compounds and in isolated perfused rat kidney was similar to losartan.
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The presence of specific AII receptors in 6 different human neuroblastoma cell lines was investigated using binding, cAMP and [Ca²⁺]_i studies. We found high affinity (0.1 nM), low capacity ((1–2)·10³ sites/cell) binding sites for [¹²⁵I](Sar-1,Ile-8)AII in one half of the cell lines studied. In the positive cell lines mathematical modeling of multiple competition curves among AII and analogs strongly indicated the presence of a homogenous class of sites, i.e., AT₁ receptors. The presence of AT₁ receptors was further substantiated by AII-induced inhibition of VIP-stimulated cAMP levels and by AII-evoked [Ca²⁺]_i transient. The density of AT₁ receptors in neuroblastoma cells was not affected by treatment with pertussis toxin and retinoic acid but was significantly increased by subacute treatment with VIP. In neuroblastoma cells, AII does not stimulate DNA synthesis, suggesting other roles rather than mitogenesis. Neuroblastoma cells represents an interesting model to investigate the function of AII in neural crest derived tissues.
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Action of AT<inf>1</inf> receptor antagonists on angiotensin II-induced tone in human isolated subcutaneous resistance arteries
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Losartan inhibits thromboxane A<inf>2</inf>-induced platelet aggregation and vascular constriction in spontaneously hypertensive rats
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Antagonist effect of losartan on angiotensin II induced contraction in five isolated smooth muscle assays

Abstract

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Trends Pharmacol. Sci.

Trends Pharmacol. Sci.

Biochem. Biophys. Res. Commun.

Angiotensin increases inositol trisphosphate and calcium in vascular smooth muscle

Hypertension

Some quantitative uses of drug antagonists

Br. J. Pharmacol.

Pharmacological analysis of the petagastrin-tiotidine interaction in the mouse isolated stomach

Br. J. Pharmacol.

Nomenclature for angiotensin receptors. A report of the Nomenclature Committee of the Council for High Blood Pressure Research

Hypertension

Nonpeptide angiotensin II receptor antagonists. VII. Cellular and biochemical pharmacology of DuP753, an orally active antihypertensive agent

J. Pharmacol. Exp. Ther.

The antagonism of acetylcholine by atropine

J. Physiol. (London)

The zig-zag tracheal strip

J. Pharm. Pharmacol.

The action of adrenaline and ergotamine on the uterus of the rabbit

J. Physiol. (London)

The quantitative effects of antagonist drugs

J. Physiol. (London)