Pharmacological Profiles of a Novel Non-peptide Angiotensin II Type I Receptor Antagonist HR720 In Vitro and In Vivo

Abstract

ABSTRACT-The pharmacological properties of 2-butyl-4-(methylthio)-1- [[2 [[[(propylamino)carbonyl] amino] sulfonyl](1,1 biphenyl)-4-yl]methyl]-1H-imidazole-5-carboxylate (HR720), a novel non-peptide angiotensin (Ang) II type I (AT1) receptor antagonist, were characterized in both in vitro and in vivo systems. In vitro autoradiography using 125I-[Sar1,IIe8]Ang II as a ligand revealed that HR720 competitively inhibited the specific binding of the ligand to the adrenal cortex. The IC50 value for the adrenal cortex was 1.5 x 10-8 M, and the IC50 for medulla was 1.4 x 10-6 M. Similar results were obtained in the adrenal cortex with CV-11974, a known potent AT1-receptor antagonist. Since AT1 receptors are known to predominate in the adrenal cortex and AT2-receptors in the adrenal medulla, it is considered that HR720 is highly selective for AT, receptors. HR720 inhibited the Ang II-induced contraction of isolated rabbit aortic strips and hu man gastroepiploic arteries in a noncompetitive manner, pD'2=9.40 and 9.62 for rabbit aorta and human artery, respectively. With CV-11974, pD'2 values of 9.84 in isolated rabbit aorta and 10.00 in human artery were obtained. HR720 did not affect the norepinephrine-, serotonin or KCl-induced contraction even at a concentration of 1 x 10-5 M. In anesthetized hamsters, HR720 induced a dose-dependent inhibition of the pressure response to Ang II. The potency of HR720 to antagonize the Ang II-induced pressure response was similar to that of CV-11974. These results demonstrate that HR720 is a potent and selective AT1 -receptor antagonist. Keywords:Renin-angiotensin system, Angiotensin II, Receptor, Antagonist, Isolated vesselThe renin-angiotensin system (RAS) plays a critical role in blood pressure regulation and in fluid and electrolytes homeostasis; it is also involved in the pathogenesis of many cardiovascular diseases (1, 2). The RAS consists of a cascade of enzymatic reactions leading to formation of angiotensin (Ang) II which is a powerful vasoconstrictor. The angiotensin converting enzyme (ACE) inhibitors have clearly demonstrated the beneficial effect of pharmacological inhibition of the RAS in the treatment of hypertension and congestive heart failure (3). Recent studies have suggested that ACE inhibitors effectively prevented the progression of atherosclerosis in high cholesterol loaded rabbit aorta (4, 5) and inhibited the progression of renal damage in the rat model of chronic renal failure (6, 7), indicating the involvement of Ang II in such pathological disorders. However, there are many reports on the unwanted side effects of ACE inhibitors such as cough and angioedema resulting from the lack of * To whom correspondence should be addressed .specificity of ACE inhibitors for Ang I (8, 9). Moreover, ACE inhibitors interfere with the kinin metabolism (10). Recent studies have demonstrated that Ang II can also be formed in non-ACE-dependent manner in several species of animals including humans (11-13). In view of these limitations of ACE inhibitors, selective blocking of Ang I...

A Systematic Comparison of the Properties of Clinically Used Angiotensin II Type 1 Receptor Antagonists

“…On the basis of these studies, the various ARBs appear to have the following affinity estimates (pK i or pIC 50 ; median with 95% confidence intervals) at mammalian AT1R: azilsartan (8.51; 4.71-10.94; n = 3), candesartan (8.43; 8.01-8.80; n = 26), eprosartan (8.26; 8.02-8.58; n = 12), irbesartan (8.72; 8.42-8.87; n = 14), losartan (7.71; 7.50-7.73; n = 63), EXP3174 (8.17;; n = 21), olmesartan (8.17; 7.99-8.60; n = 5), telmisartan (8.33; 8.12-8.53; n = 14), and valsartan (8.46; 7.95-8.48; n = 17). ARB affinity estimates based on quantitative autoradiography have yielded similar results (Jin et al, 1997). Affinity estimates based on association and dissociation rate constants yielded similar values as in the competition binding studies, e.g., for candesartan and telmisartan Maillard et al, 2002a).…”

“…Most of this work has been carried out in isolated blood vessels. The vast majority of in vitro studies on ARB effects on ANG-induced vasoconstriction has been performed with isolated rabbit aorta, but some findings have also been reported, e.g., for rat aorta , rat portal vein (Zhang et al, 1993;Morsing et al, 1999), guinea pig aorta (Mizuno et al, 1995;Hashimoto et al, 1997), rabbit mesenteric artery , dog pulmonary artery (Guimarães et al, 2011), pig and human coronary artery (Maassen vandenBrink et al, 1999), or human gastroepiploic artery (Jin et al, 1997) or human subcutaneous microvessels (Garcha et al, 1999); data with compounds that have been tested in multiple preparations indicate that the antagonist potency of a given ARB is comparable across species and vascular beds. On the basis of these studies the various ARBs appear to have the following affinity estimates (pA 2 for surmountable or pD 2 for insurmountable ARBs; median with 95% confidence intervals) at mammalian vascular AT1R ( Fig.…”

Reduction of Vascular Noradrenaline Sensitivity by AT 1 Antagonists Depends on Functional Sympathetic Innervation

“…This exclusive role of sympathetic innervation in determining the vascular response to exogenous noradrenaline provides an explanation why a similar influence of AT 1 receptors has not been observed in most isolated vascular preparations. [25][26][27] Third, Ang II is known to facilitate the release of endogenous noradrenaline by activation of presynaptic AT 1 receptors. 5,6 Because the total postsynaptic availability of noradrenaline results from both, endogenous release and exogenous application, it is feasible that suppression of facilitation by AT 1 blockade increases the dose requirement of infused noradrenaline to maintain equivalent vascular responses.…”

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“…4), now named as fonsartan, has a sulfonylurea replacement for the tetrazole moiety and 4-alkylthio substituent at imidazole ring. It is highly potent (10 times more potent than losartan) and selective noncompetitive AT 1 antagonist in isolated rabbit aorta and human gastroepiploic arteries 13 . …”