Effect of an angiotensin II receptor antagonist, CV-11974, and its prodrug, TCV-116, on production of aldosterone

Wada, Takeo; Inada, Yuji; Sanada, Tsukasa; Ojima, Mami; Shibouta, Yumiko; Noda, Masakuni; Nishikawa, Kohei

doi:10.1016/0014-2999(94)90753-6

Cited by 29 publications

(13 citation statements)

References 24 publications

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“…[33][34][35][36][37] Aldosterone, the secretion of which is stimulated by AII, is also reported to directly accelerate the hypertrophy of myocardial cells as well as interstitial fibrosis. 38 Inasmuch as AII has a stimulating effect on aldosterone secretion via AT1R, 39 the alleviation of cardiac hypertrophy is thought to be the result of inhibiting both the hypertrophy of myocardial cells and interstitial fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Effects of a Subdepressor Dose of L-158,809, an Angiotensin II Type 1 Receptor Antagonist, on Cardiac Hypertrophy and Nephropathy Via the Activated Human Renin-Angiotensin System in Double Transgenic Mice With Hypertension

et al. 1998

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he Tsukuba hypertensive mouse (THM) is a hypertensive animal model prepared by introducing human renin and angiotensinogen genes into C57BL/6 mouse. 1 In THM, the cause of hypertension is known to be a single factor, an enhancement of the reninangiotensin system (RAS). In THM, angiotensin II (AII) is 3-5 times higher in serum and that in the heart and kidney is 4-5 times higher compared to C57BL/6 mice. 2 At 6 weeks of age, when blood pressure measurement becomes possible, THM already show elevated blood pressure. In THM, the occurrence of severe cardiac hypertrophy and glomerulosclerosis, in comparison with the degree of hypertension, has been reported. 3 L -158,809 [5,7-dimethyl-2-ethyl-3-[{2'-(1H-tetrazol-5-yl)is a selective AII receptor antagonist with high potency, good per os absorption, long duration and antihypertensive efficacy after a single dose equal to that of angiotensin converting enzyme inhibition, and does not have AII agonist activity. 4,5 The affinity of L-158,809 for the AII type 1 receptor (AT1R) and its potency for the inhibition of AII responses in a variety of tissues and in vitro preparations is subnanomolar (IC50=0.2-0.8 nmol/L). L-158,809 is 50-200 times more potent than losartan, an AT1R antagonist, and 5-15 times more potent than the metabolite, EXP3174. Indeed, the affinity of L-158,809 for AT1R is similar to that of the natural hormone, AII. With respect to the subtypes of AII receptors, L-158,809 has high selectivity for the AT1R, as does losartan, unlike PD-123,177 and PD-121,981, which are selective for AII type 2 receptor (AT2R). Unlike other AT1R antagonists, the inhibitory activity of L-158,809 is observed shortly after per os administration, and the duration of activity is greater than 24 h for both intravenous and per os administration. Moreover, the per os to intravenous potency ratio is 0.8. Therefore, L-158,809 is the most potent AT1R antagonist described to date.In the present study, L-158,809 was administered to THM, and its curative effects on cardiac hypertrophy and nephropathy were examined. Methods Animals and DrugsNine male THM were assigned to each of an L-158,809 dosage group (0.3 mg/kg per day) and a no-dosage group. Nine age-matched male C57BL/6 mice were used as normal controls. In the L-158,809 group, the drug was dissolved in drinking water and administered for 8weeks from the age of 20 weeks. All the mice were euthanized at 28 weeks of age. The mice were bred in an air-conditioned room at 22±2°C and humidity of 50±10%, with a 12-h light period (from 7.00 h to 19.00 h). They were fed a breeding The effects of L-158,809, an angiotensin II type 1 receptor antagonist, on cardiac hypertrophy and nephropathy were examined using Tsukuba hypertensive mice (THM) carrying both human renin and angiotensinogen genes. Nine male THM aged 20 weeks were assigned to each of a no-dosage group and an L-158,809 dosage group, and L-158,809 was administered for 8 weeks. Nine age-matched male C57BL/6 mice were used as normal control animals. At 28 weeks of age, all of the mice w...

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Section: Discussionmentioning

confidence: 99%

Inhibitory Effects of a Subdepressor Dose of L-158,809, an Angiotensin II Type 1 Receptor Antagonist, on Cardiac Hypertrophy and Nephropathy Via the Activated Human Renin-Angiotensin System in Double Transgenic Mice With Hypertension

et al. 1998

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“…These signaling responses result in acute cellular responses such as phosphorylase stimulation in hepatocytes (Garcia-Sainz et al, 1997) or hormone production and release from adrenal cells (Aguilera, 1992;Criscione et al, 1993;Wada et al, 1994). Prolonged AT1R stimulation results in protein and DNA synthesis and proliferation (Herbert et al, 1994;Sung et al, 1994;Flesch et al, 1995;Itazaki et al, 1995;VironeOddos et al, 1997;Hines et al, 1999).…”

Section: B Antagonism At Cellular Levelmentioning

confidence: 99%

“…Prolonged AT1R stimulation results in protein and DNA synthesis and proliferation (Herbert et al, 1994;Sung et al, 1994;Flesch et al, 1995;Itazaki et al, 1995;VironeOddos et al, 1997;Hines et al, 1999). Inhibition of such responses was demonstrated in cells from rat, rabbit, guinea pig, pig, cow, and human sources, including vascular smooth muscle cells (Leung et al, 1992;Herbert et al, 1994;Sung et al, 1994;Flesch et al, 1995;Itazaki et al, 1995;Virone-Oddos et al, 1997;Fortuno et al, 1999), cardiomyocytes (Delisee et al, 1993), hepatocytes (Garcia-Sainz et al, 1997) and hepatoma cell lines (Le Bourdonnec et al, 2000), renal tubule cells (Poggioli et al, 1992;Zhang and Mayeux, 2012), adrenal cells (Aguilera, 1992;Ouali et al, 1992;Criscione et al, 1993;Wada et al, 1994), ovarial cells (Pepperell et al, 1993), and various cell lines natively expressing AT1R (Crawford et al, 1992;Ransom et al, 1992) or having been transfected with them . The ARB affinity estimates obtained in functional assays at the cellular level, largely in signal transduction assays, are generally in good agreement with those determined by competition radioligand binding assays, at least for ARBs where more than two studies have been reported (candesartan 9.36, 8.23-10.00, n = 6; irbesartan 8.…”

Section: B Antagonism At Cellular Levelmentioning

confidence: 99%

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

et al. 2013

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“…13,14) The reduction of serum aldosterone levels, which were determined through angiotensin II type 1 receptor, 15) was not significant only in the TH group. We are not able to explain this result because we did not measure the concentrations of serum and tissue angiotensin II in this study.…”

Section: Discussionmentioning

confidence: 86%

Effects of Imidapril and TA-606 on Rat Dilated Cardiomyopathy After Myocarditis

et al. 2003

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SUMMARYFor the management of chronic heart failure, both angiotensin converting enzyme inhibitors (ACEI) and angiotensin II type1 receptor blockers (ARB) are useful, however, the differences between the two groups of agents are unclear. We compared the effects of long-term treatment with an ACEI (imidapril) and an ARB (TA-606) in rats that had recovered from experimental autoimmune myocarditis (EAM). Forty-two Lewis rats were immunized with porcine cardiac myosin on day 0 and divided into 6 groups, group C (distilled water), group IL (imidapril 0.5 mg/kg/day), group IH (imidapril 2 mg/kg/day), group TL (TA-606 2 mg/kg/day), group TH (TA-606 6 mg/kg/day), and group IT (imidapril 0.5 mg/kg/day + TA-606 2 mg/kg/day). Drugs were administered from day 28. Hemodynamic parameters, heart weight/body weight ratio (HW/BW), and area of fibrosis were measured on days 70-74. Only the high dose of imidapril significantly decreased central venous pressure and significantly increased maximum dP/dt and the absolute value of minimum dP/dt. HW/BW was suppressed in groups IH, TH, and IT. Thus, in treatment of chronic heart failure in rats, a sufficient dose of ACEI was needed to improve hemodynamics and to prevent ventricular hypertrophy. The hemodynamic effects of ARB and combination therapy of both drugs at low doses were not significant. (Jpn Heart J 2003; 44: 735-744)

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Effect of an angiotensin II receptor antagonist, CV-11974, and its prodrug, TCV-116, on production of aldosterone

Cited by 29 publications

References 24 publications

Inhibitory Effects of a Subdepressor Dose of L-158,809, an Angiotensin II Type 1 Receptor Antagonist, on Cardiac Hypertrophy and Nephropathy Via the Activated Human Renin-Angiotensin System in Double Transgenic Mice With Hypertension

Inhibitory Effects of a Subdepressor Dose of L-158,809, an Angiotensin II Type 1 Receptor Antagonist, on Cardiac Hypertrophy and Nephropathy Via the Activated Human Renin-Angiotensin System in Double Transgenic Mice With Hypertension

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

Effects of Imidapril and TA-606 on Rat Dilated Cardiomyopathy After Myocarditis

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