Comparison of the Antihypertensive Effects of the New Angiotensin II(AT1) Receptor Antagonist Candesartan Cilexetil(TCV-116) and the Angiotensin Converting Enzyme Inhibitor Enalapril in Rats.

Abstract

Antihypertensive effects of an angiotensin (Ang) II receptor antagonist, candesartan cilexetil (TCV-116), were compared with those of an angiotensin converting enzyme (ACE) inhibitor, enalapril, in spontaneously hypertensive rats (SHR), 2-kidney, 1-clip hypertensive rats (2K, 1C-HR) and 1-kidney, 1-clip hypertensive rats (1K, 1C-HR). CV-11974, the active form of TCV-116, had no inhibitory activity for plasma ACE. In rats, TCV-116 inhibited the pressor responses to Ang I, Ang II, and Ang III without an effect on the bradykinin (BK)-induced depressor response. Enalapril inhibited only the Ang I-response and potentiated the BK-response. In SHR, the antihypertensive effect of TCV-116 (10 mg/kg) was larger than the maximum antihypertensive effect of enalapril and was not intensified by combination with enalapril. Administration of CV-11974 potentiated the maximum antihypertensive effect of enalapril. Although both agents reduced blood pressure in 2K, 1C-HR, only TCV-116 had a marked antihypertensive effect in 1K, 1C-HR. These findings indicate that TCV-116 is more effective than enalapril in reducing blood pressure in SHR and 1K, 1C-HR, and that the BK- and/or prostaglandin-potentiating effect of enalapril contributes little to its antihypertensive mechanism in SHR.

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

“…Such inhibition has been reported for azilsartan (Kohara et al, 1996), candesartan Wada et al, 1994Wada et al, , 1996Kohara et al, 1996;Nakano et al, 1997;Champion et al, 1998;Koike et al, 2001;Maillard et al, 2002a), eprosartan (Wang and Brooks, 1992), irbesartan Lacour et al, 1994;Christophe et al, 1995;Culman et al, 1999;Maillard et al, 2002a), losartan (Wong et al, 1990a,c; Abdelrahman (Wong et al, 1990b,d;Buhlmayer et al, 1991;Edwards et al, 1992a;Lin et al, 1992;Liu et al, 1992b;Bernhart et al, 1993;Cazaubon et al, 1993;Criscione et al, 1993;Leung et al, 1993;Noda et al, 1993;Shibouta et al, 1993;Dickinson et al, 1994;Schambye et al, 1994;Keiser et al, 1995;Mizuno et al, 1995;Hashimoto et al, 1997;Jin et al, 1997;Tamura et al, 1997a;Garcha et al, 1999;Inada et al, 1999;Maassen vandenBrink et al, 1999;Morsing et al, 1999;Balt et al, 2002;Guimarães et al, 2011;Wienen et al, 1992Wienen et al, , 1993Zhang et al, 1993…”

Angiotensin-II type 1 receptor interaction is a major regulator for liver fibrosis development in rats

“…Moreover, the serum levels of these inhibitors after administration of 8 mg/kg to rats were similar to those found in clinical practice. 13,14,27,28 The inhibitors were started 1 or 4 weeks after the pig serum treatment, which models the typical clinical situation better than the administration of the inhibitors at onset of fibrogenesis induction. Furthermore, these inhibitors were effective not only in the pig serum-induced model but also in fibrosis induced by a choline-deficient amino acid diet (data not shown).…”

“…13,14 We also examined the effect of PE and CA on the on-going fibrosis model. Four weeks after the pig serum injection, the animals in G4 and G5 started to receive PE and CA in the same way as G2 and G3.…”

Involvement of Angiotensin II and Reactive Oxygen Species in Pancreatic Fibrosis

“…The main angiotensin II receptors are G protein-coupled receptors designated as AT1R and AT2R. The balance of AT1R and AT2R expression is an important pathological factor [24]. Angiotensin II upregulates AT1R and AT2R expression in stellate cells, suggesting that angiotensin II establishes a positive feedback loop in RAS.…”