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

Abstract

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...

The endothelin receptor antagonist ameliorates the hypertensive phenotypes of transgenic hypertensive mice with renin-angiotensin genes and discloses roles of organ specific activation of endothelin system in transgenic mice

“…However, such a remarkably increased hypertension is also due to activation of systemic and local (tissue level) RAS in THM. The previous studies have already reported that local activation of RAS is involved in tissue injuries, because subdepressor dose of an AT1 receptor antagonist prevents cardiac hypertrophy and nephropathy, suggesting that local Ang II is profoundly involved in the phenotypes (Kai et al, 1998a). Furthermore, a serum level of ET-1 in THM was not remarkably elevated compared to the control, and the acute effect of SB209670 was not observed to decrease the higher blood pressure in THM (Maki et al, 1998).…”

“…3) THM facilitated pharmacological examination aimed at investigating the role of interaction of two human gene products in BP. Therefore, THM differs greatly from spontaneously hypertensive rats, a widely used model of hypertension with an unclassified genetic background of hypertension, and also differs Ang II-infused rats, in which plasma Ang II level was markedly elevated by Ang II infusion (Herizi et al, 1998;Kai et al, 1998a); however, it remains to be examined whether tissue Ang II level is increased or not in various organs such as the heart and kidney. Therefore, it is likely that the Ang II-infused model demonstrates the action of exogenous Ang II on organs as an endocrine effect.…”

“…Therefore, it is likely that the Ang II-infused model demonstrates the action of exogenous Ang II on organs as an endocrine effect. In contrast, THM have already been shown to be in an endogenously activated RAS state with elevated plasma renin, angiotensinogen, Ang I, Ang II (Fukamizu et al, 1993) and also elevated tissue renin, angiotensinogen, Ang I and Ang II in the kidney, liver, and heart (Fukamizu et al, 1994;Kai et al, 1998a). These features are helpful for researchers to explore the complex interaction between the endogenous tissue RAS and the ET system.…”

“…It has been thought that the renal injuries are attributed to the secondary effect of sustained high BP (Bidani et al, 1994;Karlsen et al, 1997), however, it is reported that tissue RAS itself can primarily cause renal injuries. Kai et al demonstrated that administration of an AT1 receptor antagonist ameliorated renal injuries without affecting systemic BP in THM (Kai et al, 1998a), suggesting that the activated RAS in the kidney of THM primarily causes renal injuries (Kai et al, 1998a,b). Since we demonstrated that the activated RAS increased ET-2, but not ET-1, gene expression in the kidney, it is indicated that the activated RAS is also related to activation of the local ET system in the kidney of THM.…”

Effects of aging and uninephrectomy on renal changes in Tsukuba hypertensive mice

“…These animals are prone to developing hypertension (13)(14)(15). Kai et al (16,17) observed albuminuria and glomerular sclerosis in 28-week-old THM. Thus, the THM is a useful model of hypertensive nephropathy induced by overproduction of angiotensin II.…”