Regulation of angiotensin-(1-7) and angiotensin II type 1 receptor by telmisartan and losartan in adriamycin-induced rat heart failure

Abstract

Aim: To investigate the possible effects of telmisartan and losartan on cardiac function in adriamycin (ADR)-induced heart failure in rats, and to explore the changes in plasma level of angiotensin-(1-7)[Ang-(1-7)] and myocardial expression of angiotensin II type 1/2 receptors (AT(1)R / AT(2)R) and Mas receptor caused by the two drugs.

Methods: Male Sprague-Dawley rats were randomly divided into 4 groups: the control group, ADR-treated heart failure group (ADR-HF), telmisartan plus ADR-treated group (Tel+ADR) and losartan plus ADR-treated group (Los+ADR). ADR was administrated (2.5 mg/kg, ip, 6 times in 2 weeks). The rats in the Tel+ADR and Los+ADR groups were treated orally with telmisartan (10 mg/kg daily po) and losartan (30 mg/kg daily), respectively, for 6 weeks. The plasma level of Ang-(1-7) was determined using ELISA. The mRNA and protein expression of myocardial Mas receptor, AT(1)R and AT(2)R were measured using RT-PCR and Western blotting, respectively.

Results: ADR significantly reduced the plasma level of Ang-(1-7) and the expression of myocardial Mas receptor and myocardial AT(2)R, while significantly increased the expression of myocardial AT(1)R. Treatment with telmisartan and losartan effectively increased the plasma level of Ang-(1-7) and suppressed myocardial AT(1)R expression, but did not influence the expression of Mas receptor and AT(2)R.

Conclusion: The protective effects of telmisartan and losartan in ADR-induced heart failure may be partially due to regulation of circulating Ang-(1-7) and myocardial AT(1)R expression.

Figure 1

Changes in body weight in each group of rats. Controls=With normal saline injection; ADR-HF=Adriamycin-induced heart failure rats; Tel+ADR=Telmisartan plus Adriamycin-treated rats; Los+ADR=Losartan plus Adriamycin-treated rats. Data are expressed as mean±SD. ^bP<0.05, ^cP<0.01 vs control group. ^fP<0.01 vs ADR-HF group. Control, n=10; ADR-HF, n=9; Tel+ADR, n=12; and Los+ADR, n=13.

Figure 2

Transthoracic echocardiography to evaluate the cardiac function of rats. Controls=With normal saline injection; ADR-HF=Adriamycin-induced heart failure rats; Tel+ADR=Telmisartan plus Adriamycin-treated rats; Los+ADR=Losartan plus Adriamycin-treated rats.

Figure 3

Plasma levels of angiotensin-(1–7) [Ang-(1–7)] were determined by ELISA in rats of the control, ADR-HF, Tel+ADR, and Los+ADR groups at the end of the study. Controls=With normal saline injection; ADR-HF=Adriamycin-induced heart failure rats; Tel+ADR=Telmisartan plus Adriamycin-treated rats; Los+ADR=Losartan plus Adriamycin-treated rats. Mean±SD. ^bP<0.05, ^cP<0.01 vs controls. ^eP<0.05 vs ADR-HF.

Figure 4

The mRNA expression levels of the Mas receptor (A), AT₁R (B), and AT₂R (C) in cardiac tissues at the end of the study were determined by RT-PCR. The amounts are expressed relative to the amount of β-actin. Controls=With normal saline injection; ADR-HF=Adriamycin-induced heart failure rats; Tel+ADR=Telmisartan plus Adriamycin-treated rats; Los+ADR=Losartan plus Adriamycin-treated rats. n=6. Mean±SD. ^bP<0.05, ^cP<0.01 vs control groups. ^fP<0.01 vs ADR-HF.

Figure 5

The protein expression levels of the Mas receptor (A), AT₁R (B), and AT₂R (C) in cardiac tissues at the end of the study were determined by Western blotting. Amounts of Mas, AT₁R, and AT₂R were expressed relative to the amount of GAPDH in each sample. Controls=With normal saline injection; ADR-HF=Adriamycin-induced heart failure rats; Tel+ADR=Telmisartan plus Adriamycin-treated rats; Los+ADR=Losartan plus Adriamycin- treated rats. Data are expressed as mean±SD. ^bP<0.05, ^cP<0.01 vs control group. ^fP<0.01 vs ADR-HF.