AT1 receptor antagonist therapy preferentially ameliorated right ventricular function and phenotype during the early phase of remodeling post-MI

Abstract

1. The influence of AII on contractile dysfunction, regulation of the tyrosine kinase-dependent signaling molecule extracellular signal-regulated kinase (ERK), and natriuretic peptide gene expression were examined in the noninfarcted left ventricle (NILV) and right ventricle (RV) during the early phase of remodeling post-myocardial infarct (MI) in the rat. The selective AT(1) receptor antagonist irbesartan was administered <10 h following coronary artery ligation, and rats were killed either at 4-day or 2-week post-MI. 2. At 4 days post-MI, left ventricular systolic pressure (LVSP: sham=125+/-12, MI=91+/-4 mmHg) was decreased, whereas left ventricular end-diastolic pressure (LVEDP: sham=9+/-2, MI=17+/-2 mm Hg), right ventricular systolic (RVSP: sham=26+/-1, MI=34+/-2 mm Hg), and end-diastolic pressures (RVEDP: sham=3+/-0.5, MI=7+/-1 mm Hg) were increased. ERK phosphorylation was significantly elevated in the NILV and RV. 3. Irbesartan (40 mg x kg(-1)/day(-1)) administration did not improve left ventricular function, or suppress increased ERK phosphorylation in the 4-day post-MI rat. By contrast, irbesartan therapy normalized RVSP (MI+irbesartan=25+/-1 mm Hg), RVEDP (MI+irbesartan=3+/-0.3 mm Hg), and reduced ERK1 (MI=3.0+/-0.6, MI+irbesartan=2.0+/-0.3-fold increase), and ERK2 (MI=3.8+/-0.8, MI+irbesartan=2.2+/-0.5-fold increase) phosphorylation. 4. In 2-week post-MI rats, biventricular dysfunction was associated with increased prepro-ANP, and prepro-BNP mRNA expression. Irbesartan therapy normalized RVSP, attenuated RVEDP, and abrogated natriuretic peptide mRNA expression (prepro-ANP; MI=9+/-2, MI+irbesartan=2+/-1-fold increase, prepro-BNP; MI=6+/-2, MI+irbesartan=1+/-1-fold increase), whereas both transcripts remained elevated in the NILV despite the partial attenuation of LVEDP. 5. These data suggest that the therapeutic benefit of irbesartan treatment during the early phase of remodeling post-MI was associated with the preferential amelioration of RV contractile function and phenotype.

Figure 1

Correlation between scar size and ventricular function in untreated 4-day post-MI rats. A significant correlation was observed between scar/body weight ratio and LVSP (a), LVEDP (b), and RVSP (c).

Figure 2

Right ventricular contractile function and the effect of irbesartan. RVSP and RVEDP were increased in the 4-day (a), and 2-week post-MI rats (b), and irbesartan therapy normalized RVSP, and ameliorated RVEDP. (a) Represents P<0.05 versus sham; (b) represents P<0.05 versus MI; and (n) in each group is indicated in Table 2.

Figure 3

Phosphorylation pattern of extracellular signal-regulated kinase (ERK1/2), and protein kinase B (PKB) in 4-day post-MI rats. (a) ERK and PKB-theonine³⁰⁸, and -serine⁴⁷³ phosphorylation in the NILV, and the effect of irbesartan (IRB). (b) Phosphorylation of ERK1/2 in the RV, and the effect of IRB.

Figure 4

Pattern of gene expression in the NILV and RV of the 2-week post-MI rat. (a) (NILV) The steady-state mRNA levels of prepro-ANP, and prepro-BNP were increased in the MI rat, as compared to sham. IRB therapy had no effect on natriuretic peptide mRNA levels. (b) (NILV) Fibronectin and prepro-ANP mRNA levels were increased in the MI rat, as compared to sham. Irbesartan treatment of MI rats did not alter the expression of either transcript. (c) (RV) The mRNA levels of prepro-ANP, prepro-BNP, and fibronectin were increased in the MI rat. Irbesartan therapy abrogated natriuretic peptide mRNA expression, whereas fibronectin mRNA remained elevated in the MI rat.