AT1 receptor antagonist therapy preferentially ameliorated right ventricular function and phenotype during the early phase of remodeling post-MI.
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.
Nguyen
Quang T
QT
Toronto General Hospital, Toronto, Ontario, Canada.
Colombo
Federico
F
Clement
Robert
R
Gosselin
Hugues
H
Rouleau
Jean-Lucien
JL
Calderone
Angelino
A
D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D000077405:Irbesartan; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism; D010641:Phenotype; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D016278:Ventricular Function, Right / Q000187:drug effects / Q000502:physiology*; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology*
D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D000077405:Irbesartan