Effect of ACE inhibitors and angiotensin II type 1 receptor antagonists on endothelial NO synthase knockout mice with heart failure.
The beneficial effects of ACE inhibitors (ACEi) or angiotensin II type 1 receptor antagonists (AT(1)-ant) are reportedly mediated by NO in heart failure (HF). We hypothesized that in the absence of endothelial NO synthase (eNOS), (1) left ventricular (LV) dysfunction and myocardial remodeling would be more severe after myocardial infarction (MI), and (2) the cardioprotective effect of ACEi and AT(1)-ant would be diminished or absent in mice with HF after MI. eNOS knockout mice (eNOS-/-) and wild-type C57BL/6J (C57) mice (+/+) were subjected to MI by ligating the left coronary artery. One month after MI, each strain was treated with vehicle, ACEi (enalapril, 20 mg/kg per day), or AT(1)-ant (valsartan, 50 mg/kg per day) for 5 months. Echocardiography was performed, and systolic blood pressure was measured before MI and monthly thereafter. Interstitial collagen fraction and myocyte cross-sectional area were examined histologically. We found that (1) compared with C57 mice, eNOS-/- mice that underwent sham surgery had significantly increased systolic blood pressure (P<0.05) and increased LV mass both initially and at 1 to 3 months, although cardiac function and histological findings did not differ between strains; (2) the development of HF and myocardial remodeling were similar after MI in both strains; and (3) ACEi improved cardiac function and remodeling in C57 mice, as evidenced by increased LV ejection fraction (LVEF) and LV shortening fraction (LVSF) and decreased diastolic LV dimension, mass, myocyte cross-sectional area, and interstitial collagen fraction, but these benefits were absent or diminished in eNOS-/- mice (for C57 versus eNOS-/-: increase in LVEF after ACEi, 14.2 +/- 2% versus -4.9 +/- 2.5%, respectively [P<0.001]; increase in LVSF, 8.6 +/- 2.1% versus -7.2 +/- 2.8%, respectively [P<0.01]; and decrease in LV mass, -16.6 +/- 15 versus 73 +/- 23 mm(3), respectively [P<0.01]). AT(1)-ant had benefits similar to those of ACEi, which were also absent or diminished in eNOS-/- mice (for C57 versus eNOS-/-: increase in LVEF after AT(1)-ant, 13.5 +/- 1.8% versus -9.8 +/- 3%, respectively [P<0.001]; increase in LVSF, 6.1 +/- 1.6% versus -3.8 +/- 3.1%, respectively [P<0.01]). Our data suggest that the absence of NO does not alter the development of HF after MI; however, it significantly decreases the cardioprotective effects of ACEi or AT(1)-ant.
Liu
Yun-He
YH
Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI 48202-2689, USA.
Xu
Jiang
J
Yang
Xiao-Ping
XP
Yang
Fang
F
Shesely
Edward
E
Carretero
Oscar A
OA
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D004195:Disease Models, Animal; D005355:Fibrosis; D006333:Heart Failure / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000150:complications; D009206:Myocardium / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D020011:Protective Agents / Q000627:therapeutic use; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000235:genetics; D020257:Ventricular Remodeling / Q000235:genetics
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D020011:Protective Agents; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse