The eNOS enhancer AVE 9488: a novel cardioprotectant against ischemia reperfusion injury.
Nitric oxide (NO) is an important regulator of vascular and myocardial function. Cardiac ischemia/reperfusion injury is reduced in mice overexpressing endothelial NO synthase (eNOS) suggesting cardioprotection by eNOS. Novel pharmacological substances, so called eNOS enhancers, upregulate eNOS expression and thereby increase NO production. We tested the effects of the eNOS enhancer AVE 9488 on cardiac ischemia/reperfusion injury in vivo in mice. After treatment with the eNOS enhancer AVE 9488 (30 mg/kg/day) or placebo for one week mice underwent 30 min of coronary artery ligation and 24 h of reperfusion in vivo. Ischemia-reperfusion damage was significantly reduced in mice treated with the eNOS enhancer when compared to placebo treated mice (infarct/area at risk 65.4 +/- 4.1 vs. 36.9 +/- 4.0%, placebo vs. eNOS enhancer, P = 0.0002). The protective effect was blunted in eNOS knockout mice treated with the eNOS enhancer (infarct/area at risk 64.1 +/- 6.2%, eNOS knockout + eNOS enhancer vs. WT + eNOS enhancer, P = ns). Reactive oxygen species were significantly reduced in mice treated with the eNOS enhancer as indicated by significantly lower malondialdehyde-thiobarbituric acid levels (placebo vs. eNOS enhancer, 3.2 +/- 0.5 vs. 0.8 +/- 0.07 micromol/l, P = 0.0003). Thus pharmacological interventions addressed to increase eNOS-derived NO production constitute a promising therapeutic approach to prevent myocardial ischemia/reperfusion injury.
Frantz
S
S
Medizinische Klinik und Poliklinik I, Universitätsklinikum Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany. Frantz_S@medizin.uni-wuerzburg.de
Adamek
A
A
Fraccarollo
D
D
Tillmanns
J
J
Widder
J D
JD
Dienesch
C
C
Schäfer
A
A
Podolskaya
A
A
Held
M
M
Ruetten
H
H
Ertl
G
G
Bauersachs
J
J
D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D015854:Up-Regulation; D000098662:Vasodilator-Stimulated Phosphoprotein
C528454:4-fluoro-N-indan-2-yl-benzamide; D001549:Benzamides; D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D000098662:Vasodilator-Stimulated Phosphoprotein; D052250:Nitric Oxide Synthase Type III