From the First Department of Internal Medicine, Fukushima Medical
College, Hikarigaoka 1, Fukushima 960–12, Japan.
Correspondence to Yukio Maruyama, MD, Professor and Chairman, First Department of Internal Medicine, Fukushima Medical College, Hikarigaoka 1, Fukushima, 960–12, Japan. E-mail yaoita{at}cc.fmu.ac.jp
Background—Z-Val-Ala-Asp(OMe)-CH2F
(ZVAD-fmk), a tripeptide inhibitor of the caspase
interleukin-1ß–converting enzyme family of cysteine proteases, may
reduce myocardial reperfusion injury in vivo by attenuating
cardiomyocyte apoptosis within the ischemic
area at risk.
Methods and Results—Sprague-Dawley rats were subjected to a
30-minute coronary occlusion followed by a 24-hour reperfusion.
An inert vehicle (dimethylsulfoxide; group 1, n=8) or ZVAD-fmk, at a
total dose of 3.3 mg/kg (group 2, n=8), was administered
intravenously every 6 hours starting at 30 minutes before
coronary occlusion until 24 hours of reperfusion. At this
24-hour point, hemodynamics were assessed by means of
cardiac catheterization; then, the rats were killed,
and the left ventricle was excised and sliced. The myocardial infarct
size/ischemic area at risk and the count of presumed
apoptotic cardiomyocytes (terminal
deoxynucleotidyl transferase–mediated dUTP-biotin
nick end labeling [TUNEL]-positive cells) within the ischemic
area at risk were assessed through
triphenyltetrazolium chloride staining and
TUNEL methods, respectively. Peak positive left ventricular
dP/dt was higher (P=.02) and left
ventricular end-diastolic pressure was lower
(P=.04) in group 2 than in group 1. The infarct
size/ischemic area at risk of group 2 (52.4±4.0%) was smaller
(P=.02) than that of group 1 (66.6±3.7%), and
TUNEL-positive cells were fewer (P=.0002) (group 2,
3.1±0.9%; group 1, 11.1±1.0%). Agarose gel electrophoresis revealed
DNA laddering in the border zone myocardium of group 1, but
DNA ladder formation was attenuated in group 2.
Conclusions—ZVAD-fmk was effective in reducing myocardial
reperfusion injury, which could at least be partially attributed to the
attenuation of cardiomyocyte apoptosis.
© 1998 American Heart Association, Inc.
Basic Science Reports
Attenuation of Ischemia/Reperfusion Injury in Rats by a Caspase Inhibitor
Key Words: myocardium • reperfusion • apoptosis • caspase
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