Affiliation:
1. From the First Department of Internal Medicine, Fukushima Medical College, Hikarigaoka 1, Fukushima 960–12, Japan.
Abstract
Background
—Z-Val-Ala-Asp(OMe)-CH
2
F (ZVAD-fmk), a tripeptide inhibitor of the caspase interleukin-1β–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.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Physiology (medical),Cardiology and Cardiovascular Medicine
Cited by
563 articles.
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