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Acute inflammatory response to lipopolysaccharide (LPS) exposure is typically associated with cardiac myocyte apoptosis, which is difficult to quantify because of heart tissue specificity. We report here that radioiodinated Annexin V (123, 125I-AnxV), a specific ligand of phosphatidylserine exposed by apoptotic cells, allows tissue detection of apoptosis in LPS-treated rat hearts. Heart 123I-AnxV uptake was significantly increased in all cardiac territories of LPS-treated rats. In contrast, 123I-human serum albumin myocardial uptake was only slightly increased in LPS-treated rat hearts, suggesting limited changes in vascular protein permeability. Autoradiography of endotoxin-treated rat heart sections with 125I-AnxV in association with deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling and caspase 3 staining allows identification of double positive cardiac myocytes. Inhibition of apoptosis by caspase inhibitors (i.e., ZVAD.fmk and DEVD.cmk) reduced 123I-AnxV myocardial uptake in LPS-treated rats. Eventually, endotoxin-treated rats displayed pathological uptake of 99mTc-annexin in the cardiac mediastinal region whereas zVAD.fmk reduced 99mTc-annexin mediastinal uptake. Our results show that radioactive 123I-AnxV signal emerging from LPS-treated rat hearts could be related to the activation of caspase-dependent apoptotic pathway in cardiac myocytes.