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© 2005 by the American Institute of Ultrasound in Medicine
J Ultrasound Med 24:967-974 • 0278-4297

The Effects of Levovist and DD-723 in Activating Platelets and Damaging Hepatic Cells of Rats

Kouichirou Shigeta, MD, PhD, Kouichi Itoh, MD, PhD, Shigeo Ookawara, MD, PhD, Nobuyuki Taniguchi, MD, PhD and Kiyoka Omoto, MD, PhD

Departments of Clinical Laboratory Medicine (K.S., K.I., N.T., K.O.) and Anatomy (S.O.), Jichi Medical School, Tochigi-ken, Japan.

Address correspondence to Kouichirou Shigeta, MD, PhD, 3311 Yakushiji, Minamikawachi-machi, Kawachi-gun, Tochigi-ken 329-0498, Japan. E-mail: shigeta{at}jichi.ac.jp

Objective. The purpose of this study was to compare platelet activation and hepatic cell damage produced by 2 ultrasonographic contrast agents with flow cytometric and ultrastructural analysis. Methods. Suspension samples were made by mixing Levovist (SH U508A; Schering AG, Berlin, Germany) or DD-723 (Nycomed; Amersham Health, Princeton, NJ) with whole blood. The final concentrations of Levovist in citrated whole blood were 0, 15, and 75 mg/mL, and those of DD-723 were 0, 5, and 50 µL/mL. After exposure to ultrasound in vitro, flow cytometric analysis was performed to determine the concentration of the CD62P activation-specific antigen. To compare the hepatic cell damage associated with these 2 agents, we divided 15 rats into 5 groups as follows: group 1, sham operation; group 2, Levovist injection only; group 3, DD-723 injection only; group 4, Levovist injection (contrast agent) and ultrasound exposure; and group 5, DD-723 injection and ultrasound exposure. The ultrasonographic contrast agents Levovist and DD-723 were administered through the femoral vein and sonicated continuously for the first minute; this was followed by sweeping for 5 minutes 10 seconds after the contrast agent was injected. The rats were perfused via the heart with a fixative solution immediately after the sweeping, and then the liver was excised; the specimens were studied with electron and light microscopy. Results. The percentage of CD62P-expressing platelets increased in both contrast agent-ultrasound exposure groups, and the percentage of CD62P-expressing platelets was greater in the Levovist group. We observed vacuolation and round deposits in the hepatocytes in both contrast agent-ultrasound exposure groups. Microbubbles were observed in the rat Kupffer cells, and a few hepatocytes were seen unexpectedly in the DD-723 group but were found in neither the Kupffer cells nor the hepatocytes in the Levovist group. Conclusions. Both contrast agents, Levovist and DD-723, produced platelet activation and structural change in the rat hepatic cells, but only the microbubbles of DD-723 were taken up by the Kupffer cells and a few hepatocytes.

Key Words: hepatocyte • Kupffer cell • platelet activation • rat • safety • ultrasonographic contrast agent • ultrasound

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Copyright © 2005 by the American Institute of Ultrasound in Medicine.