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Cardiovascular Research 2003 58(1):231-238; doi:10.1016/S0008-6363(02)00833-7
© 2003 by European Society of Cardiology
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Copyright © 2003, European Society of Cardiology

Potentiation of C-type natriuretic peptide with ultrasound and microbubbles to prevent neointimal formation after vascular injury in rats

Hiroto Takeuchia, Koji Ohmoria,*, Isao Kondoa, Akira Oshitaa, Kaori Shinomiyaa, Yang Yua, Yuichiro Takagia, Katsufumi Mizushigea, Kenji Kangawab and Masakazu Kohnoa

aSecond Department of Internal Medicine, Kagawa Medical University, 1750-1, Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan
bDepartment of Biochemistry, National Cardiovascular Center Research Institute, 5-7-1, Fujishirodai, Suita, Osaka 565-8565, Japan

* Corresponding author. Tel./fax: +81-87-891-2151. komori{at}kms.ac.jp

Objectives: Long-term intravenous infusion of high-dose C-type natriuretic peptide (CNP) is known to prevent neointimal formation after vascular injury. Ultrasound (US) irradiation during microbubbles (MBs) infusion (US/MBs) has been used for local delivery of bioactive agents. We examined whether short-term infusion of CNP could also inhibit neointimal development and whether combined US/MBs treatment at the beginning of the CNP infusion could enhance its effect. Methods: In the rat carotid artery-balloon injury model, the intima/media area (I/M) ratio 14 days after injury was compared among various short-term post-injury treatments. For combined US/MBs, a commercial echocardiograph (1.8 MHz, mechanical index 1.0) and albumin-coated octafluoropropane gas MBs were used. Results: Infusion of high-dose CNP (1.0 µg/kg/min) immediately after injury for only 24 h successfully reduced the I/M ratio (0.18±0.05) to 18% of the ratio in control rats (1.00±0.13) that underwent only balloon injury. Although low-dose CNP (0.1 µg/kg/min for 24 h) alone was not effective in reducing the I/M ratio (0.83±0.18), combined US/MBs treatment for the first 80 min of the infusion markedly reduced the I/M ratio (0.17±0.07), which persisted until 28 days after injury (0.16±0.04). Conclusions: The effects of CNP on the events occurring early after arterial injury may be important in preventing subsequent neointimal development. Thus, intravenous infusion of CNP with US/MBs at its initiation may provide a clinically feasible anti-restenosis therapy applicable immediately after vascular interventions.

KEYWORDS Natriuretic peptide; Receptors; Restenosis; Smooth muscle; Ultrasound


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