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Published ahead of print on August 27, 2004, doi:10.1164/rccm.200404-455OC
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American Journal of Respiratory and Critical Care Medicine Vol 170. pp. 1204-1211, (2004)
© 2004 American Thoracic Society
doi: 10.1164/rccm.200404-455OC

Original Article

C-type Natriuretic Peptide Ameliorates Monocrotaline-induced Pulmonary Hypertension in Rats

Takefumi Itoh, Noritoshi Nagaya, Shinsuke Murakami, Takafumi Fujii, Takashi Iwase, Hatsue Ishibashi-Ueda, Chikao Yutani, Masakazu Yamagishi, Hiroshi Kimura and Kenji Kangawa

Department of Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute, Osaka; Second Department of Internal Medicine, Nara Medical University, Nara; Department of Internal Medicine, National Cardiovascular Center; Department of Cardiac Physiology, National Cardiovascular Center Research Institute; Department of Pathology, National Cardiovascular Center; and Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka, Japan

Correspondence and requests for reprints should be addressed to Noritoshi Nagaya, M.D., Department of Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute, 5–7–1 Fujishirodai, Suita, Osaka 565–8565, Japan. E-mail: nagayann{at}hsp.ncvc.go.jp

C-type natriuretic peptide (CNP) has been shown to act as a local regulator of vascular tone and remodeling. We investigated whether CNP ameliorates monocrotaline (MCT)-induced pulmonary hypertension in rats. Rats received a continuous infusion of CNP or placebo. Significant pulmonary hypertension developed 3 weeks after MCT. However, infusion of CNP significantly attenuated the development of pulmonary hypertension and vascular remodeling. Neither systemic arterial pressure nor heart rate was altered. Interestingly, CNP enhanced Ki-67 expression, a marker for cell proliferation, in pulmonary endothelial cells and augmented lung tissue content of endothelial nitric oxide synthase. CNP significantly suppressed apoptosis of pulmonary endothelial cells, decreased the number of monocytes/macrophages, and inhibited expression of plasminogen activator inhibitor type 1, a marker for fibrinolysis impairment, in the lung. In addition, CNP significantly increased the survival rate in MCT rats. Finally, infusion of CNP after the establishment of pulmonary hypertension also had beneficial effects on hemodynamics and survival. In conclusion, infusion of CNP ameliorated MCT-induced pulmonary hypertension and improved survival. These beneficial effects may be mediated by regeneration of pulmonary endothelium, inhibition of endothelial cell apoptosis, and prevention of monocyte/macrophage infiltration and fibrinolysis impairment.

Key Words: monocrotaline • natriuretic peptides • pulmonary hypertension • vasoprotection




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