C-type natriuretic peptide ameliorates monocrotaline-induced pulmonary hypertension in rats.
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.
Itoh
Takefumi
T
Department of Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
Nagaya
Noritoshi
N
Murakami
Shinsuke
S
Fujii
Takafumi
T
Iwase
Takashi
T
Ishibashi-Ueda
Hatsue
H
Yutani
Chikao
C
Yamagishi
Masakazu
M
Kimura
Hiroshi
H
Kangawa
Kenji
K
D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D005342:Fibrinolysis / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000628:therapy*; D007279:Injections, Subcutaneous; D008297:Male; D023421:Models, Animal; D016686:Monocrotaline / Q000009:adverse effects; D020098:Natriuretic Peptide, C-Type / Q000008:administration & dosage*; D011651:Pulmonary Artery / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D020545:Respiratory Mucosa / Q000187:drug effects*; D016019:Survival Analysis; D014118:Toxins, Biological / Q000009:adverse effects; D016896:Treatment Outcome
D000959:Antihypertensive Agents; D014118:Toxins, Biological; D020098:Natriuretic Peptide, C-Type; D016686:Monocrotaline