Effects of nicorandil on monocrotaline-induced pulmonary arterial hypertension in rats.
We investigated whether nicorandil might prevent and reverse monocrotaline (MCT)-induced pulmonary arterial hypertension. Rats were injected with 50 mg/kg of MCT subcutaneously and randomized to either 7.5 mg/kg/d of nicorandil in drinking water or placebo for 3 weeks. Animals that were treated with MCT and survived for 3 weeks were assigned to either nicorandil or placebo. Nicorandil markedly attenuated pulmonary arterial hypertension with severe structural remodeling of the pulmonary vessels. The survival rate at 3 weeks after treatment was significantly increased in the nicorandil group compared with the placebo group (73% versus 39%, P<0.05). In the placebo group, endothelial nitric oxide synthase (eNOS) protein was significantly decreased, the numbers of the CD45-positive cells and those of the proliferating cell nuclear antigen-positive cells were increased in the lung tissue, and P-selectin was intensely expressed on the endothelium of the pulmonary arteries. These features were prevented by nicorandil. Late treatment with nicorandil did not palliate established pulmonary arterial hypertension nor improved survival. Thus, nicorandil inhibited development of MCT-induced pulmonary arterial hypertension but failed to reverse it. These effects were associated with marked up-regulation of diminished lung eNOS protein along with improvement of pulmonary vascular endothelial activation and anti-inflammatory and anti-proliferative effects in the lung tissue.
Hongo
Minoru
M
Department of Cardiovascular Medicine, Shinshu University School of Health Sciences, Matsumoto, Japan. hongo@hsp.md.shinshu-u.ac.jp
Mawatari
Eiichiro
E
Sakai
Akio
A
Ruan
Zonghai
Z
Koizumi
Tomonobu
T
Terasawa
Fumiko
F
Yazaki
Yoshikazu
Y
Kinoshita
Osamu
O
Ikeda
Uichi
U
Shibamoto
Toshishige
T
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005500:Follow-Up Studies; D006339:Heart Rate / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D007150:Immunohistochemistry; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008297:Male; D016686:Monocrotaline; D020108:Nicorandil / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D019007:P-Selectin / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D014665:Vasodilator Agents / Q000494:pharmacology*
D000959:Antihypertensive Agents; D015415:Biomarkers; D019007:P-Selectin; D018809:Proliferating Cell Nuclear Antigen; D014665:Vasodilator Agents; D020108:Nicorandil; D016686:Monocrotaline; D019001:Nitric Oxide Synthase; D017493:Leukocyte Common Antigens