A novel inhibitor of inducible nitric oxide synthase, ONO-1714, does not ameliorate hypoxia-induced pulmonary hypertension in rats.
A recent study showed that long-term administration of the inducible nitric oxide synthase (iNOS) inhibitor L-NIL reduced the development of pulmonary hypertension. The purpose of the present study was to identify the effect of an another iNOS inhibitor, ONO-1714, on the development of pulmonary hypertensive vascular changes in chronic hypoxic pulmonary hypertension in rats. ONO-1714 was administered to rats exposed to hypobaric hypoxia (air at 380 mmHg) for 10 days. Muscularization of normally nonmuscular peripheral arteries and medial hypertrophy of normally muscular arteries were assessed by light microscopy. iNOS mRNA and protein levels of the lung were assessed in normal and hypoxic rats. Chronic hypoxia induced pulmonary hypertension, right ventricular hypertrophy, and hypertensive pulmonary vascular changes. Although an acute single injection of ONO-1714 induced a significant increase in mean pulmonary artery pressure in chronic hypoxic pulmonary hypertensive rats, the increase was slight and transient. There were no significant differences among rats with and without long-term administration of ONO-1714 in pulmonary artery pressure, right ventricular hypertrophy, medial wall thickness of muscular arteries, and the percentage of muscularized arteries at the alveolar wall and duct levels. Although there was a significantly increased expression of iNOS as assessed with the reverse-transcription polymerase chain reaction in rats that were exposed to 10 days of hypobaric hypoxia, we could not detect a significant level of iNOS protein by Western blotting. ONO-1714 does not have a therapeutic role in preventing the development of chronic hypoxic pulmonary hypertension.
Jiang
Bao Hua
BH
Department of Anesthesiology and Critical Care Medicine, Mie University Graduate School of Medicine, 2-174, Edobashi, Tsu, Mie, 514-8507, Japan.
Maruyama
Junko
J
Department of Physiology, Mie University Graduate School of Medicine, 2-174, Edobashi, Tsu, Mie, 514-8507, Japan.
Yokochi
Ayumu
A
Department of Anesthesiology and Critical Care Medicine, Mie University Graduate School of Medicine, 2-174, Edobashi, Tsu, Mie, 514-8507, Japan.
Mitani
Yoshihide
Y
Department of Pediatrics, Mie University Graduate School of Medicine, 2-174, Edobashi, Tsu, Mie, 514-8507, Japan.
Maruyama
Kazuo
K
Department of Anesthesiology and Critical Care Medicine, Mie University Graduate School of Medicine, 2-174, Edobashi, Tsu, Mie, 514-8507, Japan. k-maru@clin.medic.mie-u.ac.jp.
D000578:Amidines / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006400:Hematocrit; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology / Q000627:therapeutic use; D006976:Hypertension, Pulmonary / Q000150:complications / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D017380:Hypertrophy, Right Ventricular / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control; D000860:Hypoxia / Q000150:complications* / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D008168:Lung / Q000098:blood supply / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
C407360:7-chloro-3-imino-5-methyl-2-azabicyclo(4.1.0)heptane; D000578:Amidines; D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D006574:Heterocyclic Compounds, 2-Ring; D012333:RNA, Messenger; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat