Pulmonary vascular iNOS induction participates in the onset of chronic hypoxic pulmonary hypertension
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
16113050
DOI
10.1152/ajplung.00023.2005
PII: 00023.2005
Knihovny.cz E-resources
- MeSH
- Administration, Oral MeSH
- Pulmonary Artery enzymology MeSH
- Time Factors MeSH
- Chronic Disease MeSH
- Hypoxia complications enzymology metabolism physiopathology MeSH
- Enzyme Inhibitors administration & dosage pharmacology MeSH
- Rats MeSH
- Lysine administration & dosage analogs & derivatives pharmacology MeSH
- NG-Nitroarginine Methyl Ester pharmacology MeSH
- Nitric Oxide MeSH
- Lung metabolism MeSH
- Hypertension, Pulmonary etiology physiopathology MeSH
- Rats, Wistar MeSH
- Nitric Oxide Synthase Type II antagonists & inhibitors biosynthesis MeSH
- Tyrosine analogs & derivatives metabolism MeSH
- Exhalation MeSH
- Dose-Response Relationship, Drug MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 3-nitrotyrosine MeSH Browser
- Enzyme Inhibitors MeSH
- Lysine MeSH
- N(6)-(1-iminoethyl)lysine MeSH Browser
- NG-Nitroarginine Methyl Ester MeSH
- Nitric Oxide MeSH
- Nitric Oxide Synthase Type II MeSH
- Tyrosine MeSH
Pathogenesis of hypoxic pulmonary hypertension is initiated by oxidative injury to the pulmonary vascular wall. Because nitric oxide (NO) can contribute to oxidative stress and because the inducible isoform of NO synthase (iNOS) is often upregulated in association with tissue injury, we hypothesized that iNOS-derived NO participates in the pulmonary vascular wall injury at the onset of hypoxic pulmonary hypertension. An effective and selective dose of an iNOS inhibitor, L-N6-(1-iminoethyl)lysine (L-NIL), for chronic peroral treatment was first determined (8 mg/l in drinking water) by measuring exhaled NO concentration and systemic arterial pressure after LPS injection under ketamine+xylazine anesthesia. A separate batch of rats was then exposed to hypoxia (10% O2) and given L-NIL or a nonselective inhibitor of all NO synthases, N(G)-nitro-L-arginine methyl ester (L-NAME, 500 mg/l), in drinking water. Both inhibitors, applied just before and during 1-wk hypoxia, equally reduced pulmonary arterial pressure (PAP) measured under ketamine+xylazine anesthesia. If hypoxia continued for 2 more wk after L-NIL treatment was discontinued, PAP was still lower than in untreated hypoxic controls. Immunostaining of lung vessels showed negligible iNOS presence in control rats, striking iNOS expression after 4 days of hypoxia, and return of iNOS immunostaining toward normally low levels after 20 days of hypoxia. Lung NO production, measured as NO concentration in exhaled air, was markedly elevated as early as on the first day of hypoxia. We conclude that transient iNOS induction in the pulmonary vascular wall at the beginning of chronic hypoxia participates in the pathogenesis of pulmonary hypertension.
References provided by Crossref.org
Hypoxia-inducible factors activator, roxadustat, increases pulmonary vascular resistance in rats
