title: Pulmonary vascular iNOS induction participates in the onset of chronic hypoxic pulmonary hypertension.
abstract: 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.
authors.affiliation: Department of Physiology, Charles University Second Medical School, Plzenska 130/221, 150 00 Prague 5, Czech Republic. vaclav.hampl@lf2.cuni.cz
authors.forename: Václav
authors.initials: V
authors.lastname: Hampl
authors.forename: Jana
authors.initials: J
authors.lastname: Bíbová
authors.forename: Alena
authors.initials: A
authors.lastname: Banasová
authors.forename: Jirí
authors.initials: J
authors.lastname: Uhlík
authors.forename: Dana
authors.initials: D
authors.lastname: Miková
authors.forename: Olga
authors.initials: O
authors.lastname: Hnilicková
authors.forename: Vera
authors.initials: V
authors.lastname: Lachmanová
authors.forename: Jan
authors.initials: J
authors.lastname: Herget
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D045853:Exhalation; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications* / Q000201:enzymology* / Q000378:metabolism / Q000503:physiopathology; D008168:Lung / Q000378:metabolism; D008239:Lysine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D011651:Pulmonary Artery / Q000201:enzymology*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; C090663:N(6)-(1-iminoethyl)lysine; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D052247:Nitric Oxide Synthase Type II; D008239:Lysine; D019331:NG-Nitroarginine Methyl Ester