title: Hypoxic exposure time dependently modulates endothelin-induced contraction of pulmonary artery smooth muscle.
abstract: Endothelins (ETs) have been implicated in the pathogenesis of hypoxia-induced pulmonary hypertension. We determined whether hypoxic exposure of rats (10% O2-90% N2, 1 atm, 1-48 days) altered contraction to ET in isolated segments of endothelium-denuded extralobar branch pulmonary artery (PA) and aorta. Hypoxic exposure increased hematocrit, right ventricular hypertrophy, and ET-1 plasma concentration. Hypoxia also caused a sustained decrease in PA but not in aorta sensitivity to ET-1. In comparison, hypoxic exposure throughout 12 days decreased time dependently the maximum contraction of PA to ET-1, BaCl2, and KCl. The hypoxia-induced decrease in maximum contraction of PA to ET-1 returned toward normal levels by 21 days and approximated control levels by 48 days. After 14 days of hypoxia, right ventricular hypertrophy correlated with decreased sensitivity of PA to ET-1. After 21 days of hypoxia, PA sensitivity to ET-2 and ET-3 was decreased, and sarafotoxin S6c-induced contraction was abolished. In conclusion, hypoxic exposure time dependently modulates the responsiveness of PA smooth muscle to ETs, BaCl2, and KCl. The hypoxia-induced changes in tissue responsiveness to ET-1 may be associated with increased plasma concentrations of this peptide.
authors.affiliation: Respiratory, Inflammatory, and Neurological Diseases Research Section, Zeneca Pharmaceuticals, Zeneca, Inc., Wilmington, Delaware 19850-5437, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Bialecki
authors.forename: C S
authors.initials: CS
authors.lastname: Fisher
authors.forename: W W
authors.initials: WW
authors.lastname: Murdoch
authors.forename: H G
authors.initials: HG
authors.lastname: Barthlow
authors.forename: R B
authors.initials: RB
authors.lastname: Stow
authors.forename: M
authors.initials: M
authors.lastname: Mallamaci
authors.forename: W
authors.initials: W
authors.lastname: Rumsey
mesh_terms: D000818:Animals; D016232:Endothelins / Q000494:pharmacology*; D000860:Hypoxia / Q000503:physiopathology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000503:physiopathology*; D011651:Pulmonary Artery / Q000187:drug effects* / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014661:Vasoconstriction / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology
chemical_list: D016232:Endothelins; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6