Hypoxic exposure time dependently modulates endothelin-induced contraction of pulmonary artery smooth muscle.
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.
Bialecki
R A
RA
Respiratory, Inflammatory, and Neurological Diseases Research Section, Zeneca Pharmaceuticals, Zeneca, Inc., Wilmington, Delaware 19850-5437, USA.
Fisher
C S
CS
Murdoch
W W
WW
Barthlow
H G
HG
Stow
R B
RB
Mallamaci
M
M
Rumsey
W
W
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
D016232:Endothelins; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6