title: Disruption of cGMP production in pulmonary arteries isolated from fetal lambs with pulmonary hypertension.
abstract: Ligation of the ductus arteriosus of the fetal sheep produces severe pulmonary hypertension at birth. Standard tissue bath techniques were used to study third- and fourth-generation pulmonary arteries and veins isolated from fetal sheep with pulmonary hypertension created by ligation of the ductus arteriosus 11-12 days before birth as well as from age-matched control sheep. Vessels pretreated with indomethacin and propranolol were submaximally preconstricted with norepinephrine before exposure to A-23187 (10(-8) to 3 x 10(-7) M), sodium nitroprusside (SNP; 10(-9) to 10(-5) M), and nitric oxide (NO) gas (1-973 ppm). Pulmonary veins in both control and ligated animals relaxed similarly and completely to A-23187, SNP, and NO. Control pulmonary arteries relaxed by 16 +/- 2% to A-23187 and relaxed completely to SNP and NO, with concentration-response curves shifted rightward of those observed in pulmonary veins. Pulmonary arteries from ligated animals did not relax at all to A-23187. SNP relaxations in ligated arteries were shifted rightward of control. Ligated arteries relaxed by only 11 +/- 5% to the highest dose of NO. However, control and ligated pulmonary arteries relaxed similarly to 8-bromoguanosine 3',5'-cyclic monophosphate (8-bromo-cGMP; 10(-5) to 10(-3) M) and atrial natriuretic peptide (10(-9) to 10(-7) M). These data are most simply explained by decreased arterial vascular smooth muscle sensitivity to NO at the level of soluble guanylate cyclase.
authors.affiliation: Department of Pediatrics, State University of New York at Buffalo 14214, USA.
authors.forename: R H
authors.initials: RH
authors.lastname: Steinhorn
authors.forename: J A
authors.initials: JA
authors.lastname: Russell
authors.forename: F C
authors.initials: FC
authors.lastname: Morin
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000096:biosynthesis* / Q000494:pharmacology; D004373:Ductus Arteriosus; D005333:Fetus / Q000378:metabolism*; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism*; D008026:Ligation; D009569:Nitric Oxide / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000196:embryology / Q000378:metabolism*; D012756:Sheep; D014661:Vasoconstriction; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D014665:Vasodilator Agents; D009599:Nitroprusside; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D009320:Atrial Natriuretic Factor; D006152:Cyclic GMP