Disruption of cGMP production in pulmonary arteries isolated from fetal lambs with pulmonary hypertension

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.