Contractile properties of intralobar pulmonary arteries and veins in the fetal lamb model of congenital diaphragmatic hernia.
OBJECTIVE
Pulmonary hypertension plays a significant role in the pathophysiology of congenital diaphragmatic hernia (CDH). Although there has been an intensive research effort directed at mediators that may cause pulmonary vasoconstriction, no single agent has been identified. The authors hypothesize that there may be an alteration in the cGMP-nitric oxide (NO) pathway of vasodilatation contributing to the pulmonary hypertension observed in CDH. The purpose of these studies is to begin to elucidate vasoactive properties of pulmonary vessels with particular attention to the cGMP-NO pathway of vasodilatation in fetal lambs with CDH.


METHODS
Fourth-generation pulmonary arteries and pulmonary veins were dissected from both right and left lungs of eight, 139-day gestational fetuses with surgically created CDH. Vessels were studied with standard isolated tissue bath techniques. Experiments examined basal release of NO in endothelium-intact PVs and PAs of both right and left lungs by measuring the contractile force of vessels constricted with norepinephrine (NE) in the presence and absence of the nitric oxide synthase (NOS) inhibitor N(omega)-nitro-L-arginine (L-NA). Concentration-response curves to the vasodilating agents zaprinast and A23187 were also obtained in vessels contracted by NE.


RESULTS
Left and right pulmonary artery responses to NE are enhanced over those of historic controls. Pretreatment of left pulmonary arteries with L-NA enhances the vasoconstrictor response to NE, whereas right PAs show no increased response. Relaxation responses to A23187 and zaprinast, in both left and right pulmonary arteries were not different from control lambs. Relaxation responses of both left and right pulmonary veins to A23187 and zaprinast are blunted compared with controls. This blunting is significantly more in left pulmonary veins than right. Further, right but not left pulmonary veins display enhanced vasoconstrictive response to NE after L-NA pretreatment.


CONCLUSIONS
The NO-cGMP pathway of vasodilatation is abnormal in the near term, fetal lamb with CDH. These abnormalities were most apparent in pulmonary veins and may reflect abnormal NOS activity or content between left and right lungs of the fetal lamb with CDH. Pulmonary arteries from CDH lambs have basal and stimulated NO release equal to that of historic controls but appear to be hypersensitive to exogenous vasoconstrictors.
Irish
M S
MS
Department of Surgery, The Buffalo Institute of Fetal Therapy of The Children's Hospital of Buffalo and The State University of New York at Buffalo School of Medicine and Biomedical Sciences, 14222, USA.
Glick
P L
PL
Russell
J
J
Kapur
P
P
Bambini
D A
DA
Holm
B A
BA
Steinhorn
R H
RH
D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D006152:Cyclic GMP / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005333:Fetus / Q000601:surgery*; D006548:Hernia, Diaphragmatic / Q000503:physiopathology*; D007476:Ionophores / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011651:Pulmonary Artery / Q000196:embryology / Q000503:physiopathology*; D011667:Pulmonary Veins / Q000196:embryology / Q000503:physiopathology*; D011688:Purinones / Q000494:pharmacology; D012756:Sheep; D014661:Vasoconstriction / Q000502:physiology*; D014664:Vasodilation / Q000502:physiology*
D007476:Ionophores; D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D009569:Nitric Oxide; D000001:Calcimycin; C011145:zaprinast; D006152:Cyclic GMP