Chronic nitric oxide inhibition in utero produces persistent pulmonary hypertension in newborn lambs.
Persistent pulmonary hypertension of the newborn (PPHN) is associated with chronic intrauterine events. Acute nitric oxide (NO) inhibition attenuates the normal increase in pulmonary blood flow at birth. We investigated whether chronic NO inhibition in utero causes persistent pulmonary hypertension. 11 fetal lambs received either a continuous infusion of N omega-nitro-L-arginine (an NO synthesis inhibitor) or 0.9% saline. Before infusion, acetylcholine (dependent upon endogenous NO production) and sodium nitroprusside (which releases its own NO) produced potent pulmonary vasodilation. After 10.5 +/- 1.5 d of infusion, acetylcholine did not produce pulmonary vasodilation in N omega-nitric-L-arginine-treated fetal lambs, but did in saline-treated fetal lambs; sodium nitroprusside produced pulmonary vasodilation in both groups. Immediately after birth, at 140 d of gestation, during the 3-h study period, mean pulmonary arterial pressure did not decrease in N omega-nitro-L-arginine-treated lambs; the increase in pulmonary blood flow and decrease in pulmonary vascular resistance were markedly attenuated compared to saline-treated lambs. These hemodynamic derangements were reversed by L-arginine. There were no anatomic abnormalities in the pulmonary circulation. Chronic NO inhibition in utero reproduces many of the physiologic derangements of PPHN. Intrauterine events which result in endothelial dysfunction and inhibition of NO may produce the physiologic derrangements of PPHN.
Fineman
J R
JR
Department of Pediatrics, University of California San Francisco 94143-0106.
Wong
J
J
Morin
F C
FC
Wild
L M
LM
Soifer
S J
SJ
D000818:Animals; D000831:Animals, Newborn / Q000502:physiology; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001794:Blood Pressure; D005260:Female; D005333:Fetus / Q000502:physiology*; D006801:Humans; D007231:Infant, Newborn; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000502:physiology*; D019335:Nitroarginine; D010547:Persistent Fetal Circulation Syndrome / Q000209:etiology*; D011247:Pregnancy; D011652:Pulmonary Circulation; D012756:Sheep; D014655:Vascular Resistance
D019335:Nitroarginine; D009569:Nitric Oxide; D001120:Arginine