Oxygen-Induced Vasodilation Is Blunted in Pulmonary Arterioles
From Fetal Rats With Nitrofen-Induced Congenital
By Christopher P. Coppola and John R. Gosche
New Haven, Connecticut
Persistent pulmonary hypertension
contributes to the high mortality rate associated with con-
genital diaphragmatic hernia (CDH). Oxygen is an important
stimulus for pulmonary vasodilation in the perinatal period.
The authors have investigated the responses of isolated
pulmonary arterioles from fetal rats with and without CDH to
an increase in oxygen tension.
CDHs were induced in fetal rats by feeding nitrofen
to timed-pregnant rats at midgestation. A third-generation
pulmonary arteriole was isolated from the right lung at term.
Isolated arterioles were pressurized at their “optimal dis-
tending pressure.” Diameter changes in response to an in-
crease in oxygen tension from 25 to 40 mm Hg (“hypoxic”
conditions) to 90 to 150 mm Hg (“normoxic” conditions)
were recorded for K
preconstricted arterioles from control
rats, from rats with nitrofen-induced CDH, and from rats that
were nitrofen exposed but did not have a CDH.
“Normoxic” exposure reversed the K
tion in control arterioles by 124 Ϯ 26%. In contrast, arterioles
from rats with nitrofen-induced CDH dilated signiﬁcantly less
than controls (20 Ϯ 15% of the K
responses of arterioles from rats that were nitrofen exposed
but did not get a CDH were not different (
Ͼ .05) from
Oxygen-induced vasodilation is blunted in pul-
monary arterioles from rats with nitrofen-induced CDH.
Blunted oxygen-induced vasodilation may contribute to per-
sistent pulmonary hypertension in CDH.
J Pediatr Surg 36:593-597. Copyright
2001 by W.B.
INDEX WORDS: Congenital diaphragmatic hernia, nitrofen,
ULMONARY HYPERTENSION and persistent fe-
tal circulation are common causes of morbidity and
mortality in infants with congenital diaphragmatic her-
nias (CDH). Currently, the etiology of the pulmonary
hypertension associated with CDH remains poorly un-
derstood. Persistent pulmonary hypertension in the new-
born period (PPHN) may reﬂect a failure of the normal
physiologic mechanisms that contribute to pulmonary
vasodilation at birth.
Similar deﬁcits also might contrib-
ute to pulmonary hypertension in infants with CDH.
Increases in intraalveolar and intravascular oxygen
tension cause pulmonary vasodilation and are potent
stimuli for the decrease in pulmonary vascular resistance
that occurs at birth.
We have reported previously that
the vasoconstriction induced by hypoxia is blunted in
isolated third-generation pulmonary arterioles from fetal
rats with nitrofen-induced CDH.
We hypothesized that
this blunted hypoxic vasoconstrictor response might be
attributable to a blunting of the vasodilation that would
have occurred in response to a change from the relatively
hypoxic fetal environment to the “normoxic” environ-
ment in the tissue chamber. In this report we present data
from experiments to evaluate the responses of isolated
third-generation pulmonary arterioles from control fetal
rats and from fetal rats with nitrofen-induced CDH to an
increase in oxygen tension.
MATERIALS AND METHODS
All experimental procedures were approved by our institutional
Animal Care and Use Committee, and were performed in accordance
with the National Research Council’s guide for the care and use of
Preparation of Pulmonary Microvessels
Timed-pregnant Sprague-Dawley rats were purchased from a com-
mercial vendor, and were housed in an AAALAC-approved animal
care facility. A total of 28 term fetuses were taken from 20 timed-
pregnant rats for use in these studies. No more than 2 fetuses from the
same maternal rat were included in the same treatment group.
On day 12 of gestation (sperm positive, day 1), pregnant rats were
fed either 75 mg of nitrofen, 2,4 dichlorophenyl-p-nitrophenyl ether
(Zhejiang Chemicals, Hangzhou, Peoples Republic of China) dissolved
From the Pediatric Surgical Research Laboratory, Division of
Pediatric Surgery, Department of Surgery, Yale University School of
Medicine, New Haven, CT.
Presented at the 30th Annual Meeting of the American Pediatric
Surgical Association, Rancho Mirage, CA, May 17, 1999.
Supported in part by a research grant from the American Lung
Association, Connecticut afﬁliate, #RG-004-N.
Address reprint requests to John R. Gosche, MD, PhD, Department
of Surgery, Yale University School of Medicine, 333 Cedar St, FMB
132, New Haven, CT 06520.
Copyright © 2001 by W.B. Saunders Company
Journal of Pediatric Surgery,
Vol 36, No 4 (April), 2001: pp 593-597