Nitric oxide inhibition causes intrauterine growth retardation and hind-limb disruptions in rats

Diket, Albert L.; Pierce, Maria R.; Munshi, Upender K.; Voelker, Cynthia A; Eloby-Childress, Sandra; Greenberg, Samantha; Zhang, Xiaojing; Clark, David A.; Miller, Mark J.S.

doi:10.1016/0002-9378(94)90141-4

Cited by 124 publications

(57 citation statements)

References 17 publications

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“…35,41 Similar defects have been described in mice deficient in endothelial NO synthase, 36,42 but not in other NO synthase isoforms. An association between the NOS3 A922G polymorphism and orofacial clefts has been reported.…”

Section: Discussionsupporting

confidence: 62%

“…But even small differences of unknown characteristics of the studied populations may influence the results as Intrauterine growth restriction was found in mice treated with NO synthase inhibitors and mice deficient in endothelial NO synthase. 35,36 Maternal nitrite/nitrate plasma levels have been found to be decreased in pregnancies with intrauterine growth restriction. 37,38 Treatment with the NO donor L-arginine was able to increase birth weight in those cases.…”

Section: Discussionmentioning

confidence: 99%

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Impact of maternal endothelial nitric oxide synthase gene polymorphisms on blood pressure, protein excretion and fetal outcome in pregnancy

Hocher

Hügle

et al. 2008

J Hum Hypertens

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A genetic association study was conducted to assess whether genetically determined alterations of the nitric oxide system are associated with clinical markers of preeclampsia. A large number of Caucasian women were consecutively included after delivery and genotyped for the endothelial nitric oxide synthase gene (NOS3) polymorphisms G894T, T789C (n ¼ 1502) and intron 4a/b (n ¼ 2186). There are no significant differences in mean blood pressure (BP), protein excretion or new-onset peripheral oedema between any of the genotypes over the course of pregnancy. Neither particular haplotypes nor the combined presence of any two alleles is associated with those markers of pre-eclampsia. The maternal polymorphisms do not seem to influence fetal growth, birth weight or the incidence of congenital malformations. We demonstrate in a large Caucasian population that maternal polymorphisms of the NOS3 gene are not related to clinical markers of pre-eclampsia. The functional relevance of the NOS3 variants alone does not seem to be strong enough to affect BP regulation during pregnancy.

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Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Impact of maternal endothelial nitric oxide synthase gene polymorphisms on blood pressure, protein excretion and fetal outcome in pregnancy

Hocher

Hügle

et al. 2008

J Hum Hypertens

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“…In our study, the effects of L-NAME treatment on whole-body metabolism also could have interfered with lung development. Finally, it has been suggested that the hemorrhagic necrosis of the fetal hindlimbs observed after oral L-NAME administration to the dam may be related to inhibition of fetal NO synthesis by L-NAME having crossed the placenta (32). Vascular endothelial growth factor (VEGF) is recognized as a key factor in lung angiogenesis.…”

Section: Lung Growth In Growth-restricted Rat Pupsmentioning

confidence: 99%

Effect of Nω-Nitro-l-Arginine Methyl Ester–Induced Intrauterine Growth Restriction on Postnatal Lung Growth in Rats

2005

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Infants with intrauterine growth restriction (IUGR) are at high risk for morbidity and mortality. Preeclampsia, one of the leading causes of IUGR, begins during the canalicular phase of lung development. The aim of our study was to determine whether induced IUGR was responsible for abnormal lung development in rat pups. We randomized pregnant Sprague-Dawley rats to daily gavage with either the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME; n ϭ 5, 50 mg · kg Ϫ1 · dϪ1 ) or pure water (n ϭ 6). The pups were weighed at birth and on postnatal days 7 and 14. At each of these time points, pups were killed and their lung growth was assessed on the basis of lung volume and light-microscopy morphometric data. At birth, body weight, total alveolar surface area, and alveolar surface density were significantly decreased and alveolar size was significantly increased in the L-NAME group, compared with the control group. On day 7, body weight was similar in the two groups, and the only significant difference was smaller total alveolar surface area in the L-NAME group. On day 14, neither body weight nor lung morphometric parameters were significantly different between the L-NAME group and the controls. These results suggest that postnatal catch-up growth may completely correct the lung development disorders present at birth in IUGR pups, in parallel with the catch-up body weight gain. Studies have established that intrauterine growth restriction (IUGR) is correlated with increased morbidity and mortality (1-3). Despite the huge strides made in neonatal medicine over the past 15 y, the risk for respiratory distress syndrome, intraventricular hemorrhage, and necrotizing enterocolitis, as well as length of stay and hospital costs, remain higher in growth-restricted newborns (3). Importantly, the adverse effects of IUGR are long lasting, one of the most common long-term consequences being respiratory disease (4 -7).Preeclampsia is among the leading causes of IUGR. The placental vascular abnormalities associated with preeclampsia impair maternofetal exchanges, thereby restricting fetal growth (8). Impairments in maternofetal exchanges begin during the third trimester of pregnancy, during which lung development is at the canalicular phase, characterized by formation of the distal airways, blood vessels, and alveolar-capillary barrier (9).Although the pathophysiology of preeclampsia remains unclear, experimental evidence points to a key role for nitric oxide (NO) (10 -13). NO synthase (NOS) inhibition during the last third of pregnancy in rats was followed by hypertension and proteinuria in the dams and by IUGR and high fetal mortality in the offspring, a combination that replicated preeclampsia in humans (14 -16). In rats, IUGR induced by NOS inhibition was associated with hindlimb necrosis at birth (17). To our knowledge, the long-term development of the offspring was not documented. These data prompted us to assess whether lung development was impaired in rat pups with IUGR induced by NOS inhibition in the ...

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“…The L-arginine analog L-NAME, a nonselective inhibitor of NOS, has been shown to be teratogenic when administered to rats (3)(4)(5)(6)(7)(8). Limb reduction defects with associated characteristic areas of macroscopic hemorrhage were the most common phenotypic alterations noted (3)(4)(5)(6)(7)(8).…”

mentioning

confidence: 99%

The Nitric Oxide Synthesis Inhibitor Nω-Nitro-L-Arginine Methyl Ester (L-NAME) Causes Limb Defects in Mouse Fetuses: Protective Effect of Acute Hyperoxia

2003

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In the present study the relationship between exposure to the nitric oxide synthesis inhibitor N -nitro-L-arginine methyl ester (L-NAME) and the induction of limb defects, with respect to stage specificity and dose dependency, was investigated in the mouse. ICR (CD-1) mice were dosed s.c with L-NAME at 50 or 90 mg/kg on gestation d 12, 13, 14, 15, or 16. A group of animals treated with vehicle on gestation d 14 served as control. Uterine contents were evaluated for teratogenesis on gestation d 18. A treatment-related disruption of limb development was noted. The effect was dose dependent and phase specific. L-NAME became teratogenically operational on gestation d 13 and elicited its maximum effect on gestation d 14, whereas no significant teratogenicity was observed when exposure occurred after gestation d 15. In utero exposure to L-NAME also reduced embryo viability relative to controls. When the higher dose was injected on gestation d 16, a significant number of dams delivered preterm. In a parallel study, the ability of hyperoxia to prevent limb teratogenesis was investigated. To this aim, a group of L-NAMEtreated animals (90 mg/kg s.c. on gestation d 14) were exposed to 98 to 100% O 2 for 12 h. L-NAME-treated mice breathing room air served as positive controls. In response to hyperoxia, a significant decrement of L-NAME-induced limb defects was found. This study characterizes for the first time the teratogenic capacity of L-NAME in the mouse. Results obtained with hyperoxia fit the hypothesis that hypoxic tissue damage may play a contributory role in L-NAME-induced limb defects. NO is a colorless gaseous molecule involved in the regulation of diverse important physiologic processes, including vascular tone, platelet reactivity, smooth muscle contractility, neurotransmission, and the cytotoxic action of immune cells (1). NO is generated endogenously during the conversion of L-arginine to citrulline by a family of enzymes known as NOS. At least three isoforms of NOS have been isolated, including the constitutive eNOS and neuronal NOS isoforms, and the inducible isoform, iNOS (1). Pharmacologic manipulation of NOS activity can be achieved by several classes of NOS inhibitors including L-arginine analogs, which act by denying NOS its substrate in a competitive manner (2).The L-arginine analog L-NAME, a nonselective inhibitor of NOS, has been shown to be teratogenic when administered to rats (3-8). Limb reduction defects with associated characteristic areas of macroscopic hemorrhage were the most common phenotypic alterations noted (3-8). L-NAME is not the only L-arginine analog known to cause dysmelia, as N -nitro-Larginine also induced limb defects (9). Notably, disruptions similar to those induced by L-arginine analogs have been noted in knockout mice lacking eNOS (10, 11). The current state of knowledge on L-NAME teratogenicity also includes the following facts: 1) the period of fetal vulnerability has an onset relatively late in gestation (3-5); 2) both oral (3-6) and parenteral (5) treatments are effective;...

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Nitric oxide inhibition causes intrauterine growth retardation and hind-limb disruptions in rats

Cited by 124 publications

References 17 publications

Impact of maternal endothelial nitric oxide synthase gene polymorphisms on blood pressure, protein excretion and fetal outcome in pregnancy

Impact of maternal endothelial nitric oxide synthase gene polymorphisms on blood pressure, protein excretion and fetal outcome in pregnancy

Effect of Nω-Nitro-l-Arginine Methyl Ester–Induced Intrauterine Growth Restriction on Postnatal Lung Growth in Rats

The Nitric Oxide Synthesis Inhibitor Nω-Nitro-L-Arginine Methyl Ester (L-NAME) Causes Limb Defects in Mouse Fetuses: Protective Effect of Acute Hyperoxia

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