Inducible Nitric Oxide Synthase and the Regulation of Central Vessel Caliber in the Fetal Rat

Bustamante, Sergio; Pang, Ying; Romero, Silvia; Pierce, Maria R.; Voelker, Cynthia A; Thompson, Jane H.; Sandoval, Manuel; Liu, Xiaoping; Miller, Mark J.S.

doi:10.1161/01.cir.94.8.1948

Cited by 48 publications

(23 citation statements)

References 33 publications

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“…Instead, we found that TNFα and iNOS mRNA expression was significantly increased in the maternally LPS-injected DA compared with in the maternally PBS-injected DA. Bustamante et al showed that a NO inhibitor closed the LPS-induced PDA, 15 which is consistent with the findings of the present study. Therefore, we think that NO plays a primary role in PDA by LPS-induced infection.…”

supporting

confidence: 93%

“…31 In the in vivo experiment by Vucovich et al, mice but not rats were treated, and newborn term gestation mice were injected with LPS at 30 min of age and then the DA was assessed after a 4-h period of observation. Therefore, the duration of LPS exposure was much shorter in their study than our and Bustamante's experiments, 15 where chronic inflammatory responses were observed. Thus, we suggest that maternal LPS administration is a suitable method to investi- …”

Section: Tumor Necrosis Factor α Inducible No Synthase and Tlr4 Mrnamentioning

confidence: 50%

“…Bustamante et al demonstrated that maternal administration of LPS dilated the fetal DA. 15 Therefore, it is intriguing to elucidate the effect of LPS on the patency of the DA regarding both functional (vasoconstriction) and anatomical (vascular remodeling) closure. 16 Functional closure of the DA is promoted by several factors such as an increase in arterial oxygen tension, a decrease in circulating PGE2, and a decrease in nitric oxide (NO) in the luminal endothelium.…”

Section: Maternal Administration Of Lps Delayed Closure Of the Da In mentioning

confidence: 99%

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Lipopolysaccharide Delays Closure of the Rat Ductus Arteriosus by Induction of Inducible Nitric Oxide Synthase But Not Prostaglandin E<sub>2</sub>

Kajimura

Akaike

Minamisawa

2016

Circ J

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Background:The incidence of patent ductus arteriosus is known to be higher in premature neonates with infection than in those without infection. However, the detailed mechanism has not been investigated. Methods and Results:Lipopolysaccharide (LPS; 100 μg/kg) was injected into timed-pregnant Wistar rats on day 18 and 19 of pregnancy. The fetuses were delivered by cesarean section on gestational day 21. Using a rapid wholebody freezing method, it was found that closure of the ductus arteriosus (DA) was significantly delayed in neonates from LPS-injected rats after birth. Histological analysis demonstrated that there was no difference in vascular remodeling of the DA. Quantitative reverse transcriptase-polymerase chain reaction analysis showed that the tumor necrosis factor α and inducible nitric oxide synthase (iNOS) mRNA expression level was significantly increased, but there was no difference in cyclooxygenase 2 and prostaglandin receptor, EP4, mRNA expression in the DA from LPS-injected rats. Moreover, the NOS inhibitor, Nω-Nitro-L-arginine methyl ester hydrochloride, significantly prevented the delayed closure of the DA after birth in neonates from LPS-injected rats. Conclusions:The present study demonstrated that LPS-mediated infection delayed closure of the rat DA without apparent histological changes. iNOS, but not prostaglandin E2, may play a primary role in delayed functional closure of the DA. (Circ J 2016; 80: 703 -711)

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supporting

confidence: 93%

Section: Tumor Necrosis Factor α Inducible No Synthase and Tlr4 Mrnamentioning

confidence: 50%

Section: Maternal Administration Of Lps Delayed Closure Of the Da In mentioning

confidence: 99%

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Lipopolysaccharide Delays Closure of the Rat Ductus Arteriosus by Induction of Inducible Nitric Oxide Synthase But Not Prostaglandin E<sub>2</sub>

Kajimura

Akaike

Minamisawa

2016

Circ J

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“…7 Although prostaglandins (PGs) are considered the dominant vasodilators opposing ductal constriction in the later part of gestation, 6 Kajimura et al suggest an even greater complexity in the mechanisms regulating ductus arteriosus, wherein • NO also plays an critical role in ductal patency, particularly in the setting of maternal chorioamnionitis. 5 Consistent with work by Bustmante et al showing that injection of lipopolysaccharide (LPS) to pregnant dams inhibits postnatal decreases in the diameter of the ductus via mechanisms related to • NO release, 8 Kajimura et al show that LPS injection increases expression of inducible nitric oxide synthase (NOS), but not PG expression, in delayed closure of the ductus. Such basic science discoveries are consistent with notable clinical observations.…”

supporting

confidence: 58%

Patent Ductus Arteriosus　– A Complex Problem in Need of a Solid Conceptual Foundation –

Backes

Smith

2016

Circ J

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Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp contrast, among premature infants, premature birth interrupts the normal maturation of ductal contractile mechanisms, leaving the ductus more susceptible to vasodilatory factors. 7 Although prostaglandins (PGs) are considered the dominant vasodilators opposing ductal constriction in the later part of gestation, 6 Kajimura et al suggest an even greater complexity in the mechanisms regulating ductus arteriosus, wherein • NO also plays an critical role in ductal patency, particularly in the setting of maternal chorioamnionitis. Another important finding in the present study by Kajimura et al is that use of a NOS inhibitor precursor, L-N G -nitroarginine methyl ester hydrochloride (L-NAME, which undergoes hydrolysis in vivo to produce L-N G -nitroarginine, the functional NOS inhibitor) prevented delayed closure of the ductus after birth in pups from LPS-injected rats. 5 These observations suggest that maternal risk factors, such as chorioamnionitis, can influence the mechanisms of DA regulation, wherein the use of treatments interfering with • NO synthesis or function could be useful adjuncts to achieve PDA closure in this subpopulation of infants, and provide a basis for more targeted interventions on the PDA. 5 To that end, Seidner et al showed, among preterm newborn baboons, that the combined use of indomethacin and L-NAME produces a much greater degree of ductus constriction than does indomethacin alone, corresponding to the synergistic interaction of • NO and PG in ductal regulation. 10 However, • NO blockade may not be therapeutically beneficial, because of the nonspecific nature of currently available treatments. 7 Although a phase I and II study by Keller et al showed higher rates of ductal closure with combined L-N G -monomethyl Arginine citrate (L-NMMA, a he ductus arteriosus (DA) is an essential component of the fetal circulation, shunting blood away from the high-resistance pulmonary vascular bed toward the placenta. At birth, the placental circulation is removed, and the lungs become the source of oxygenated blood; thus, shunting through the ductus becomes potentially harmful. Although closure of the ductus occurs within hours after birth in the majority of term infants, a persistent patent DA (PDA), defined as a ductus that fails to close within 72 h postnatal age, is seen in the majority of infants born extremely premature (<28 weeks of gestation). 1 A PDA is often a precursor to heart failure, prolonged ventilator dependency, necrotizing enterocolitis, and bronchopulmonary dysplasia. Moreover, recent evidence shows higher mortality in infants with a PDA than in agematched infants with closed ductus. 2 However, the extent to which these adverse consequences are attributable to the PDA remains unknown. Despite nearly 6 decades of basic and clinical research, fundamental questions on the evaluation and treatment of PDA in preterm infants remain unanswered. Article p 703Rather than approaching the PDA as an ...

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“…There is mounting evidence that NO has important vasodilatory action in the fetal circulation as it does in the adult (21). Despite the apparent role of both eNOS and iNOS in regulating the fetal circulation (21), initiation of L-NAME-induced limb disruption seems to be primarily dependent on eNOS inhibition.…”

Section: Tiboni Et Almentioning

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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Inducible Nitric Oxide Synthase and the Regulation of Central Vessel Caliber in the Fetal Rat

Abstract: We suggest that nitric oxide, generated by iNOS, plays a significant role in control of major vessel and ductus arteriosus caliber in the rat fetus. In regard to the nitrergic regulation of the circulation, the fetus is clearly different from the adult.

Cited by 48 publications

References 33 publications

Lipopolysaccharide Delays Closure of the Rat Ductus Arteriosus by Induction of Inducible Nitric Oxide Synthase But Not Prostaglandin E<sub>2</sub>

Lipopolysaccharide Delays Closure of the Rat Ductus Arteriosus by Induction of Inducible Nitric Oxide Synthase But Not Prostaglandin E<sub>2</sub>

Patent Ductus Arteriosus　– A Complex Problem in Need of a Solid Conceptual Foundation –

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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Inducible Nitric Oxide Synthase and the Regulation of Central Vessel Caliber in the Fetal Rat

Abstract: We suggest that nitric oxide, generated by iNOS, plays a significant role in control of major vessel and ductus arteriosus caliber in the rat fetus. In regard to the nitrergic regulation of the circulation, the fetus is clearly different from the adult.

Cited by 48 publications

References 33 publications

Lipopolysaccharide Delays Closure of the Rat Ductus Arteriosus by Induction of Inducible Nitric Oxide Synthase But Not Prostaglandin E<sub>2</sub>

Lipopolysaccharide Delays Closure of the Rat Ductus Arteriosus by Induction of Inducible Nitric Oxide Synthase But Not Prostaglandin E<sub>2</sub>

Patent Ductus Arteriosus – A Complex Problem in Need of a Solid Conceptual Foundation –

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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Patent Ductus Arteriosus　– A Complex Problem in Need of a Solid Conceptual Foundation –