Advertisement

Endothelin receptor A antagonism prevents hypoxia-induced intrauterine growth restriction in the rat

      Abstract

      OBJECTIVE: Our purpose was to investigate the hypothesis that endothelin plays a critical role in maternal hypoxia-induced intrauterine growth restriction. STUDY DESIGN: Chronic indwelling venous and arterial catheters were placed on day 17 of a 22-day gestation in timed-pregnant Sprague-Dawley rats. Twelve rats were infused with saline solution and 12 with 6 mg/kg per day FR139317, an endothelin receptor A–specific antagonist. For gestational days 18 to 21 half the rats in each infusion group were housed in a normoxic environment and the other half in a hypoxic (14% oxygen) environment. On day 21 an arterial blood gas level was determined, the rats were then anesthetized, and a hysterotomy was performed. The weight of each pup and its corresponding placenta was recorded. Statistical significance was determined by analysis of variance. RESULTS: Among the rats receiving saline solution infusions, fetal weights were 20% less and placental weights were 11% less for those housed in a hypoxic environment compared with those housed in a normoxic environment (p < 0.003). Among the rats receiving FR139317 infusions, fetal and placental weights were not significantly different for those in a hypoxic environment compared with those in a normoxic environment. The fetal and placental weights for the rats receiving FR139317 infusion in hypoxic or normoxic environments were similar to those receiving saline solution in a normoxic environment. CONCLUSIONS: Endothelin plays a critical role in hypoxia-induced intrauterine growth restriction. Infusion of an endothelin antagonist prevents the intrauterine growth restriction caused by chronic hypoxia. (Am J Obstet Gynecol 1997;176:73-6.)

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to American Journal of Obstetrics & Gynecology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Scott K
        • Usher R
        Fetal malnutrition: its incidence, causes and effects.
        Am J Obstet Gynecol. 1966; 94: 951-963
        • Williams RL
        • Creasy RK
        • Cunningham GC
        • et al.
        Fetal growth and perinatal viability in California.
        Obstet Gynecol. 1982; 59: 624-632
        • Wigglesworth JS
        Experimental growth retardation in the foetal rat.
        J Pathol Bacteriol. 1964; 88: 1-13
        • Creasy RK
        • Barrett CT
        • de Swiet M
        • et al.
        Experimental intrauterine growth retardation in the sheep.
        Am J Obstet Gynecol. 1972; 112: 566-573
        • Ahokas RA
        • Park GC
        • Lubarsky SL
        • Friedman SA
        • Sibai BM
        Effect of chronic nitric oxide synthesis inhibition on maternal hemodynamics and organ blood flows in the pregnant rat [abstract].
        Am J Obstet Gynecol. 1995; 172: 272
        • Molnar M
        • Suto T
        • Toth T
        • Hertelendy F
        Prolonged blockade of nitric oxide synthesis in gravid rats produces sustained hypertension, proteinuria, thrombocytopenia, and intrauterine growth retardation.
        Am J Obstet Gynecol. 1994; 170: 1458-1466
        • Van Geijn HP
        • Kaylor WM
        • Nicola KR
        • Zuspan FP
        Induction of severe intrauterine growth retardation in the Sprague-Dawley rat.
        Am J Obstet Gynecol. 1980; 137: 43-47
        • Elton TS
        • Oparil S
        • Taylor GR
        • et al.
        Normobaric hypoxia stimulates endothelin-1 gene expression in the rat.
        Am J Physiol. 1992; 263: R1260-R1264
        • Li H
        • Chen S
        • Chen Y
        • et al.
        Enhanced endothelin-1 and endothelin receptor gene expression in chronic hypoxia.
        J Appl Physiol. 1994; 77: 1451-1459
        • Ferri C
        • Bellini C
        • DeAngelis C
        • et al.
        Circulating endothelin-1 concentrations in patients with chronic hypoxia.
        J Clin Pathol. 1995; 48: 519-524
        • De Nucci G
        • Thomas R
        • D'Orleans-Juste P
        • Antunes E
        • Walder C
        • Warner TD
        • et al.
        Pressor effects of circulating endothelin are limited by its removal in the pulmonary circulation and by the release of prostacyclin and endothelium-derived relaxing factor.
        Proc Natl Acad Sci U S A. 1988; 85: 9797-9800
        • Sogabe K
        • Nirei H
        • Shoubo M
        • Nomoto A
        • Ao S
        • Notsu Y
        • et al.
        Pharmacological profile of FR139317, a novel, potent ETA receptor antagonist.
        J Pharmacol Exp Ther. 1993; 264: 1040-1046
        • Lerman A
        • Hildebrand Jr, FL
        • Aarhus LL
        • Burnett Jr, JC
        Endothelin has biological actions at pathophysiological concentrations.
        Circulation. 1991; 83: 1808-1814
        • Lueder FL
        • Bangalore SA
        • Glass S
        Experimental intrauterine growth retardation: prolonged maternal hypoxia reduces placental blood flow and retards fetal growth in the rat [abstract].
        Pediatr Res. 1993; 33: 193A
        • Neerhof MG
        • Thaete LG
        • Silver RK
        • et al.
        Chronic endothelin infusion produces intrauterine growth restriction, fetal wastage, and hypertension in the rat [abstract].
        Pediatr Res. 1995; 37: 226A
        • McQueen J
        • Kingdom JCP
        • Connell JM
        • Whittle MJ
        Fetal endothelin levels and placental vascular endothelin receptors in intrauterine growth retardation.
        Obstet Gynecol. 1993; 82: 992-998
        • Furuhashi N
        • Kimura H
        • Nagae H
        • Yajima A
        Maternal plasma endothelin levels and fetal status in normal and preeclamptic pregnancies.
        Gynecol Obstet Invest. 1995; 39: 88-92