Prolonged blockade of nitric oxide synthesis in gravid rats produces sustained hypertension, proteinuria, thrombocytopenia, and intrauterine growth retardation*,**,*,★★

Presented in part at the Thirteenth Annual Meeting of the Society of Perinatal Obstetricians, San Francisco, California, February 8-13, 1993.
https://doi.org/10.1016/S0002-9378(94)70179-2Get rights and content

Abstract

OBJECTIVE: Our purpose was to test the hypothesis that chronic inhibition of nitric oxide synthesis in pregnant rats can produce a preeclampsia-like syndrome. STUDY DESIGN: Pregnant rats were instrumented on day 14 of gestation (parturition day 21 to 22) and infused continuously through a venous catheter with L-nitro-arginine, a potent inhibitor of nitric oxide synthase, or with sterile saline solution from day 18 until 24 hours post partum. A group of virgin rats was treated identically. Blood pressure was recorded in unrestrained animals with an aortic catheter for 30 minutes before infusion and repeated each day throughout the experiment. Urinary albumin, platelet count, weight of newborn pups, blood chemistry, and several other parameters were determined. Data were analyzed by one-way, repeated-measures analysis of variance, with Dunnett's t test or by Student t test. RESULTS: Mean arterial pressure increased from 102.6 ± 2.8 to a mean maximum of 152.5 ± 7.3 on the second day of infusion and remained in this range until delivery, after which it fell significantly, in spite of continuing infusion of L-nitro-arginine. This treatment increased urinary albumin (milligrams per 24 hours) from 8.3 ± 1.5 to 56.3 ± 14.3 in gravid and from 8.2 ± 0.8 to 18.2 ± 2.4 in virgin rats. Weight of newborn pups was reduced by c-arginine from 5.62 ± 0.10 to 3.37 ± 0.32 gm (p < 0.005) without affecting time of delivery or litter size. Platelet count was reduced 58% in gravid and 50% in virgin rats. CONCLUSION: Chronic inhibition of nitric oxide synthesis in gravid rats leads to sustained hypertension, proteinuria, thrombocytopenia, and intrauterine growth retardation, providing a simple animal model for preeclampsia. (AM J OBSTET GYNECOL 1994;170:1458-66.)

Section snippets

Reagents

Ketamine hydrochloride (Ketanest) and pentobarbital sodium (Nembutal) were purchased from Parke-Davis (München, Germany) and from Veterinary Laboratories (Lenexa, Kan.), respectively. L-NAME and all other chemicals used in this study were obtained from Sigma (St. Louis).

Experimental protocol

Wistar-derived, timed-pregnant and virgin rats (LATI, Gödöllö, Hungary) were housed individually in standard metabolic cages, allowing for the collection of urine and recording of food and water consumption throughout the study.

RESULTS

The mean body weight, food and water intake, and urine volume before (control) and on the third day of infusion (treated) are summarized in Table I. In spite of similar food intake, the body weight of L-NAME–treated mothers was lower than that of saline solution–treated controls, probably reflecting the significant growth retardation of conceptuses. Interestingly, L-NAME infusion significantly increased urine volume in both pregnant and virgin groups compared with corresponding saline

COMMENT

A previous study3 has demonstrated that an 8-hour infusion of L-NAME brought about a marked hypertension in chronically instrumented conscious rats and abolished the refractoriness to angiotensin II, vasopressin, and norepinephrine, a hallmark of hemodynamic changes surrounding preeclampsia.14, 15 By means of the same animal model the current investigation was undertaken to evaluate the long-term effects of controlled, continuous intravenous infusion of L-NAME on blood pressure, fetal

References (29)

  • C Baylis et al.

    Adverse interactions between pregnancy and a new model of systemic hypertension produced by chronic blockade of endothelial derived relaxing factor (EDRF) in the rat

    Clin Exp Hypertens Hypertens Pregnancy

    (1992)
  • G Fejes-Tóth et al.

    Evidence against role of antidiuretic hormone in support of blood pressure during dehydration

    Am J Physiol

    (1985)
  • G Brecher et al.

    Morphology and enumeration of human blood platelets

    J Appl Physiol

    (1950)
  • J Armin et al.

    The plasma, cell and blood volumes of albino rabbits as estimated by the dye (T1824) and 32P marked cell methods

    J Physiol

    (1953)
  • Cited by (306)

    View all citing articles on Scopus
    *

    From the Departments of Obstetrics and Gynecologya and Pharmacological and Physiological Science,b St. Louis University School of Medicine, the Institute of Pathophysiology, Semmelweis Medical University,c and the Department of Pathology, Veszprém County Hospital.d

    **

    Supported in part by the Hungarian Kidney Foundation.

    *

    Reprint requests: Frank Hertelendy, PhD, DSc, Department of Obstetrics and Gynecology, St. Louis University Health Sciences Center, 3635 Vista Ave. at Grand Blvd., P.O. Box 15250, St. Louis, MO 63110-0250.

    ★★

    0002-9378/94 $3.00 + 0 6/1/53321

    View full text