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Influence of ETB Receptor Antagonism on Pregnancy Outcome in Rats

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Abstract

Objective

To determine the effect of endothelin-B (ETB)-selective receptor antagonism on pregnancy outcome in normal rats.

Methods

ETB receptor antagonist (A-192621; 5.0, 10.0, and 15.0 mg/kg per day) or vehicle was infused subcutaneously for 7 days by osmotic pump. Infusion was begun on day 14 of a 22-day gestation. Nonpregnant animals were treated similarly, and blood pressure (BP) responses and plasma antagonist levels were compared to those in pregnant animals. Mean arterial pressure (MAP) was measured on days 1, 4, and 7 of the infusion. Plasma ETB antagonist levels were measured on day 7 of infusion. On gestational day 21, fetal and placental weights and viability were evaluated at hysterotomy. Data were analyzed by analysis of variance and are presented at mean ± standard error of the mean.

Results

Fetal and placental weights were significantly lower at doses of 10 and 15 mg/kg per day of the ETB antagonist compared with vehicle-treated controls (P < .001); these effects were less severe at 15 than at 10 mg/kg per day despite a fourfold higher plasma level of antagonist. Mean arterial pressure was significantly higher at 10 and 15 mg/kg per day compared with controls, but only on infusion day 1 (P < .05). In contrast, MAPs for nonpregnant rats were elevated throughout the infusion at all doses of the ETB antagonist (P < .05).

Conclusions

ETB receptor antagonism inhibited fetal growth and increased maternal MAP in a dose-dependent manner, although the effect on BP was not sustained in pregnant animals. ETB receptor antagonism is detrimental to pregnancy outcome in the rat.

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Authors and Affiliations

  1. Division of Maternal-Fetal Medicine, Department of Obstetrics & Gynecology, Northwestern University Medical School, Evanston Northwestern Healthcare, 2650 Ridge Avenue, Suite 1600 WH, 60201, Evanston, IL, USA

    Kevin M. Madsen MD, Mark G. Neerhof DO, Jerry L. Wessale PhD & Larry G. Thaete PhD

  2. Pharmaceutical Discovery, Abbott Laboratories, Abbott Park, Illinois, USA

    Kevin M. Madsen MD, Mark G. Neerhof DO, Jerry L. Wessale PhD & Larry G. Thaete PhD

Authors
  1. Kevin M. Madsen MD
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  2. Mark G. Neerhof DO
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  3. Jerry L. Wessale PhD
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  4. Larry G. Thaete PhD
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Additional information

This study was supported by NIH grant HD34777 and by March of Dimes Birth Defects Foundation grant 6-FY99-0649. The ETB receptor antagonist was generously provided by Abbott Laboratories (Abbott Park, IL).

Plasma samples were assayed for A-192621 by Ms. Bach Nguyen and Dr. Kennan Marsh, Dept. 4EK, Pharmaceutical Products Division, Abbott Laboratories. We are grateful to Ms. Xiaopei Gao at Evanston Northwestern Healthcare for her technical assistance.

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Madsen, K.M., Neerhof, M.G., Wessale, J.L. et al. Influence of ETB Receptor Antagonism on Pregnancy Outcome in Rats. Reprod. Sci. 8, 239–244 (2001). https://doi.org/10.1177/107155760100800409

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