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Infusion of Pregnant Rats with Calcitonin Gene-Related Peptide (CGRP)_8-37, a CGRP Receptor Antagonist, Increases Blood Pressure and Fetal Mortality and Decreases Fetal Growth¹

^a Departments of Obstetrics/Gynecology and ^b Internal Medicine, The University of Texas Medical Branch, Galveston, Texas 77555-1062

Calcitonin gene-related peptide (CGRP) is the most potent endogenous vasodilatory peptide, and is involved in the regulation of blood flow to vital organs. We have previously shown that CGRP may be involved in vascular adaptations that occur during pregnancy, and that steroid hormones may be involved in these mechanisms. We hypothesized that endogenous CGRP is required for maintaining blood pressure and fetoplacental growth in pregnant rats, and that progesterone will enhance CGRP effects. The vasodilatory effects of CGRP are known to be inhibited by a competitive CGRP receptor antagonist, the C-terminal fragment CGRP_8-37. In the present study, we investigated whether continuous s.c. infusion of CGRP_8-37 to pregnant rats will reduce fetoplacental growth and increase systolic blood pressure. We also assessed whether progesterone will alter the effects of CGRP_8-37 on blood pressure during postpartum. Groups of five pregnant rats were s.c. infused with varying doses of CGRP_8-37 from Day 17 of pregnancy. Daily systolic blood pressures, pup weight, mortality at term delivery, and fetoplacental weights on Day 20 of gestation were measured. CGRP_8-37 at a dose of 0.083 mg day^-1 kg^-1 body weight (BW) showed no effects; however, doses of 0.33 and 1.33 mg day^-1 kg^-1 BW increased (P < 0.05) blood pressure during pregnancy, and these elevated blood pressures persisted during postpartum with the highest dose used. Progesterone (2 mg per injection, twice a day; s.c.) treatment significantly elevated blood pressure in rats infused with CGRP_8-37 during postpartum, suggesting that progesterone regulates CGRP-induced vascular effects. CGRP_8-37 infusion caused significant reductions in pup weight with an increase in mortality rate, and these effects were dose-dependent. Placental and fetal weights were also decreased prior to term on Day 20 of gestation, 72 h after CGRP_8-37 infusion, indicating effects on uteroplacental tissues. Therefore, we suggest that endogenous CGRP plays an important role in maintaining normal fetoplacental development, fetal survival, and vascular adaptations during pregnancy.

First decision: 19 November 2001.

¹ This work was supported in part by the National Institutes of Health through grants HL-58144, HD 30273, and HD-98-004.

² Correspondence: Chandrasekhar Yallampalli, Department of Obstetrics and Gynecology, 301 University Blvd., Medical Research Building Room 11.138, Galveston, TX 77555-1062. FAX: 409 747 0475; chyallam{at}utmb.edu

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