To explore the role of calcitonin gene-related peptide (CGRP) in rat pregnancy, we determined the density of myometrial CGRP-encoded nerve fibre terminals and examined, in an organ bath, the relaxant effect of the peptide on uterine strips near parturition. Comparisons were made with the uterus and aorta of nonpregnant rats. In the myometrium, CGRP immunoreactive nerve fibers were abundant in nonpregnant rats and scarce at the parturient stage. In the aorta there was no variation in the density of CGRP fibres with gestation. In nonpregnant rats only, CGRP relaxed spontaneous and tetrodotoxin (TTX)-sensitive electrically-evoked uterine contractions (EC50 40 nM, Emax 80%). The effect was antagonized by CGRP[8-37] (pKB 6.47) but was not affected by either blockers of nitricoxid synthase or ATP-sensitive potassium channels. CGRP was also able to relax contractions evoked by direct depolarization of the cells (TTX-insensitive contractions) (EC50, 2 nM, Emax 70%). In aorta contracted with arginine vasopressin, CGRP-induced relaxation was the same in nonpregnant and parturient animals. It was antagonized by CGRP [8-371 (pKB 6.90) and was abolished in presence of the nitric oxide synthase inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME). Amylin neither relaxed the uterus nor the aorta. In pregnant rats, the relaxant effect of CGRP on the uterus was limited on day 21 and was totally absent on day 22 of gestation. We conclude that the primary relaxant effect of CGRP on the uterus occurs at the level of myometrial smooth muscle cells. In the myometrium, gestation decreases CGRP innervation and impairs the relaxant responses to CGRP. Such changes are not observed in vascular tissues like aorta.

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The 125 I-labeled endothelin-1 ([ 125 I]ET-1) binding sites in microvillous membranes from early gestation and term human placentas were investigated. The K d s for [125 I]ET-1 binding to early gestation (68 Ϯ 15 pmol/l) and term (45 Ϯ 8 pmol/l) microvilli (n ¼ 4) were not significantly different. The density of binding sites decreased significantly, from 243 Ϯ 80 fmol/mg protein in early gestation microvilli to 54 Ϯ 10 fmol/mg protein in term microvilli. The endothelin (ET) receptor (ET-R) subtype profiles were determined by competition binding studies with unlabeled ET-1, ET-3, and selective agonists and antagonists for ET A -R and ET B -R. In early gestation placental microvilli, we observed the presence of 72% ET B -R, (mainly ET B2 -R subtype), and 28% ET A -R. Only ET B -R (mainly the ET B2 -R subtype) was present in term placental microvilli. We suggest that the ET B -R on the placental microvillous membrane is involved in specific trophoblastic functions and may play a major role in ET clearance by modulating the amounts of ETs in the maternal intervillous blood space.

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