UTERINE RELAXATION RESPONSES TO CALCITONIN-GENE-RELATED PEPTIDE AND CALCITONIN-GENE-RELATED PEPTIDE RECEPTORS DECREASED DURING LABOR IN RATS

OBJECTIVES: Our purpose was to investigate (1) whether uterine relaxat ion responses to calcitonin gene-related peptide are differentially re gulated during pregnancy and labor, (2) the involvement of nitric oxid e in smooth muscle relaxant action of calcitonin gene-related peptide in the rat uterus, (3) whether receptors for calcitonin gene-related p eptide are expressed in rat uterus, and if so (4) whether the concentr ations of these receptors are differently regulated during pregnancy a nd labor. STUDY DESIGN: Rats were killed on day 18 of gestation, at th e time of spontaneous labor, or postpartum day 2. The uteri were remov ed for in vitro contractility measurements, nitric oxide production, a nd calcitonin gene-related peptide receptor binding assay. RESULTS: (1 ) Calcitonin gene-related peptide induced a dose-dependent relaxation in spontaneously contracting uterine strips from pregnant rats on day 18 of gestation; (2) the relaxation effects of calcitonin gene-related peptide on the uterus were decreased during spontaneous delivery at t erm and post partum compared with that during pregnancy; (3) calcitoni n gene-related peptide-induced relaxation was inhibited by pretreatmen t of the uterine tissue with a calcitonin gene-related peptide recepto r antagonist, calcitonin gene-related peptide(8-37); (4) nitric oxide synthesis inhibitor (N-G-nitro-L-arginine methyl ester) and soluble gu anylate cyclase inhibitor (LY83583) significantly decreased calcitonin gene-related peptide-induced relaxation of the rat uterus during preg nancy; (5) calcitonin gene-related peptide increased the uterine nitri c oxide production in pregnant rats, and this increase was obliterated in the presence of calcitonin gene-related peptide(8-37); and (6) cal citonin gene-related peptide receptors are present in rat uterus, and the concentration of these receptors dramatically increases during pre gnancy and decreases during labor at term. CONCLUSIONS: Calcitonin gen e-related peptide inhibits uterine spontaneous contractions in rats du ring pregnancy but not during labor and post partum. The inhibitory ef fects of calcitonin gene-related peptide on uterine contractility appe ar to be modulated, at least in part, by the activation of nitric oxid e generation in the rat uterus. Changes in calcitonin gene-related pep tide receptors could contribute to the changes in calcitonin gene-rela ted peptide-mediated uterine relaxation during pregnancy and labor.