Vasodilator Effects of Parathyroid Hormone,Parathyroid Hormone-Related Protein,and Calcitonin Gene-Related Peptide in the Human Fetal-Placental Circulation

Abstract

OBJECTIVE: The purpose of our study was to determine the vasoactivity of calcitonin gene- related peptide (CGRP), parathyroid hormone (PTH), and parathyroid hormone-related protein (PTHrP) in the human fetal-placental circulation in vitro.

METHODS: Dually perfused placental cotyledons from term pregnancies were used in this study.

RESULTS: Calcitonin gene-related peptide, PTHrP (both 10^-10-10^-6 mol/L), and PTH (10^-8-10^-6 mol/L) demonstrated a significant concentration-dependent vasodilator effect (P = .0007, P = .0172, P = .0063, respectively), following preconstriction with a thromboxane mimetic U46619. The CGRP-1 receptor inhibitor CGRP_8-37 (10 ^-6 mol/L) significantly in hibited (P = .0131) the CGRP-induced vasodilator effect, while the nitric oxide synthesis inhibitor n-nitro-l-arginine showed no inhibitory effect.

CONCLUSIONS: These results demonstrate the vasodilator effects of CGRP, PTH, and PTHrP in the human fetal-placental circulation. Calcitonin gene-related peptide and PTHrP were of equal potency, and both were approximately 100 times more potent than PTH. This study also suggests the CGRP may exert its vasodilator effect through two classes of receptors in the human placenta and may do so independently of nitric oxide. (J Soc Gynecol Invest 1994;1: 19-24)

Keywords

Calcitonin gene-related peptide parathyroid hormone parathyroid hormone-related protein placenta vasodilation.

Get full access to this article

View all access options for this article.

References

Myatt L. Current topic: Control of vascular resistance in the human placenta . Placenta 1992;13:329-41.

Zaidi M. , Moonga BS , Bevis PJ , Bascal ZA , Breimer LH The calcitonin gene peptides: Biology and clinical relevance. Crit Rev Clin Lab Sci 1990;28:109-74.

Samuelson UE , Dalsgaard CJ , Lundberg JM , Hökfelt T. Calcitonin gene-related peptide inhibits spontaneous contractions in human uterus and fallopian tube . Neurosci Lett 1985;62:225-30.

Firth KF , Pipkin FB Human α- and β-calcitonin gene-related peptides are vasodilators in human chorionic plate vasculature. Am J Obstet Gynecol 1989;161:1318-9.

Fiscus RR , Wang X. , Hao H. hCGRP8-37 antagonizes vasodilations and cAMP responses to rat CGRP in rat caudal artery. Ann NY Acad Sci 1992 ;657:513-5.

Fiscus RR , Wang X. , Han C. , Ali CD , Murad J. , Murad F. Calcitonin gene-related peptide (CGRP)-induced cyclic AMP, cyclic GMP and vasorelaxant responses in rat thoracic aorta are antagonized by blockers of endothelium-derived relaxant factor (EDRF). Neuropeptides 1991;20: 133-43.

Mok Lls , Nickols GA , Thompson JC Parathyroid hormone as a smooth muscle relaxant. Endocr Rev 1989;10: 420-36.

Lafond J. , Auger D. , Fortier J. , Brunette MG Parathyroid hormone receptor in human placental syncytiotrophoblast brush border and basal plasma membranes. Endocrinology 1988;123:2834-40.

Moseley JM , Kubotta M. , Diefenbach-Jagger H. , et al. Parathyroid hormone-related protein purified from a human lung cell line. Proc Natl Acad Sci 1987;84:5048-52.

10.

Burtis WJ Parathyroid hormone-related protein: Structure, function, and measurement . Clin Chem 1992;38:2171-83.

11.

Hellmen P. , Ridefelt P. , Juhlin C. , Åkerström G. , Rastad J. , Gylfe E. Parathyroid-like regulation of parathyroid-hormone-related protein release and cytoplasmic calcium in cytotrophoblast cells of human placenta . Arch Biochem Biophys 1992;293:174-80.

12.

Maclsaac RJ , Heath JA , Rodda CP , et al. Role of the fetal parathyroid and parathyroid hormone-related protein in the regulation of placental transport of calcium, magnesium and inorganic phosphate. Reprod Fertil Dev 1991;3:447-57.

13.

Glance DG , Elder MG , Bloxam DL , Myatt L. The effect of the components of the renin-angiotensin system on the isolated perfused human placental cotyledon. Am J Obstet Gynecol 1985;151:387-91.

14.

Ferguson JE , Gorman JV , Martin TJ , Bruns DE , Bruns ME Parathyroid hormone-related peptide (PTHrP) mRNA is expressed in human pregnant uterus (abstract). 13th Annual Meeting, American Society of Bone and Mineral Research, San Diego, California , August 24-28, 1991.

15.

Ferguson JE , Mills SE , Bruns DE , et al. Localization of the uterine muscle relaxant parathyroid hormone-related protein (PTHrP) in human amnion: Light and electron microscopic immunocytochemistry (abstract). 40th Meeting, Society for Gynecologic Investigation, Toronto, Ontario, Canada, March 31-April 3, 1993.

16.

Shew RL , Yee JA , Kliewer DB , Keflemariam YJ , McNeill DL Parathyroid hormone-related protein inhibits stimulated uterine contraction in vitro. J Bone Miner Res 1991; 6:955-9.

17.

Erk A. , MacDonald PC , Casey ML Parathyroid hormone [PTH1-34] and parathyroid-related protein (PTH-rP) stimulation of adenylate cyclase in human myometrial smooth muscle cells and human endometrial stromal cells. Abstract. 40th Meeting, Society for Gynecologic Investigation, Toronto, Ontario, Canada, March 31-April 3, 1993.

18.

Kemp BE , Mosely JM , Rodda CP Parathyroid hormone-related protein of malignancy: Active synthetic fragments . Science 1987;238:1568-70.

19.

Caulfield MP , McKee RL , Goldman ME The bovine renal parathyroid hormone (PTH) receptor has equal affinity for two different amino acid sequences: The receptor binding domains of PTH and PTH-related protein are located within the 14-34 region. Endocrinology 1990;127:83-7.

20.

Nickols GA , Nickols MA , Helwig JJ Binding of parathyroid hormone and parathyroid hormone-related protein to vascular smooth muscle of rabbit renal microvessels. Endocrinology 1990;126:721-7.

21.

Yang D. , Van Buren GA , Clark KE Effect of calcitonin gene-related peptide on the uterine vasculature of the nonpregnant ewe. Am J Obstet Gynecol 1992;167:178-84.

22.

Nelson SH , Steinsland OS , Suresh MS Possible physiologic role of calcitonin gene-related peptide in the human uterine artery. Am J Obstet Gynecol 1993;168:605-11.

23.

Jansen I. Characterization of calcitonin gene-related peptide (CGRP) receptors in guinea pig basilar artery. Neuropeptides 1992;21:73-9.

24.

Jansen I. , Mortensen A. , Edvinsson L. Characterization of calcitonin gene-related peptide receptors in human cerebral vessels: Vasomotor responses and cAMP accumulation. Ann NY Acad Sci 1992;657:435-40.

25.

Ralevic V. , Khalil Z. , Dusting GJ , Helme RD Nitric oxide and sensory nerves are involved in the vasodilator response to acetylcholine but not calcitonin gene-related peptide in rat skin microvasculature . Br J Pharmacol 1992;106:650-5.