The endothelium synthesizes and releases paracrine hormones that regulate the contraction of vascular smooth muscle cells. In addition to the well- described vasorelaxant factors recent experiments indicate that the endothelium also releases vasoconstrictor compounds (e.g., endothelin). The objective of this investigation is to study the role on endothelin in the modulation of fetoplacental vascular resistance in humans and to study its potential role in high-risk pregnancies associated with maternal hypertension and decreased fetoplacental blood flow. The vasoconstrictor action of endothelin is dependent on its local concentration, the presence of specific high affinity receptor sites, and post-receptor coupling to effector mechanisms to cause vasoconstriction. We will compare endothelin production, binding sites, vascular responsiveness and endothelin- stimulated eicosanoid production in placentas from normal pregnancies with placentas from high-risk pregnancies due to pregnancy-induced hypertension, essential hypertension, intrauterine growth retardation and diabetes mellitus. Endothelin-1, endothelin-2, endothelin-3 and endothelin (1-38) will be measured using sensitive and specific assays which combine extraction, HPLC fractionation and radioimmunoassay. The dually perfused isolated placental cotyledon will be used to study endothelin production, vascular responsiveness to endothelin and the relationship between endothelin and eicosanoids. Endothelin receptor sites will be characterized using ligand binding techniques in a membrane fraction prepared from placental vessels. These experiments will provide important new information on the production and actions of endothelin in human pregnancy and provide insights critical to our understanding of the pathogenesis of vasoconstriction in high-risk pregnancies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL044373-01A1
Application #
3363089
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Project Start
1991-02-01
Project End
1995-01-31
Budget Start
1991-02-01
Budget End
1992-01-31
Support Year
1
Fiscal Year
1991
Total Cost
Indirect Cost
Name
North Shore University Hospital
Department
Type
DUNS #
City
Manhasset
State
NY
Country
United States
Zip Code
11030
Mento, P F; Pica, M E; Hilepo, J et al. (1998) Increased expression of glomerular AT1 receptors in rats with myocardial infarction. Am J Physiol 275:H1247-53
Mento, P F; Maita, M E; Wilkes, B M (1996) Renal hemodynamics in rats with myocardial infarction: selective antagonism of angiotensin receptor subtypes. Am J Physiol 271:H2306-12
Vernace, M A; Mento, P F; Maita, M E et al. (1995) Osmolar regulation of endothelin signaling in rat renal medullary interstitial cells. J Clin Invest 96:183-91
Vernace, M A; Mento, P F; Maita, M E et al. (1994) Effects of angiotensin receptor subtype inhibitors on plasma angiotensin clearance. Hypertension 23:853-6
Wilkes, B M; Mento, P F; Hollander, A M (1994) Reduced thromboxane receptor affinity and vasoconstrictor responses in placentae from diabetic pregnancies. Placenta 15:845-55
Wilkes, B M; Macica, C M; Mento, P F (1994) Endothelin-1 conversion and receptor characterization in human placental arteries. Am J Physiol 267:E242-9
Wilkes, B M; Susin, M; Mento, P F (1993) Localization of endothelin-1-like immunoreactivity in human placenta. J Histochem Cytochem 41:535-41
Wilkes, B M; Mento, P F; Vernace, M A (1993) Angiotensin responsiveness in hyperfiltering and nonhyperfiltering diabetic rats. J Am Soc Nephrol 4:1346-53
Mento, P F; Maita, M E; Murphy, W R et al. (1993) Comparison of angiotensin converting enzyme and renin inhibition in rats following myocardial infarction. J Cardiovasc Pharmacol 21:791-6
Wilkes, B M; Hollander, A M; Sung, S Y et al. (1992) Cyclooxygenase inhibitors blunt thromboxane action in human placental arteries by blocking thromboxane receptors. Am J Physiol 263:E718-23

Showing the most recent 10 out of 13 publications