The placenta produces vasoactive hormones which act locally to modulate the maternal-placental and fetal-placental circulations and, more distally, to modulate maternal and fetal vascular tone and reactivity. Abnormalities in the balance between vasodepressor and vasopressor hormones produced by the placenta may contribute to the pathogenesis of toxemia of pregnancy, the second most common cause of maternal death in the United States. During normal pregnancy the blood pressure raising effect of angiotensin II (AII) is diminished, presumably because of elevated circulating prostaglandins (PGs) produced by the placenta. In toxemic patients, hyperresponsiveness to AII occurs which may contribute to the pathogenesis of the disorder. We will test the hypothesis that accentuated responses to AII in toxemia result from either increased binding of AII to specific receptor sites, augmented post-receptor events, or by modulation of target organ effects by prostacyclin (PGI2). In preliminary experiments performed on human placentas, we have demonstrated the presence of functional high affinity receptor sites for AII. In the first phase of this proposal we will study the physiology of AII-PGI2 interactions in the normal human placenta. Using the isolated perfused human placental cotyledon, we will study the relationship between AII, PGs and vascular resistance. The generation of AII and PGs in the placental circulation will be measured, ligand binding studies will be performed to characterize placental PGI2 receptor sites, and the effects of AII and PGI2 on the placental adenylate cyclase system will be studied. The cell type(s) containing AII and PGI2 binding sites will be determined by autoradiography. In the second phase of this proposal we will investigate the AII-PG relationship in placentas derived from patients with toxemia of pregnancy. Using the methods developed in the first part of these studies, we will compare placentas obtained from normal and toxemic pregnancies with respect to the affinity and density of AII and PGI2 receptors, vascular responsiveness to AII and PGI2, and the effects of AII and PGI2 on placental adenylate cyclase. These studies will lead to a better understanding of the relationship between PG production and vascular reactivity to AII in the human placenta and may lead to new treatments for toxemia of pregnancy.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Unknown (R23)
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Human Embryology and Development Subcommittee 2 (HED)
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North Shore University Hospital
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Hedberg, A; Mento, P F; Liu, E C et al. (1989) Evidence for functional thromboxane A2-prostaglandin H2 receptors in human placenta. Am J Physiol 256:E256-63
Verburg, K M; Kleinert, H D; Kadam, J R et al. (1989) Effects of chronic infusion of renin inhibitor A-64662 in sodium-depleted monkeys. Hypertension 13:262-72
Mento, P F; Holt, W F; Murphy, W R et al. (1989) Combined renin and converting enzyme inhibition in rats. Hypertension 13:741-8
Wilkes, B M; Solomon, J; Maita, M et al. (1989) Characterization of glomerular thromboxane receptor sites in the rat. Am J Physiol 256:F1111-6
Wilkes, B M (1988) Increased angiotensin II receptor binding with age in isolated rat glomeruli. Kidney Int 34:241-7
Wilkes, B M; Pion, I; Sollott, S et al. (1988) Intrarenal renin-angiotensin system modulates glomerular angiotensin receptors in the rat. Am J Physiol 254:F345-50
Wilkes, B M; Mento, P F (1988) Bradykinin-induced vasoconstriction and thromboxane release in perfused human placenta. Am J Physiol 254:E681-6
Wilkes, B M (1987) Reduced glomerular angiotensin II receptor density in diabetes mellitus in the rat: time course and mechanism. Endocrinology 120:1291-8
Wilkes, B M; Hollenberg, N K (1987) Protection against acute renal failure by prior acute renal failure: differences between myohemoglobinuric and ischemic models. Nephron 47:220-6
Wilkes, B M; Mento, P F (1987) Glomerular angiotensin II receptor modulation in glycerol-induced acute renal failure. Am J Physiol 252:F109-14