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. 1993 Nov;92(5):2240–2248. doi: 10.1172/JCI116827

Myometrial angiotensin II receptor subtypes change during ovine pregnancy.

B E Cox 1, M A Ipson 1, P W Shaul 1, K E Kamm 1, C R Rosenfeld 1
PMCID: PMC288404  PMID: 8227339

Abstract

Although regulation of angiotensin II receptor (AT) binding in vascular and uterine smooth muscle is similar in nonpregnant animals, studies suggest it may differ during pregnancy. We, therefore, examined binding characteristics of myometrial AT receptors in nulliparous (n = 7), pregnant (n = 24, 110-139 d of gestation), and postpartum (n = 21, 5 to > or = 130 d) sheep and compared this to vascular receptor binding. We also determined if changes in myometrial binding reflect alterations in receptor subtype. By using plasma membrane preparations from myometrium and medial layer of abdominal aorta, we determined receptor density and affinity employing radioligand binding; myometrial AT receptor subtypes were assessed by inhibiting [125I]-ANG II binding with subtype-specific antagonists. Compared to nulliparous ewes, myometrial AT receptor density fell approximately 90% during pregnancy (1,486 +/- 167 vs. 130 +/- 16 fmol/mg protein) and returned to nulliparous values > or = 4 wk postpartum; vascular binding was unchanged. Nulliparous myometrium expressed predominantly AT2 receptors (AT1/AT2 congruent to 15%/85%), whereas AT1 receptors predominated during pregnancy (AT1/AT2 congruent to 80%/20%). By 5 d postpartum AT1/AT2 congruent to 40%/60%, and > 4 wk postpartum AT2 receptors again predominated (AT1/AT2 congruent to 15%/85%). In studies of ANG II-induced force generation, myometrium from pregnant ewes (n = 10) demonstrated dose-dependent increases in force (P < 0.001), which were inhibited with an AT1 receptor antagonist. Postpartum myometrial responses were less at doses > or = 10(-9) M (P < 0.05) and unaffected by AT2 receptor antagonists. Vascular and myometrial AT receptor binding are differentially regulated during ovine pregnancy, the latter primarily reflecting decreases in AT2 receptor expression. This is the first description of reversible changes in AT receptor subtype in adult mammals.

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Selected References

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  1. Aguilera G., Catt K. Regulation of vascular angiotensin II receptors in the rat during altered sodium intake. Circ Res. 1981 Sep;49(3):751–758. doi: 10.1161/01.res.49.3.751. [DOI] [PubMed] [Google Scholar]
  2. Aguilera G., Hauger R. L., Catt K. J. Control of aldosterone secretion during sodium restriction: adrenal receptor regulation and increased adrenal sensitivity to angiotensin II. Proc Natl Acad Sci U S A. 1978 Feb;75(2):975–979. doi: 10.1073/pnas.75.2.975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Blair-West J. R., Coghlan J. P., Denton D. A., Scoggins B. A., Wintour E. M. The pressor effect of angiotensin II in pregnant sheep. Aust J Exp Biol Med Sci. 1972 Dec;50(6):739–744. doi: 10.1038/icb.1972.67. [DOI] [PubMed] [Google Scholar]
  4. Bottari S. P., King I. N., Reichlin S., Dahlstroem I., Lydon N., de Gasparo M. The angiotensin AT2 receptor stimulates protein tyrosine phosphatase activity and mediates inhibition of particulate guanylate cyclase. Biochem Biophys Res Commun. 1992 Feb 28;183(1):206–211. doi: 10.1016/0006-291x(92)91629-5. [DOI] [PubMed] [Google Scholar]
  5. Brown G. P., Venuto R. C. Angiotensin II receptor alterations during pregnancy in rabbits. Am J Physiol. 1986 Jul;251(1 Pt 1):E58–E64. doi: 10.1152/ajpendo.1986.251.1.E58. [DOI] [PubMed] [Google Scholar]
  6. CHESLEY L. C., TALLEDO E., BOHLER C. S., ZUSPAN F. P. VASCULAR REACTIVITY TO ANGIOTENSIN II AND NOREPINEPHRINE IN PREGNANT WOMEN. Am J Obstet Gynecol. 1965 Mar 15;91:837–842. doi: 10.1016/0002-9378(65)90462-x. [DOI] [PubMed] [Google Scholar]
  7. Catt K. J., Mendelsohn F. A., Millan M. A., Aguilera G. The role of angiotensin II receptors in vascular regulation. J Cardiovasc Pharmacol. 1984;6 (Suppl 4):S575–S586. doi: 10.1097/00005344-198406004-00004. [DOI] [PubMed] [Google Scholar]
  8. Chiu A. T., Herblin W. F., McCall D. E., Ardecky R. J., Carini D. J., Duncia J. V., Pease L. J., Wong P. C., Wexler R. R., Johnson A. L. Identification of angiotensin II receptor subtypes. Biochem Biophys Res Commun. 1989 Nov 30;165(1):196–203. doi: 10.1016/0006-291x(89)91054-1. [DOI] [PubMed] [Google Scholar]
  9. Chiu A. T., McCall D. E., Nguyen T. T., Carini D. J., Duncia J. V., Herblin W. F., Uyeda R. T., Wong P. C., Wexler R. R., Johnson A. L. Discrimination of angiotensin II receptor subtypes by dithiothreitol. Eur J Pharmacol. 1989 Oct 24;170(1-2):117–118. doi: 10.1016/0014-2999(89)90145-3. [DOI] [PubMed] [Google Scholar]
  10. Criscione L., Thomann H., Whitebread S., de Gasparo M., Bühlmayer P., Herold P., Ostermayer F., Kamber B. Binding characteristics and vascular effects of various angiotensin II antagonists. J Cardiovasc Pharmacol. 1990;16 (Suppl 4):S56–S59. doi: 10.1097/00005344-199016004-00012. [DOI] [PubMed] [Google Scholar]
  11. Cunningham F. G., Cox K., Gant N. F. Further observations on the nature of pressor responsivity to angiotensin II in human pregnancy. Obstet Gynecol. 1975 Nov;46(5):581–583. [PubMed] [Google Scholar]
  12. Devynck M. A., Meyer P. Angiotensin receptors in vascular tissue. Am J Med. 1976 Nov;61(5):758–767. doi: 10.1016/0002-9343(76)90157-1. [DOI] [PubMed] [Google Scholar]
  13. Devynck M. A., Pernollet M. G., Macdonald G. J., Matthews P. G., Raisman R. S., Meyer P. Alterations of adrenal and uterine angiotensin II receptors during variation of sodium intake and/or experimental hypertension. Clin Sci Mol Med Suppl. 1978 Dec;4:171S–174S. doi: 10.1042/cs055171s. [DOI] [PubMed] [Google Scholar]
  14. Devynck M. A., Rouzaire-Dubois B., Chevillotte E., Meyer P. Variations in the number of uterine angiotensin receptors following changes in plasma angiotensin levels. Eur J Pharmacol. 1976 Nov;40(1):27–37. doi: 10.1016/0014-2999(76)90350-2. [DOI] [PubMed] [Google Scholar]
  15. Donker A. J., Min I., Venuto R. C. The conscious instrumented rabbit: a model for the study of mechanisms of blood pressure regulation during pregnancy. Hypertension. 1983 Jul-Aug;5(4):514–520. doi: 10.1161/01.hyp.5.4.514. [DOI] [PubMed] [Google Scholar]
  16. Dudley D. T., Panek R. L., Major T. C., Lu G. H., Bruns R. F., Klinkefus B. A., Hodges J. C., Weishaar R. E. Subclasses of angiotensin II binding sites and their functional significance. Mol Pharmacol. 1990 Sep;38(3):370–377. [PubMed] [Google Scholar]
  17. Gant N. F., Chand S., Whalley P. J., MacDonald P. C. The nature of pressor responsiveness to angiotensin II in human pregnancy. Obstet Gynecol. 1974 Jun;43(6):854–854. [PubMed] [Google Scholar]
  18. Gant N. F., Daley G. L., Chand S., Whalley P. J., MacDonald P. C. A study of angiotensin II pressor response throughout primigravid pregnancy. J Clin Invest. 1973 Nov;52(11):2682–2689. doi: 10.1172/JCI107462. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Grady E. F., Sechi L. A., Griffin C. A., Schambelan M., Kalinyak J. E. Expression of AT2 receptors in the developing rat fetus. J Clin Invest. 1991 Sep;88(3):921–933. doi: 10.1172/JCI115395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Gunther S., Gimbrone M. A., Jr, Alexander R. W. Regulation by angiotensin II of its receptors in resistance blood vessels. Nature. 1980 Sep 18;287(5779):230–232. doi: 10.1038/287230a0. [DOI] [PubMed] [Google Scholar]
  21. Herblin W. F., Chiu A. T., McCall D. E., Ardecky R. J., Carini D. J., Duncia J. V., Pease L. J., Wong P. C., Wexler R. R., Johnson A. L. Angiotensin II receptor heterogeneity. Am J Hypertens. 1991 Apr;4(4 Pt 2):299S–302S. doi: 10.1093/ajh/4.4.299s. [DOI] [PubMed] [Google Scholar]
  22. Kurauchi O., Mizutani S., Nomura S., Furuhashi M., Kasugai M., Tomoda Y. Changes in the binding of angiotensin II to rat placental receptor by estrogen and progesterone. Horm Metab Res. 1989 Oct;21(10):558–560. doi: 10.1055/s-2007-1009287. [DOI] [PubMed] [Google Scholar]
  23. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  24. Liggins G. C., Fairclough R. J., Grieves S. A., Forster C. S., Knox B. S. Parturition in the sheep. Ciba Found Symp. 1977;(47):5–30. doi: 10.1002/9780470720295.ch2. [DOI] [PubMed] [Google Scholar]
  25. McPherson G. A. Analysis of radioligand binding experiments. A collection of computer programs for the IBM PC. J Pharmacol Methods. 1985 Nov;14(3):213–228. doi: 10.1016/0160-5402(85)90034-8. [DOI] [PubMed] [Google Scholar]
  26. Munson P. J., Rodbard D. Ligand: a versatile computerized approach for characterization of ligand-binding systems. Anal Biochem. 1980 Sep 1;107(1):220–239. doi: 10.1016/0003-2697(80)90515-1. [DOI] [PubMed] [Google Scholar]
  27. Naden R. P., Coultrup S., Arant B. S., Rosenfeld C. R. Metabolic clearance of angiotensin II in pregnant and nonpregnant sheep. Am J Physiol. 1985 Jul;249(1 Pt 1):E49–E55. doi: 10.1152/ajpendo.1985.249.1.E49. [DOI] [PubMed] [Google Scholar]
  28. Naden R. P., Gant N. F., Jr, Rosenfeld C. R. The pressor response to angiotensin II: the roles of peripheral and cardiac responses in pregnant and nonpregnant sheep. Am J Obstet Gynecol. 1984 Feb 15;148(4):450–457. doi: 10.1016/0002-9378(84)90725-7. [DOI] [PubMed] [Google Scholar]
  29. Obermüller N., Unger T., Culman J., Gohlke P., de Gasparo M., Bottari S. P. Distribution of angiotensin II receptor subtypes in rat brain nuclei. Neurosci Lett. 1991 Oct 28;132(1):11–15. doi: 10.1016/0304-3940(91)90420-x. [DOI] [PubMed] [Google Scholar]
  30. Paller M. S. Mechanism of decreased pressor responsiveness to ANG II, NE, and vasopressin in pregnant rats. Am J Physiol. 1984 Jul;247(1 Pt 2):H100–H108. doi: 10.1152/ajpheart.1984.247.1.H100. [DOI] [PubMed] [Google Scholar]
  31. Parent A., Schiffrin E. L., St-Louis J. Receptors for Arg8-vasopressin, angiotensin II, and atrial natriuretic peptide in the mesenteric vasculature of pregnant rats. Can J Physiol Pharmacol. 1991 Feb;69(2):137–144. doi: 10.1139/y91-020. [DOI] [PubMed] [Google Scholar]
  32. Parker C. R., Jr, Everett R. B., Whalley P. J., Quirk J. G., Jr, Gant N. F., MacDonald P. C. Hormone production during pregnancy in the primigravid patient. II. Plasma levels of deoxycorticosterone throughout pregnancy of normal women and women who developed pregnancy-induced hypertension. Am J Obstet Gynecol. 1980 Nov 15;138(6):626–631. [PubMed] [Google Scholar]
  33. Rosenfeld C. R. Distribution of cardiac output in ovine pregnancy. Am J Physiol. 1977 Mar;232(3):H231–H235. doi: 10.1152/ajpheart.1977.232.3.H231. [DOI] [PubMed] [Google Scholar]
  34. Rosenfeld C. R., Gant N. F., Jr The chronically instrumental ewe: a model for studying vascular reactivity to angiotensin II in pregnancy. J Clin Invest. 1981 Feb;67(2):486–492. doi: 10.1172/JCI110057. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Rosenfeld C. R., Killam A. P., Battaglia F. C., Makowski E. L., Meschia G. Effect of estradiol-17, on the magnitude and distribution of uterine blood flow in nonpregnant, oophorectomized ewes. Pediatr Res. 1973 Mar;7(3):139–148. doi: 10.1203/00006450-197303000-00006. [DOI] [PubMed] [Google Scholar]
  36. Rosenfeld C. R., Worley R. J., Milewich L., Grant N. F., Jr, Parker C. R., Jr Ovine fetoplacental sulfoconjugation and aromatization of dehydroepiandrosterone. Endocrinology. 1980 Jun;106(6):1971–1979. doi: 10.1210/endo-106-6-1971. [DOI] [PubMed] [Google Scholar]
  37. Schiffrin E. L., Franks D. J., Gutkowska J. Effect of aldosterone on vascular angiotensin II receptors in the rat. Can J Physiol Pharmacol. 1985 Dec;63(12):1522–1527. doi: 10.1139/y85-250. [DOI] [PubMed] [Google Scholar]
  38. Schiffrin E. L., Gutkowska J., Genest J. Effect of angiotensin II and deoxycorticosterone infusion on vascular angiotensin II receptors in rats. Am J Physiol. 1984 Apr;246(4 Pt 2):H608–H614. doi: 10.1152/ajpheart.1984.246.4.H608. [DOI] [PubMed] [Google Scholar]
  39. Schirar A., Capponi A., Catt K. J. Elevation of uterine angiotensin II receptors during early pregnancy in the rat. Endocrinology. 1980 May;106(5):1521–1527. doi: 10.1210/endo-106-5-1521. [DOI] [PubMed] [Google Scholar]
  40. Schirar A., Capponi A., Catt K. J. Regulation of uterine angiotensin II receptors by estrogen and progesterone. Endocrinology. 1980 Jan;106(1):5–12. doi: 10.1210/endo-106-1-5. [DOI] [PubMed] [Google Scholar]
  41. Siddiqi T. A., Austin J. E., Holroyd J. C., Clark K. E. Modulation of angiotensin II pressor responsiveness by circulating levels of angiotensin II in pregnant sheep. Am J Obstet Gynecol. 1983 Feb 15;145(4):458–464. doi: 10.1016/0002-9378(83)90317-4. [DOI] [PubMed] [Google Scholar]
  42. Siddiqi T. A., Koenig B. B., Clark K. E. Pregnancy causes a decrease in the number and affinity of myometrial angiotensin II receptors. Obstet Gynecol. 1986 Dec;68(6):820–824. [PubMed] [Google Scholar]
  43. Talledo O. E. Renin-angiotensin system in normal and toxemic pregnancies. I. Angiotensin infusion test. Am J Obstet Gynecol. 1966 Sep 1;96(1):141–143. doi: 10.1016/s0002-9378(16)34655-5. [DOI] [PubMed] [Google Scholar]
  44. Whitebread S., Mele M., Kamber B., de Gasparo M. Preliminary biochemical characterization of two angiotensin II receptor subtypes. Biochem Biophys Res Commun. 1989 Aug 30;163(1):284–291. doi: 10.1016/0006-291x(89)92133-5. [DOI] [PubMed] [Google Scholar]
  45. Wilson M., Morganti A. A., Zervoudakis I., Letcher R. L., Romney B. M., Von Oeyon P., Papera S., Sealey J. E., Laragh J. H. Blood pressure, the renin-aldosterone system and sex steroids throughout normal pregnancy. Am J Med. 1980 Jan;68(1):97–104. doi: 10.1016/0002-9343(80)90178-3. [DOI] [PubMed] [Google Scholar]

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