Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1986 Jan;77(1):236–245. doi: 10.1172/JCI112282

Evidence against the hypothesis that prostaglandins are the vasodepressor agents of pregnancy. Serial studies in chronically instrumented, conscious rats.

K P Conrad, M C Colpoys
PMCID: PMC423332  PMID: 3944253

Abstract

Renal hemodynamics increase dramatically during pregnancy, and pressor responsiveness to exogenous administration of vasoconstrictors is attenuated. We investigated whether or not vasodilatory prostaglandins mediate these phenomena. Trained, chronically instrumented, conscious pregnant rats were used. Control values of glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were elevated at midgestation (P less than 0.01 and P = 0.05 from prepregnant means, respectively), and effective renal vascular resistance was decreased (P = 0.05). Indomethacin (4.5-6.5 mg/kg body weight [BW]) failed to decrease renal hemodynamics at this stage of pregnancy; in fact, it raised GFR somewhat further (P less than 0.05). Systemic pressor responsiveness to bolus administration of norepinephrine and angiotensin II (AII) was significantly attenuated by at least gestational day 20. Neither indomethacin (7 mg/kg BW) or meclofenamate (6 mg/kg BW) affected the refractory response. The renal vasculature was also relatively unresponsive to an intravenous infusion of AII (5 ng X kg-1 X min-1) during late gestation (day 19); in particular, the fall in ERPF in response to AII (16 +/- 3%) was markedly less than that observed in the prepregnant condition (34 +/- 3%; P less than 0.05). Indomethacin (6 mg/kg BW) failed to restore this blunted response, and further attenuation was evident, despite the presence of the inhibitor (gestational day 21). We conclude that vasodilatory prostaglandins do not appear to mediate the rise in renal hemodynamics, and the attenuation of the systemic and renal pressor responsiveness observed during pregnancy, insofar as these phenomena were unaffected by acute cyclooxygenase inhibition in unstressed, conscious rats.

Full text

PDF
236

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bellucci A., Wilkes B. M. Mechanism of sodium modulation of glomerular angiotensin receptors in the rat. J Clin Invest. 1984 Nov;74(5):1593–1600. doi: 10.1172/JCI111575. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Benzoni D., Vincent M., Betend B., Sassard J. Urinary excretion of prostaglandins and electrolytes in developing children. Kidney Int. 1981 Sep;20(3):386–388. doi: 10.1038/ki.1981.150. [DOI] [PubMed] [Google Scholar]
  3. Berl T., Raz A., Wald H., Horowitz J., Czaczkes W. Prostaglandin synthesis inhibition and the action of vasopressin: studies in man and rat. Am J Physiol. 1977 Jun;232(6):F529–F537. doi: 10.1152/ajprenal.1977.232.6.F529. [DOI] [PubMed] [Google Scholar]
  4. Bing R. F., Russell G. I., Thurston H., Swales J. D., Godfrey N., Lazarus Y., Jackson J. Chemical renal medullectomy. Effect on urinary prostaglandin E2 and plasma renin in response to variations in sodium intake and in relation to blood pressure. Hypertension. 1983 Nov-Dec;5(6):951–957. doi: 10.1161/01.hyp.5.6.951. [DOI] [PubMed] [Google Scholar]
  5. Bohr D. F., Webb R. C. Vascular smooth muscle function and its changes in hypertension. Am J Med. 1984 Oct 5;77(4A):3–16. doi: 10.1016/s0002-9343(84)80032-7. [DOI] [PubMed] [Google Scholar]
  6. Burger B. M., Hopkins T., Tulloch A., Hollenberg N. K. The role of angiotensin in the canine renal vascular response to barbiturate anesthesia. Circ Res. 1976 Mar;38(3):196–202. doi: 10.1161/01.res.38.3.196. [DOI] [PubMed] [Google Scholar]
  7. Carvalho J. S., Shapiro R., Hopper P., Page L. B. Methods for serial study of renin-angiotensin system in the unanesthetized rat. Am J Physiol. 1975 Feb;228(2):369–375. doi: 10.1152/ajplegacy.1975.228.2.369. [DOI] [PubMed] [Google Scholar]
  8. Churchi-l S. E., Bengele H. H., Alexander E. A. Sodium balance during pregnancy in the rat. Am J Physiol. 1980 Jul;239(1):R143–R148. doi: 10.1152/ajpregu.1980.239.1.R143. [DOI] [PubMed] [Google Scholar]
  9. Conrad K. P. Renal hemodynamics during pregnancy in chronically catheterized, conscious rats. Kidney Int. 1984 Jul;26(1):24–29. doi: 10.1038/ki.1984.129. [DOI] [PubMed] [Google Scholar]
  10. DANFORTH D. N., MANALO-ESTRELLA P., BUCKINGHAM J. C. THE EFFECT OF PREGNANCY AND OF ENOVID ON THE RABBIT VASCULATURE. Am J Obstet Gynecol. 1964 Apr 1;88:952–962. doi: 10.1016/0002-9378(64)90741-0. [DOI] [PubMed] [Google Scholar]
  11. Davison J. M., Hytten F. E. Glomerular filtration during and after pregnancy. J Obstet Gynaecol Br Commonw. 1974 Aug;81(8):588–595. doi: 10.1111/j.1471-0528.1974.tb00522.x. [DOI] [PubMed] [Google Scholar]
  12. Donker A. J., Arisz L., Brentjens J. R., van der Hem G. K., Hollemans H. J. The effect of indomethacin on kidney function and plasma renin activity in man. Nephron. 1976;17(4):288–296. doi: 10.1159/000180733. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. Dray F., Charbonnel B., Maclouf J. Radioimmunoassay of prostaglandins Falpha, E1 and E2 in human plasma. Eur J Clin Invest. 1975 Jul 29;5(4):311–318. doi: 10.1111/j.1365-2362.1975.tb00459.x. [DOI] [PubMed] [Google Scholar]
  15. Dunn M. J. Prostaglandins and Bartter's syndrome. Kidney Int. 1981 Jan;19(1):86–102. doi: 10.1038/ki.1981.12. [DOI] [PubMed] [Google Scholar]
  16. FUHR J., KACZMARCZYK J., KRUTTGEN C. D. Eine einfache colorimetrische Methode zur Inulinbestimmung für Nieren-Clearance-Untersuchungen bei Stoffwechselgesunden und Diabetikern. Klin Wochenschr. 1955 Aug 1;33(29-30):729–730. doi: 10.1007/BF01473295. [DOI] [PubMed] [Google Scholar]
  17. Flower R. J. Drugs which inhibit prostaglandin biosynthesis. Pharmacol Rev. 1974 Mar;26(1):33–67. [PubMed] [Google Scholar]
  18. Fray J. C., Siwek L. G., Strull W. M., Steller R. N., Wilson J. M. Influence of dietary sodium on renin activity and arterial pressure during anesthesia. Am J Physiol. 1976 Oct;231(4):1185–1190. doi: 10.1152/ajplegacy.1976.231.4.1185. [DOI] [PubMed] [Google Scholar]
  19. Freeman R. H., Davis J. O., Villarreal D. Role of renal prostaglandins in the control of renin release. Circ Res. 1984 Jan;54(1):1–9. doi: 10.1161/01.res.54.1.1. [DOI] [PubMed] [Google Scholar]
  20. Frölich J. C., Wilson T. W., Sweetman B. J., Smigel M., Nies A. S., Carr K., Watson J. T., Oates J. A. Urinary prostaglandins. Identification and origin. J Clin Invest. 1975 Apr;55(4):763–770. doi: 10.1172/JCI107987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Fuchs K. I., Moore L. G., Rounds S. Pulmonary vascular reactivity is blunted in pregnant rats. J Appl Physiol Respir Environ Exerc Physiol. 1982 Sep;53(3):703–707. doi: 10.1152/jappl.1982.53.3.703. [DOI] [PubMed] [Google Scholar]
  22. Gant N. F., Worley R. J., Everett R. B., MacDonald P. C. Control of vascular responsiveness during human pregnancy. Kidney Int. 1980 Aug;18(2):253–258. doi: 10.1038/ki.1980.133. [DOI] [PubMed] [Google Scholar]
  23. Gellai M., Valtin H. Chronic vascular constrictions and measurements of renal function in conscious rats. Kidney Int. 1979 Apr;15(4):419–426. doi: 10.1038/ki.1979.54. [DOI] [PubMed] [Google Scholar]
  24. Gerber J. G., Payne N. A., Murphy R. C., Nies A. S. Prostacyclin produced by the pregnant uterus in the dog may act as a circulating vasodepressor substance. J Clin Invest. 1981 Mar;67(3):632–636. doi: 10.1172/JCI110077. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Goodman R. P., Killam A. P., Brash A. R., Branch R. A. Prostacyclin production during pregnancy: comparison of production during normal pregnancy and pregnancy complicated by hypertension. Am J Obstet Gynecol. 1982 Apr 1;142(7):817–822. doi: 10.1016/s0002-9378(16)32525-x. [DOI] [PubMed] [Google Scholar]
  26. Hart J. L. Barium responsiveness of the rat aorta and femoral artery during pregnancy. Life Sci. 1982 Jan 11;30(2):163–169. doi: 10.1016/0024-3205(82)90648-8. [DOI] [PubMed] [Google Scholar]
  27. Hart J. L. Effects of pregnancy on spontaneous contraction and barium responsiveness of the rat portal vein. Biol Res Pregnancy Perinatol. 1984;5(2):78–83. [PubMed] [Google Scholar]
  28. Hassid A., Williams C. Vasoconstrictor-evoked prostaglandin synthesis in cultured vascular smooth muscle. Am J Physiol. 1983 Sep;245(3):C278–C282. doi: 10.1152/ajpcell.1983.245.3.C278. [DOI] [PubMed] [Google Scholar]
  29. Haylor J., Lote C. J. Renal function in conscious rats after indomethacin. Evidence for a tubular action of endogenous prostaglandins. J Physiol. 1980 Jan;298:371–381. doi: 10.1113/jphysiol.1980.sp013087. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Johnson M. D., Malvin R. L. Plasma renin activity during pentobarbital anesthesia and graded hemorrhage in dogs. Am J Physiol. 1975 Oct;229(4):1098–1101. doi: 10.1152/ajplegacy.1975.229.4.1098. [DOI] [PubMed] [Google Scholar]
  31. Johnston I. D. The endocrine response to trauma. Adv Clin Chem. 1972;15:255–285. doi: 10.1016/s0065-2423(08)60161-4. [DOI] [PubMed] [Google Scholar]
  32. Keeton T. K., Campbell W. B. The pharmacologic alteration of renin release. Pharmacol Rev. 1980 Jun;32(2):81–227. [PubMed] [Google Scholar]
  33. Klein K. L., Scott W. J., Clark K. E., Wilson J. G. Indomethacin--placental transfer, cytotoxicity, and teratology in the rat. Am J Obstet Gynecol. 1981 Oct 15;141(4):448–452. doi: 10.1016/0002-9378(81)90610-4. [DOI] [PubMed] [Google Scholar]
  34. Leyssac P. P., Christensen P., Hill R., Skinner S. L. Indomethacin blockade of renal PGE-synthesis: effect on total renal and tubular function and plasma renin concentration in hydropenic rats and on their response to isotonic saline. Acta Physiol Scand. 1975 Aug;94(4):484–496. doi: 10.1111/j.1748-1716.1975.tb05908.x. [DOI] [PubMed] [Google Scholar]
  35. Lifschitz M. D. Prostaglandins and renal blood flow: in vivo studies. Kidney Int. 1981 Jun;19(6):781–785. doi: 10.1038/ki.1981.80. [DOI] [PubMed] [Google Scholar]
  36. Linas S. L., Dickmann D. Mechanism of the decreased renal blood flow in the potassium-depleted conscious rat. Kidney Int. 1982 May;21(5):757–764. doi: 10.1038/ki.1982.94. [DOI] [PubMed] [Google Scholar]
  37. MacGillivray I., Rose G. A., Rowe B. Blood pressure survey in pregnancy. Clin Sci. 1969 Oct;37(2):395–407. [PubMed] [Google Scholar]
  38. Maddox D. A., Price D. C., Rector F. C., Jr Effects of surgery on plasma volume and salt and water excretion in rats. Am J Physiol. 1977 Dec;233(6):F600–F606. doi: 10.1152/ajprenal.1977.233.6.F600. [DOI] [PubMed] [Google Scholar]
  39. McLaughlin M. K., Quinn P. M., Farnham J. S. Differential sensitivity to angiotensin II in pregnant rabbits. Am J Obstet Gynecol. 1983 Jul 15;146(6):633–638. doi: 10.1016/0002-9378(83)91004-9. [DOI] [PubMed] [Google Scholar]
  40. Mizutani S., Yoshino M., Oya M., Noto H., Inamoto Y., Sakura H., Kawashima Y. A comparison of angiotensinase and placental leucine aminopeptidase during normal pregnancy. Clin Biochem. 1979 Apr;12(2):50–51. doi: 10.1016/s0009-9120(79)80005-3. [DOI] [PubMed] [Google Scholar]
  41. Momma K., Takeuchi H. Constriction of fetal ductus arteriosus by non-steroidal anti-inflammatory drugs. Prostaglandins. 1983 Oct;26(4):631–643. doi: 10.1016/0090-6980(83)90200-9. [DOI] [PubMed] [Google Scholar]
  42. Moore L. G., Reeves J. T. Pregnancy blunts pulmonary vascular reactivity in dogs. Am J Physiol. 1980 Sep;239(3):H297–H301. doi: 10.1152/ajpheart.1980.239.3.H297. [DOI] [PubMed] [Google Scholar]
  43. Naden R. P., Iliya C. A., Arant B. S., Jr, Gant N. F., Jr, Rosenfeld C. R. Hemodynamic effects of indomethacin in chronically instrumented pregnant sheep. Am J Obstet Gynecol. 1985 Feb 15;151(4):484–494. doi: 10.1016/0002-9378(85)90275-3. [DOI] [PubMed] [Google Scholar]
  44. Nadler J., Zipser R. D., Coleman R., Horton R. Stimulation of renal prostaglandins by pressor hormones in man: comparison of prostaglandin E2 and prostacyclin (6 keto prostaglandin F1 alpha). J Clin Endocrinol Metab. 1983 Jun;56(6):1260–1265. doi: 10.1210/jcem-56-6-1260. [DOI] [PubMed] [Google Scholar]
  45. Noel G. L., Suh H. K., Stone J. G., Frantz A. G. Human prolactin and growth hormone release during surgery and other conditions of stress. J Clin Endocrinol Metab. 1972 Dec;35(6):840–851. doi: 10.1210/jcem-35-6-840. [DOI] [PubMed] [Google Scholar]
  46. O'Brien P. M., Broughton Pipkin F. The effects of deprivation of prostaglandin precursors on vascular sensitivity to angiotensin II and on the kidney in the pregnant rabbit. Br J Pharmacol. 1979 Jan;65(1):29–34. doi: 10.1111/j.1476-5381.1979.tb17330.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Oyama T. Endocrine responses to anaesthetic agents. Br J Anaesth. 1973 Mar;45(3):276–281. doi: 10.1093/bja/45.3.276. [DOI] [PubMed] [Google Scholar]
  48. 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]
  49. Pedersen E. B., Christensen N. J., Christensen P., Johannesen P., Kornerup H. J., Kristensen S., Lauritsen J. G., Leyssac P. P., Rasmussen A., Wohlert M. Preeclampsia -- a state of prostaglandin deficiency? Urinary prostaglandin excretion, the renin-aldosterone system, and circulating catecholamines in preeclampsia. Hypertension. 1983 Jan-Feb;5(1):105–111. doi: 10.1161/01.hyp.5.1.105. [DOI] [PubMed] [Google Scholar]
  50. Pettinger W. A., Tanaka K., Keeton K., Campbell W. B., Brooks S. N. Renin release, an artifact of anesthesia and its implications in rats. Proc Soc Exp Biol Med. 1975 Mar;148(3):625–630. doi: 10.3181/00379727-148-38597. [DOI] [PubMed] [Google Scholar]
  51. 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]
  52. SIMS E. A., KRANTZ K. E. Serial studies of renal function during pregnancy and the puerperium in normal women. J Clin Invest. 1958 Dec;37(12):1764–1774. doi: 10.1172/JCI103769. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Samuelsson B., Granström E., Green K., Hamberg M., Hammarström S. Prostaglandins. Annu Rev Biochem. 1975;44:669–695. doi: 10.1146/annurev.bi.44.070175.003321. [DOI] [PubMed] [Google Scholar]
  54. Seligman S. A. Baroreceptor reflex function in pre-eclampsia. J Obstet Gynaecol Br Commonw. 1971 May;78(5):413–416. doi: 10.1111/j.1471-0528.1971.tb00294.x. [DOI] [PubMed] [Google Scholar]
  55. 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]
  56. Smith H. W., Finkelstein N., Aliminosa L., Crawford B., Graber M. THE RENAL CLEARANCES OF SUBSTITUTED HIPPURIC ACID DERIVATIVES AND OTHER AROMATIC ACIDS IN DOG AND MAN. J Clin Invest. 1945 May;24(3):388–404. doi: 10.1172/JCI101618. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Speroff L. An essay: prostaglandins and toxemia of pregnancy. Prostaglandins. 1973 May;3(5):721–728. doi: 10.1016/0090-6980(73)90107-x. [DOI] [PubMed] [Google Scholar]
  58. Swain J. A., Heyndrickx G. R., Boettcher D. H., Vatner S. F. Prostaglandin control of renal circulation in the unanesthetized dog and baboon. Am J Physiol. 1975 Sep;229(3):826–830. doi: 10.1152/ajplegacy.1975.229.3.826. [DOI] [PubMed] [Google Scholar]
  59. Terragno N. A., Terragno D. A., McGiff J. C. Contribution of prostaglandins to the renal circulation in conscious, anesthetized, and laparotomized dogs. Circ Res. 1977 Jun;40(6):590–595. doi: 10.1161/01.res.40.6.590. [DOI] [PubMed] [Google Scholar]
  60. Ueland K., Novy M. J., Peterson E. N., Metcalfe J. Maternal cardiovascular dynamics. IV. The influence of gestational age on the maternal cardiovascular response to posture and exercise. Am J Obstet Gynecol. 1969 Jul 15;104(6):856–864. [PubMed] [Google Scholar]
  61. Venuto R. C., Donker A. J. Prostaglandin E2, plasma renin activity, and renal function throughout rabbit pregnancy. J Lab Clin Med. 1982 Feb;99(2):239–246. [PubMed] [Google Scholar]
  62. Venuto R. C., O'Dorisio T., Stein J. H., Ferris T. F. Uterine prostaglandin E secretion and uterine blood flow in the pregnant rabbit. J Clin Invest. 1975 Jan;55(1):193–197. doi: 10.1172/JCI107911. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Venuto R., Min I., Barone P., Donker A., Cunningham E. Blood pressure control in pregnant rabbits: norepinephrine and prostaglandin interactions. Am J Physiol. 1984 Nov;247(5 Pt 2):R786–R791. doi: 10.1152/ajpregu.1984.247.5.R786. [DOI] [PubMed] [Google Scholar]
  64. Wagner K., Neumayer H. H., Schultze G., Schwietzer G., Schudrowitsch L., Ruf W., Molzahn M. Influence of prostaglandin A1 on renal filtration, hemodynamics and excretion. Investigations in chronically instrumented conscious dogs on a low- and high-sodium diet. Ren Physiol. 1983 Jul-Aug;6(4):186–196. [PubMed] [Google Scholar]
  65. Walker B. R. Antidiuresis and decreased sodium excretion during cyclo-oxygenase inhibition in the conscious dog. Ren Physiol. 1983;6(2):53–62. doi: 10.1159/000172881. [DOI] [PubMed] [Google Scholar]
  66. Walker L. A., Buscemi-Bergin M., Gellai M. Renal hemodynamics in conscious rats: effects of anesthesia, surgery, and recovery. Am J Physiol. 1983 Jul;245(1):F67–F74. doi: 10.1152/ajprenal.1983.245.1.F67. [DOI] [PubMed] [Google Scholar]
  67. Whalen J. B., Clancey C. J., Farley D. B., Van Orden D. E. Plasma prostaglandins in pregnancy. Obstet Gynecol. 1978 Jan;51(1):52–55. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES