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Pre-eclampsia: A hypothesis for its etiology
Medml Hypotheses(lW3) 27,15?-162 0 LangmanGroupUK Ltd 1988
Pre-eclampsia: A Hypothesis for its Etiology TIMOTHY J. HARDY* and PATRICIA B. WILLIAMS Eastern
Virginia
Medical
School,
P-0. Box 1980, Norfolk, VA 23501.
Abstract - A hypothesis is presented according to which the etiology of pregnancyinduced hypertension can be attributed to increased number of active uterine and arteriolar alpha-adrenergic myometrial receptors from pre-eclamptic patients in comparison with the alpha-adrenergic myometrial and arteriolar receptors from non-pre-eclamptic patients. This condition could result in the increased uterine wall irritability and the decreased uteroplacental blood flow in pre-eclampsia. It is suggested that progesterone fails to induce a reduction in alpha,-adrenergic receptors in the pre-eclamptic patient. This will require pre-eclamptic patients and matched controls to test the hypothesis.
Introduction
Characteristics of a normal pregnancy
Pre-eclampsia is a disease peculiar to humans. Clinical features of pre-eclampsia include hypertension, proteinuria and edema. Symptoms are rarely apparent before twenty weeks gestation. When symptoms appear, there is an association with trophoblastic disease. The incidence of pre-eclampsia is higher with the first pregnancy and with twins, There appears to be a familial pattern. In addition, approximately 10% of all women develop hypertension during pregnancy. Any proposed mechanism or etiology of preeclampsia should be able to explain the above predispositions and associations.
The normal physiology and changes during pregnancy must be considered along with the specific. deviations from normal that occur in preeclamptic patients. During normal pregnancy, the uterus increases in weight, ten-fold, from about 70 to 1100 (1). During the first 20 weeks the myometrial cells multiply. In the second half of pregnancy, the cells hypertrophy to accommodate the growing fetus. The inside surface area of the uterus increases approximately 500- to lOOO-fold from the nongravid state (2). Fetal growth, to a certain extent, parallels the growth of the uterus. The fetus grows exponentially until the fifteenth week at which time its rate of growth approaches a linear curve (2). During pregnancy, the cardiovascular system undergoes profoundchange. Blood volume increases 30% during pregnancy. Caridac output, as measured by Uceland and Metcalfe, increases steadily the first 20-24 weeks to a 30-40% in-
* Current address: The Providence Hospital 11.50 Varnum Street, N.E.: Washington. D.C. 20077
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MEDICAL
158 crease over the nonpregnant state and remains elevated during the third trimester (3). Blood flow to the uterus increases to approximately 500 ml/min at the end of normal pregnancy (3,, 4). Oxygen consumption of the pregnant uterus increases from 4.8 cc/min at 10 weeks to 22 cc/min at 28 weeks (5). Blood flows to the myometrium and traverses it to the uteroplacental bed, a low resitance cascular bed. The uteroplacental bed has been likened to an arteriovenous tistula (6). Effect of pre-eclampsia
on fetal development
All of the above changes presumably occur as an adaptation to accommodate and nourish the growing fetus. Quite a .different story evolves during the severe pre-eclamptic patient’s pregnancy. Several physiologic changes differentiate between a normal pregnancy and severe eclampsia. During pre-eclampsia the blood pressure is increased over normal. Browne and Veal1 (7) estimated a reduction of 50% of the uteroplacental blood flow by injecting radiolabelled sodium into maternal placental lakes of preeclamptic patients. Also noted was an increase in placental infarcts. These adaptations in the circulatory system in pre-eclampsia have been cited to support the uterine ischemia theory by Beker. Dexter. Dieckmann, Page and others (8, 9, IO. 11. 12). Response of myometrium to adrenergic agonists It is generally agreed that the myometrium
contracts in response to alpha-adrenergic stimulation (13, 14). During pregnancy, the myometrium has a blunted response to an infusion of catecholamines or to stimulation of the hypogastric nerve. Uterine alpha-adrenergic receptors of rabbits decrease in number per milligram protein during pregnancy. At day eight of a thirty day gestation period, the alpha-receptors have decreased by 67%. By day 30, the alpha-receptors have increased to almost pre-pregnant levels or 97% of nongravid levels. This reduction in alpha-receptors corresponds to a relative insensitivity of the uterus to catecholamines and hypogastric nerve stimulation (15). Hypogastric nerve stimulation, on day 0 of gestation and day 30 of gestation, results in uterine myometrial contraction. The mechanism of myometrial inhibition during pregnancy, suggested by Vallieres and associates (lS), is that the alpha-receptors
HYPOTHESES
are decreased due to an action of progesterone: thus, the betal-adrenergic receptors become the dominant receptors. The uterus of pregnant animals then either relaxes or does not respond to adrenergic stimulation via the hypogastric nerve (16. 17, 18). A similar study by Williams and Lefkowitz (19) showed a significant reduction in the number of [jH]DHE binding sites in progesterone primed uteri of rabbits as opposed to uteri primed with estrogen. Assuming that a decrease in myometrial alphareceptors similar to that in rabbits also occurs in humans. then the same mechanism as advanced for the rabbit model could be offered to explain why the gravid uterus is insensitive to catecholamines and hypogastric nerve stimulation. A significant decrease in the number of alpha,receptors would cause unmasking of the beta?adrenergic receptors with concomitant relaxation or no response to catecholamines or to hypogastric nerve stimulation. The explanation of increased uterine irritability and decreased uteroplacental blood flow of pre-eclamptic patients could likewise be explained on the basis of the ratio of alpha)- to betaz-receptors. Williams and Lefkowitz (19) as well as Vallieres and associates (15) implied that progesterone regulates alpha-adrenergic receptors causing a reduction of their number. We propose that this is a normal occurrence in pregnancy. Progesterone reduces the number of active alpha,-adrenergic receptors of myometrium and arterioles making beta?-receptors of the uterus dominant. Furthermore, we propose that in women with pre-eclampsia, progesterone fails to induce a reduction in the active number of alpha,-adrenergic receptors in the myometrium and arterioles to the extent that the uterine and arteriolar alpha,-receptors remain dominant. Alternatively, the number of active alpha,-adrenergic receptors of the preeclamptic patients’ uteri and arterioles could be high to begin with, and progesterone fails to induce a sufficient reduction in the number of active alpha,-adrenergic receptors of the pre-eclamptic patients’ relatively insensitive to pressor hormones and hypogastric stimulation. Therefore. it follows that the pre-eclamptic patients’ uteri are sensitive to catecholamines and hypogastric nerve stimulation throughout most of their pregnancy. In support of our hypothesis, Pritchard and McDonald (20) noted that vasospasm is a, common finding in pre-eclampsia-eclampsia.
PRE-ECLAMPSLA
A HYPOTHESIS
FOR ITS ETIOLOGY
Landesman and co-workers (21) noted arteriolar constriction sufficient to intermittently abolish capillary circulation. It has been proposed, by and subsequent many. that vasoconstriction ischemia causes end organ damage. The kidney suffers vascular spasm proximal to the glomeruli, thereby. reducing significantly glomerular filtrate causing ischemic damage and leakage of glomerular filtrate. A similar scenario is proposed for the damage evidenced at autopsy of the liver, brain and other organs (22, 23). Mechamsm of vasoconstriction During nvrmal pregnancy, the cardiac output, as noted, increases 50%. The plasma volume increases 30%. The increased production of aldosterone causes retention of fluid and salt. which is naturietic, partially Progesterone, offsets aldosterone-induced salt retaining properties (24). In normal pregnancy, systemic vascular resistance decreases, and there is a refractoriness of the systemic vasculature to pressor agents (25). It is proposed that progesterone is the hormone that induces this refractoriness of the systemic vasculature to pressor agents. Furthermore. as noted above. progesterone fails to induce refractoriness of the systemic vasculature in women who develop pre-eclampsia. It follows that the number of active alpha,-adrenergic receptors arc not decreased in the arterioles of women who develop pre-eclampsia. However, aldosterone is still increased and induces watei and salt retention. This leads to increased blood pressure and decreased refractoriness of the Lasculature which leads to vasoconstriction in response to pressor substances. Therefore. if this hypothesis holds true, the myometrium and arterioles remain sensitive to pressor hormones. Aldosterone secretion thus causes an increase in vascular volume. Increased renin stimulates angiotensin synthesis, which then increases systemic vascular resistance. Since the arterioles arc alpha,-dominant and sensitive to pressers, this effect is additive with angiotension. The increased blood pressure disturbs the equilhbrium (compensatory mechanisms cause a decrease in aldosterone, angiotensin, and renin). As noted by Watanabe and others (26, 27).. severe pre-eciamptic patients have decreased secretory rate of aldosterone, angioterisin, and rcnin. This represents an attempt to compensate for the increased sensitivity of the alphal-adrenoreceptors of the myometrium and arterioles of
159
the severe, pre-eclamptic patient. Progesterone production by the placenta continues to increase. Studies implicate progesterone as the causal agent of increased aldosterone and renin secretion (22). Radio&and binding techniques Several studies suggest there are at least two types of alpha receptors, alpha, and alpha?. The role of alpha-adrenergic receptors in a specific tissue may be studied by radioligand binding techniques. Newer radioligands are specific for each type of alpha receptor. ‘H-prazosin is a specific alpha, antagonist and has been used to characterize alpha,-receptors (28. 29). Recently, Bottari and associates (30) used “H-prazosin to characterize human myometrium alpha,-receptors. The criteria for defining a receptor by radioligand binding assay include: (1) Saturability of the receptor sites with the radioligand. Receptor sites should be finite in number. (3) Rate of dissociation (Kd) should be pharmacologically reasonable. (3) Binding of radioligand to receptor should be stereospecific. (4) Binding should bc shown to be associated with a pharmacologic or physiologic event. If the physiological effect is reversible, then binding of radioligand should be reversible. (5) Binding of the radioligand should be displaced by agonist and antagonist in a rank order of potency that is consistent with biological data. (6) The radioligand should reflect alpha,adrenergic specificity. (7) Compounds that do not possess alpha-adrenergic activity should not bind to the receptor sites (31, 32). Specific binding of the radioligand must be quahtitated. It can be measured indirectly as the difference between total binding of the radioligand and nonspecific binding of the radioligand. In other words. the radioligand bound in the assay may not exclusively bind only to receptor\. It also may bind. in varying degrees. to other elements present in the assay medium. Competitive binding experiments using another potent unlabeled alpha-antagonist can be used to determine the degree of nonspecific binding. In their binding study, Vallieres and associates (15) used dihydroergocryptine, which labels both alpha,- and alpha--receptors. Therefore, the hypothesis they advanced. that alpha,-receptors decreased. is speculation. It is also noted that Vallieres and associates attributed this reduction in binding to progesterone. To substantiate the speculation that predominantly alpha,-receptors are affected in pree-
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MEDICAL HYPOTHESES
clampsia, women with a history of preeclampsia and matched controls who have no history of preeclampsia are being studied. The uteri from hysterectomy of premenopausal women will be assayed by 3H-prazosin radioligand binding to determine the normal alpha,-receptor population. As mentioned above, it is expected that the uteri of women with a history of preeclampsia will have a larger number of active alphar-receptors than the matched controls. Effects of alpha-adrenergic calcium plux
stimulation on
The two types of alpha-adrenergic receptors have different effects on cellular calcium metabolism. Alpha,-receptors have been associated with the initiation of transmembrane calcium fluxes (33) and increased turnover of the cellular phosphotidylinositol pool. Alpha*-receptors have been shown to reduce the ability of other agents to activate adenylate cyclase (34, 35, 36). The steps between alpha-adrenergic activation and contraction have not been fully elucidated. The role of calcium is only partially understood. It is generally agreed that the concentration of cytoplasmic calcium is increased as a result of alpha-adrenergic activation. The increased cytoplasmic calcium results in myofilament shortening. The source of the increased calcium is a combination of an increase in the rate of Ca++ influx and the release of calcium ion from intracellular storage sites (37, 38). The ubiquitous role of calcium in adrenergitally mediated muscular contraction explains many current clinical uses of calcium channel blockers. In Europe, clinical trials have shown that calcium channel blockers can effectively reduce or abolish unwanted myometrial contraction (39, 40). Clinical trials of calcium channel blockers have been used to forestall premature labor (41, 42). A useful clinical trial could be directed at reducing the uterine and vasomotor hyperactivity of patients with pre-eclampsia. Effective relaxation of the gravid uterus by these drugs has been demonstrated (41). The proposed idea that alpha,-receptors dominate the uterus of the preeclamptic patient suggests that this may be an effective therapy. Proposed pathophysiology
of preeclampsia
As mentioned above, the uterus, during pregnancy, increases in size and surface area. We propose that, during pregnancy, progesterone causes a decrease in the active number of alphar-
receptors of the myometrium and arterioles. This would make the uterus less sensitive to pressor agents like angiotensin II and prevent increased myometrial tone in response to pressor agents. Thus this mechanism, if indeed present, would provide a viable means for the fetal-placental unit to regulate blood flow through the uteroplacental vascular bed by secreting pressor hormones. Pressor hormones would increase cardiac output without increasing myometrial tone. If myometrial tone is increased, the flow of blood could be shunted away from the uteroplacental bed due to increased resistance in the uteroplacental bed. If pre-eclamptic patients have an increased number of active alpha,-receptors in the myometrium, the myometrium would be more sensitive to pressor agents. This predisposition to pre-eclampsia would be expressed when several conditions are met: (1) The uterus is sensitive to the relative amount of pressers in its environment. (2) The fetal-placental unit senses a need for more nutrients and more oxygen. (3) The uteroplacental vascular blood supply is unable to meet the needs of the fetal-placental unit. Under these conditions, the fetal-placental unit is thought to secrete pressor hormones to increase the blood supply to the uteroplacental vascular bed to meet fetal placental needs as suggested by Symmonds (6), who hypothesizes that the fetoplacental unit can regulate placental bed blood flow. However, if the myometrium in pre-eclampsia is more sensitive to pressor hormones, myometrial tone increases and blood is shunted away from the uteroplacental vascular bed. Therefore, the very hormone secreted by the fetal-placental unit to meet its needs has, under these circumstances, caused a greater need. In response, the fetal-placental unit senses a greater need and increases secretion of pressor hormones, thus producing a positive feed back loop as described by Page (12). This would initiate Page’s “inner vicious circle,” which is self-perpetuating. Symmonds (6) described a similar scenario that would initiate Page’s “inner vicious circle.” He postulated that a relative increase in angiotensin II or a decrease in local vasodilator prostaglandins would cause an increase in vascular tone and likewise would initiate Page’s “inner vicious circle .” The three factors necessary in women predisposed towards pre-eclampsia change with time
161
PRE-ECLAMPSIA: A HYPOTHESIS FOR ITS ETIOLOGY
during the pregnancy. The uterus enlarges and the surface area increases. The ability of the uteroplacental vascular bed and the ability to supply the needed nutrients and oxygen change with position, dietary and nutritional status, oxygenation, and hematocrit of the maternal blood. At the same time, the needs of the fetal placental unit are modest during the first few weeks of gestation and continue to increase till about midway through pregnancy. During the second half of pregnancy, the needs of the fetal placental unit level off as the normal fetus attains a rate of growth of approximately 125 g/wk. conditions conducive to the development of pre-eclampsia
The above stated interactions between genetic predisposition and the three factors would account for the increased tendency of women carrying twins and primiparous women to develop pre-eclampsia. With twins, the increased needs of the fetal placenta1 unit(s) taxes the uteroplacental vascular system to meet the needs. Thus, factors 2 and 3 are more likely to be met. Primigravid uteri have a less vascularized uterus. Therefore, uteroplacental blood supply may be greater in the multipara than the primigravida. Trophoblastic disease causes a rapid rate of growth during the first trimester. Therefore, the blood supply is taxed to a greater degree during the first trimester and beginning of the second trimester (22). Conclusions
adjunct to calcium channel blockers. Also the therapy must be started early in pregnancy since it has been shown that the decreased blood volume characteristic of pre-eclamptic patients develops long before clinical signs such as hypertension or edema become apparent (43). This and other approaches might avoid reaching the critical point that Page delineated until the betaz-receptors in the uterus become dominant or until the fetus can safely be delivered. And finally, a trial of large doses of a progesterone analog should be used to reduce the number of alpha!-adrenergic receptors of arterioles and myometrium. This approach would increase the possibility of a beta?-receptor dominance in the uterus and arterioles. Acknowledgement This work was supported in part by the Fraternal Order of Eagles and the American Heart Association and its Virginia Affiliate.
References 1. Pritchard J A. McDonald P C. Maternal adaptation to pregnancy. p 181 in Williams* Obstetrics. 17th ed. (J A Pritchard, N F Grant. P C McDonald. eds) AppletonCenturv-Crofts. New York. 1976. 2. Moore’K L. The Developing Human. 2nd ed. Saunders. Philadelphia, 1977. 3. Ureland K. Metacalfe J. Circulatory changes in pregnancy. Clinical Obstetrics and Gynecology 18-42, 1975. 4. Assali N S, Douglass R A. Baird W W, Nickolson D B, Syemoto R. Measurement of uterine blood flow and uterine metabolism: IV. Results in normal pregnancy. American Journal of Obstetrics and Gynecology 66: 246, 1953.
Our research is aimed at determining if. the alpha*-receptors of the pre-eclamptic uterus and arterioles are characteristically and/or duantitiatively different than the normal gravid uterus. If the above hypothesis proves to be valid, it will provide a more informed approach to therapy which could be aimed at diminishing the effect of the three factors that provoke the disease process in predisposed women. An approach to Factor 3 might be to increase the hematocrit of pregnant women, which enhances oxygen carrying capacity, and to introduce supplemental elemental nutrition intravenously. Of course, these would be adjunctive to bed rest in left lateral decubitus position with nasal oxygen. Also. the use of calcium channel blockers should. as mentioned before, be investigated in clinical trials. MgS04 may prove to be only an
5. Assali N S, Rauramo L, Peltonen T. Measurement of uterine blood flow and uterine metabolism: VIII. Uterine and fetal blood flow and oxygen consumption in early human pregnancy. American Journal of Obstetrics and Gynecology 79: 86. 1969. 6. Symmonds E M. Aetiology of pre-eclampsia: A review. Journal of the Royal Society of Medicine 73: 871. 1980. 7. Browne J C M, Veal1 N. The maternal placental blood flow in normotensive and hypertensive women. British Journal
of Obstetrics and Gynaecology J C. The effects of pregnancy lation. American Journal of Obstetrics 18: 368. 1969.
8. Beker
60: 141, 1953. on blood circuand Gynecology
9. Beker J C. Etiology of eclampsia. Journal of Obstetrics and Gvnaecologv of the British Empire 55: 757. 1948. 10. Dexter L. Weiss, E W, Haynes F W, Sise H S. Hyper. tensive toxemia of pregnancy: Preeclampsia and eclampsia. Journal of the American Medical Association 122: 145. 1943. 11. Dieckman W J, Pottinger R E. Etiology of preeclamsiaeclampsia: VI. Sodium. potassium. nitrogen, and water content of muscle and skin in preeclampsia. American Journal of Obstetrics and Gynecology 71: 596. 1956.
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MEDICAL HYPOTHESES
12 Page E W. Placental origin of eclampsia. American 29. Karliner J S. Barnes P, Hamilton C A, Dolery C T. Alpha-adrenergic receptors in guinea-pig myocardium: Journal of Obstetrics and Gynecology 37: 296, 1934. 13. Hoffman B B, Lavin T N. Lefkowitz R J. Ruffolo R R, Identification by binding of a new radioligand, ‘HBiochemical and Biophysical Research Jr. Alpha adrenergic receptor subtypes in rabbit uterus: prazosin. Mediation of myometrial contraction and regulation by Communications 90: 142. 1979. estrogens. Journal of Pharmacology and Experimental 30. Bottari S P, Vauequlin G, Lescraines J P, Kaivez E, Therapeutics 219: 290, 1981. Volaer A. Identification and characterization of alpha 14. Milles M D, Marshall J M. Uterine response to nerve one adrenergic receptors in human myometrium by ‘H stimulation: Relation to hormonal status and catecholprazosin binding. Biochemical Pharmacology 32: 925, amines. American Journal of Physiology 209: 859, 1965. , 1983. 15 Vallieres J. Fortier M, Bukowieki L. Alpha- and beta31. Richelson E. Studying, neurotransmitter receptors: adrenergic receptors in isolated rabbit uterine membranes: Binding and biological assays. p 4 in Neuroreceptbrs in Study of receptor alterations by pregnancy. Biology of Health and Disease. (J Marwaha. WH Anderson. eds1, Reproduction 19: 318. 1978. Karger, New York, 1484. 16. Saver J. Jett-Jackson C E. Reynolds S R. Reactivity of 32. Williams L T. Mullikin D, Lefkowitz R J. Identification the uterus to pre-sacral nerve stimulation and to of alpha adrenergic receptors in uterine smooth muscle epinephrine, pitruition and pilocarpine administration membranes by (‘H) dihydroergocryptine binding. during certain sexual states in the anesthetized rabbit. Journal of Biological Chemistry 251: 6915, 1976. American Journal of Physiology 111: 250, 1935. 33. Van Breeman C. Blockade of membrane calcium fluxes 17. Labate J S. Influence of cocaine on the uterine reaction by lanthanum in relation to vascular smooth muscle induced by adrenaline and hypogastric nerve stimulation. contractility. Archives Internationales De Physiologie Et Journal of Pharmacology and- Experimental Therapy De Biochemie 77: 710, 1969. 72: 370, 1941. 34. Garcia-Sain J A, Hoffman B B. Shih-Ying L. Lefkowitz, 18. Shoefield B M. The innervation of cervix and cornu uteri R J, and Fain J N. Role of alpha 1 adrenoreceptors in in the rabbit. Joural of Physiology 117: 317. 1952. the turnover of phosphatidyl inositol and of alpha 2 19. Williams L T. Lefkowitz R J. Regulation of rabbit adreno-receptors in the regulation of cyclic amp accumumyometrial alpha adrenergic receptors by estrogen and lation in hamster adipocytes. Life Science 27: 953. 1980. progesterone. Journal of Clinical Investigation 60: 815. 35 Fain J N. Garcia-Sainz J N. Role of phosphatidylinositol 1977. turnover in alpha 1 and of adenylate cyclase inhibition 20. Pritchard J A, McDonald P C. Hypertensive disorders in alpha 2 Cffects of catecholamines. Life Science in pregnancy. p 529 in Williams’ Obstetrics. 17th ed. 26: 1183, 1980. (J A Pritchard. N F Grant, P C McDonald. eds) 36. Jard S, Cantan B, Jakobs R H. Angiotensin II and alpha Appleton-Century-Crofts, New York, 1985. adrenergic agonists inhibit rat liver adenylate cyclase. 21. Landesman R. Douglas R G, Holze E. The bulbas Journal of Biological Chemistry 256: 2603, 1981. conjunctival vascular bed in the toxemias of pregnancy. 37. Deth R C, Casteels R. A study of releasable calcium American Journal of Obstetrics and Gynecology 68: 170. fractions in smooth muscle cells of the rabbit aorta. 1984. Journal of General Physiology 69: 401. 1977. 22. Chesley L C. Hypertensive Disorders in Pregnancy. 38. Grun G, Fleckenstein A. Byon K. Hemmung der motilAppleton-Century-Crofts, New York. 1978. itat isolierten uterus-steifen aus gravidem und nicht-grav23. Sheehan H L. Lynch J B. Pathology of Toxemia of Pregidem menschichen myometrium durch Ca++-antagonisten nancy. Churchill Livingstone. London. 1973. und sympathomimetica. Arzneimittel-Forschung 24. Landar R L. Lugibihl K. Inhibition of the sodium21: 1585-1971. retaining influence of aldosterone by progesterone. 39. Fleckenstein A. Grun G, Tritthart H. Byon K. Uterus Journal-of Clinical Endocrinology 18: li37: 1958. relaxation durch hochaktive Ca++-antagonistische 25. Matsuura S, Naden R P. Grant N F Jr. Parkes C R. hemmstoffe des electromechanischen koppelun wie Rosenfeld C R. Effect of hypertonic saline on vascular isoptin (verapamil. iproveratril), substanz D600 and responses to angiotensin II in pregnancy. American segontin (prenylamin) (versuchen am isolierten uterus Journal of Obstetrics and Gynecology 147: 231. 1983. virgineller ratten). Klinische Wochenschrift 49: 32, 1971. 26. Watanabe M, Meekes C I. Gray M J, Sims E A. 40. Csapo A I. Puri C P, Turro S. Henzl M R. Deactivation Solomon S. Aldosterone secretion rates in abnormal of the uterus during normal and premature labor by the pregnancy. Journal of Clinical Endocrinology 25: 1665, calcium antagonist nicardipine. American Journal of 1965. Obstetrics and Gynecology 142: 483, 1982. 27. Weir R J. Fraser R, Lever A F. Morton J J. Brown J J. 41. Andersson K E. Inhibition of uterine activity by the Krazewski A, Mellevine G M, Robertson J 1. Tree M. calcium antagonist nifedipine. p 101 in Premature Labor. Plasma renin, renin substrate. angiotensin II, and aldosRoyal College of Obstetricians and Gynecologists, 1977. terone in hypertensive disease of pregnancy. Lancet 42. Gant. N F. Whalley P J, Chard S, and MacDonald P C. 1: 291. 1973. A prospective study of angiotensin II pressor respon28. Greengrass P. Bremner R. Binding characteristics of ‘Hsiveness in pregnancies complicated by chronic essential prazosin to brain alpha adrenergic receptors. European hypertension.American Journal of Obstetrics and GyneJournal of Pharmacology 55: 323. 1979. cology 127: 36’). 1977.
Pre-eclampsia: A Hypothesis for its Etiology TIMOTHY J. HARDY* and PATRICIA B. WILLIAMS Eastern
Virginia
Medical
School,
P-0. Box 1980, Norfolk, VA 23501.
Abstract - A hypothesis is presented according to which the etiology of pregnancyinduced hypertension can be attributed to increased number of active uterine and arteriolar alpha-adrenergic myometrial receptors from pre-eclamptic patients in comparison with the alpha-adrenergic myometrial and arteriolar receptors from non-pre-eclamptic patients. This condition could result in the increased uterine wall irritability and the decreased uteroplacental blood flow in pre-eclampsia. It is suggested that progesterone fails to induce a reduction in alpha,-adrenergic receptors in the pre-eclamptic patient. This will require pre-eclamptic patients and matched controls to test the hypothesis.
Introduction
Characteristics of a normal pregnancy
Pre-eclampsia is a disease peculiar to humans. Clinical features of pre-eclampsia include hypertension, proteinuria and edema. Symptoms are rarely apparent before twenty weeks gestation. When symptoms appear, there is an association with trophoblastic disease. The incidence of pre-eclampsia is higher with the first pregnancy and with twins, There appears to be a familial pattern. In addition, approximately 10% of all women develop hypertension during pregnancy. Any proposed mechanism or etiology of preeclampsia should be able to explain the above predispositions and associations.
The normal physiology and changes during pregnancy must be considered along with the specific. deviations from normal that occur in preeclamptic patients. During normal pregnancy, the uterus increases in weight, ten-fold, from about 70 to 1100 (1). During the first 20 weeks the myometrial cells multiply. In the second half of pregnancy, the cells hypertrophy to accommodate the growing fetus. The inside surface area of the uterus increases approximately 500- to lOOO-fold from the nongravid state (2). Fetal growth, to a certain extent, parallels the growth of the uterus. The fetus grows exponentially until the fifteenth week at which time its rate of growth approaches a linear curve (2). During pregnancy, the cardiovascular system undergoes profoundchange. Blood volume increases 30% during pregnancy. Caridac output, as measured by Uceland and Metcalfe, increases steadily the first 20-24 weeks to a 30-40% in-
* Current address: The Providence Hospital 11.50 Varnum Street, N.E.: Washington. D.C. 20077
157
MEDICAL
158 crease over the nonpregnant state and remains elevated during the third trimester (3). Blood flow to the uterus increases to approximately 500 ml/min at the end of normal pregnancy (3,, 4). Oxygen consumption of the pregnant uterus increases from 4.8 cc/min at 10 weeks to 22 cc/min at 28 weeks (5). Blood flows to the myometrium and traverses it to the uteroplacental bed, a low resitance cascular bed. The uteroplacental bed has been likened to an arteriovenous tistula (6). Effect of pre-eclampsia
on fetal development
All of the above changes presumably occur as an adaptation to accommodate and nourish the growing fetus. Quite a .different story evolves during the severe pre-eclamptic patient’s pregnancy. Several physiologic changes differentiate between a normal pregnancy and severe eclampsia. During pre-eclampsia the blood pressure is increased over normal. Browne and Veal1 (7) estimated a reduction of 50% of the uteroplacental blood flow by injecting radiolabelled sodium into maternal placental lakes of preeclamptic patients. Also noted was an increase in placental infarcts. These adaptations in the circulatory system in pre-eclampsia have been cited to support the uterine ischemia theory by Beker. Dexter. Dieckmann, Page and others (8, 9, IO. 11. 12). Response of myometrium to adrenergic agonists It is generally agreed that the myometrium
contracts in response to alpha-adrenergic stimulation (13, 14). During pregnancy, the myometrium has a blunted response to an infusion of catecholamines or to stimulation of the hypogastric nerve. Uterine alpha-adrenergic receptors of rabbits decrease in number per milligram protein during pregnancy. At day eight of a thirty day gestation period, the alpha-receptors have decreased by 67%. By day 30, the alpha-receptors have increased to almost pre-pregnant levels or 97% of nongravid levels. This reduction in alpha-receptors corresponds to a relative insensitivity of the uterus to catecholamines and hypogastric nerve stimulation (15). Hypogastric nerve stimulation, on day 0 of gestation and day 30 of gestation, results in uterine myometrial contraction. The mechanism of myometrial inhibition during pregnancy, suggested by Vallieres and associates (lS), is that the alpha-receptors
HYPOTHESES
are decreased due to an action of progesterone: thus, the betal-adrenergic receptors become the dominant receptors. The uterus of pregnant animals then either relaxes or does not respond to adrenergic stimulation via the hypogastric nerve (16. 17, 18). A similar study by Williams and Lefkowitz (19) showed a significant reduction in the number of [jH]DHE binding sites in progesterone primed uteri of rabbits as opposed to uteri primed with estrogen. Assuming that a decrease in myometrial alphareceptors similar to that in rabbits also occurs in humans. then the same mechanism as advanced for the rabbit model could be offered to explain why the gravid uterus is insensitive to catecholamines and hypogastric nerve stimulation. A significant decrease in the number of alpha,receptors would cause unmasking of the beta?adrenergic receptors with concomitant relaxation or no response to catecholamines or to hypogastric nerve stimulation. The explanation of increased uterine irritability and decreased uteroplacental blood flow of pre-eclamptic patients could likewise be explained on the basis of the ratio of alpha)- to betaz-receptors. Williams and Lefkowitz (19) as well as Vallieres and associates (15) implied that progesterone regulates alpha-adrenergic receptors causing a reduction of their number. We propose that this is a normal occurrence in pregnancy. Progesterone reduces the number of active alpha,-adrenergic receptors of myometrium and arterioles making beta?-receptors of the uterus dominant. Furthermore, we propose that in women with pre-eclampsia, progesterone fails to induce a reduction in the active number of alpha,-adrenergic receptors in the myometrium and arterioles to the extent that the uterine and arteriolar alpha,-receptors remain dominant. Alternatively, the number of active alpha,-adrenergic receptors of the preeclamptic patients’ uteri and arterioles could be high to begin with, and progesterone fails to induce a sufficient reduction in the number of active alpha,-adrenergic receptors of the pre-eclamptic patients’ relatively insensitive to pressor hormones and hypogastric stimulation. Therefore. it follows that the pre-eclamptic patients’ uteri are sensitive to catecholamines and hypogastric nerve stimulation throughout most of their pregnancy. In support of our hypothesis, Pritchard and McDonald (20) noted that vasospasm is a, common finding in pre-eclampsia-eclampsia.
PRE-ECLAMPSLA
A HYPOTHESIS
FOR ITS ETIOLOGY
Landesman and co-workers (21) noted arteriolar constriction sufficient to intermittently abolish capillary circulation. It has been proposed, by and subsequent many. that vasoconstriction ischemia causes end organ damage. The kidney suffers vascular spasm proximal to the glomeruli, thereby. reducing significantly glomerular filtrate causing ischemic damage and leakage of glomerular filtrate. A similar scenario is proposed for the damage evidenced at autopsy of the liver, brain and other organs (22, 23). Mechamsm of vasoconstriction During nvrmal pregnancy, the cardiac output, as noted, increases 50%. The plasma volume increases 30%. The increased production of aldosterone causes retention of fluid and salt. which is naturietic, partially Progesterone, offsets aldosterone-induced salt retaining properties (24). In normal pregnancy, systemic vascular resistance decreases, and there is a refractoriness of the systemic vasculature to pressor agents (25). It is proposed that progesterone is the hormone that induces this refractoriness of the systemic vasculature to pressor agents. Furthermore. as noted above. progesterone fails to induce refractoriness of the systemic vasculature in women who develop pre-eclampsia. It follows that the number of active alpha,-adrenergic receptors arc not decreased in the arterioles of women who develop pre-eclampsia. However, aldosterone is still increased and induces watei and salt retention. This leads to increased blood pressure and decreased refractoriness of the Lasculature which leads to vasoconstriction in response to pressor substances. Therefore. if this hypothesis holds true, the myometrium and arterioles remain sensitive to pressor hormones. Aldosterone secretion thus causes an increase in vascular volume. Increased renin stimulates angiotensin synthesis, which then increases systemic vascular resistance. Since the arterioles arc alpha,-dominant and sensitive to pressers, this effect is additive with angiotension. The increased blood pressure disturbs the equilhbrium (compensatory mechanisms cause a decrease in aldosterone, angiotensin, and renin). As noted by Watanabe and others (26, 27).. severe pre-eciamptic patients have decreased secretory rate of aldosterone, angioterisin, and rcnin. This represents an attempt to compensate for the increased sensitivity of the alphal-adrenoreceptors of the myometrium and arterioles of
159
the severe, pre-eclamptic patient. Progesterone production by the placenta continues to increase. Studies implicate progesterone as the causal agent of increased aldosterone and renin secretion (22). Radio&and binding techniques Several studies suggest there are at least two types of alpha receptors, alpha, and alpha?. The role of alpha-adrenergic receptors in a specific tissue may be studied by radioligand binding techniques. Newer radioligands are specific for each type of alpha receptor. ‘H-prazosin is a specific alpha, antagonist and has been used to characterize alpha,-receptors (28. 29). Recently, Bottari and associates (30) used “H-prazosin to characterize human myometrium alpha,-receptors. The criteria for defining a receptor by radioligand binding assay include: (1) Saturability of the receptor sites with the radioligand. Receptor sites should be finite in number. (3) Rate of dissociation (Kd) should be pharmacologically reasonable. (3) Binding of radioligand to receptor should be stereospecific. (4) Binding should bc shown to be associated with a pharmacologic or physiologic event. If the physiological effect is reversible, then binding of radioligand should be reversible. (5) Binding of the radioligand should be displaced by agonist and antagonist in a rank order of potency that is consistent with biological data. (6) The radioligand should reflect alpha,adrenergic specificity. (7) Compounds that do not possess alpha-adrenergic activity should not bind to the receptor sites (31, 32). Specific binding of the radioligand must be quahtitated. It can be measured indirectly as the difference between total binding of the radioligand and nonspecific binding of the radioligand. In other words. the radioligand bound in the assay may not exclusively bind only to receptor\. It also may bind. in varying degrees. to other elements present in the assay medium. Competitive binding experiments using another potent unlabeled alpha-antagonist can be used to determine the degree of nonspecific binding. In their binding study, Vallieres and associates (15) used dihydroergocryptine, which labels both alpha,- and alpha--receptors. Therefore, the hypothesis they advanced. that alpha,-receptors decreased. is speculation. It is also noted that Vallieres and associates attributed this reduction in binding to progesterone. To substantiate the speculation that predominantly alpha,-receptors are affected in pree-
160
MEDICAL HYPOTHESES
clampsia, women with a history of preeclampsia and matched controls who have no history of preeclampsia are being studied. The uteri from hysterectomy of premenopausal women will be assayed by 3H-prazosin radioligand binding to determine the normal alpha,-receptor population. As mentioned above, it is expected that the uteri of women with a history of preeclampsia will have a larger number of active alphar-receptors than the matched controls. Effects of alpha-adrenergic calcium plux
stimulation on
The two types of alpha-adrenergic receptors have different effects on cellular calcium metabolism. Alpha,-receptors have been associated with the initiation of transmembrane calcium fluxes (33) and increased turnover of the cellular phosphotidylinositol pool. Alpha*-receptors have been shown to reduce the ability of other agents to activate adenylate cyclase (34, 35, 36). The steps between alpha-adrenergic activation and contraction have not been fully elucidated. The role of calcium is only partially understood. It is generally agreed that the concentration of cytoplasmic calcium is increased as a result of alpha-adrenergic activation. The increased cytoplasmic calcium results in myofilament shortening. The source of the increased calcium is a combination of an increase in the rate of Ca++ influx and the release of calcium ion from intracellular storage sites (37, 38). The ubiquitous role of calcium in adrenergitally mediated muscular contraction explains many current clinical uses of calcium channel blockers. In Europe, clinical trials have shown that calcium channel blockers can effectively reduce or abolish unwanted myometrial contraction (39, 40). Clinical trials of calcium channel blockers have been used to forestall premature labor (41, 42). A useful clinical trial could be directed at reducing the uterine and vasomotor hyperactivity of patients with pre-eclampsia. Effective relaxation of the gravid uterus by these drugs has been demonstrated (41). The proposed idea that alpha,-receptors dominate the uterus of the preeclamptic patient suggests that this may be an effective therapy. Proposed pathophysiology
of preeclampsia
As mentioned above, the uterus, during pregnancy, increases in size and surface area. We propose that, during pregnancy, progesterone causes a decrease in the active number of alphar-
receptors of the myometrium and arterioles. This would make the uterus less sensitive to pressor agents like angiotensin II and prevent increased myometrial tone in response to pressor agents. Thus this mechanism, if indeed present, would provide a viable means for the fetal-placental unit to regulate blood flow through the uteroplacental vascular bed by secreting pressor hormones. Pressor hormones would increase cardiac output without increasing myometrial tone. If myometrial tone is increased, the flow of blood could be shunted away from the uteroplacental bed due to increased resistance in the uteroplacental bed. If pre-eclamptic patients have an increased number of active alpha,-receptors in the myometrium, the myometrium would be more sensitive to pressor agents. This predisposition to pre-eclampsia would be expressed when several conditions are met: (1) The uterus is sensitive to the relative amount of pressers in its environment. (2) The fetal-placental unit senses a need for more nutrients and more oxygen. (3) The uteroplacental vascular blood supply is unable to meet the needs of the fetal-placental unit. Under these conditions, the fetal-placental unit is thought to secrete pressor hormones to increase the blood supply to the uteroplacental vascular bed to meet fetal placental needs as suggested by Symmonds (6), who hypothesizes that the fetoplacental unit can regulate placental bed blood flow. However, if the myometrium in pre-eclampsia is more sensitive to pressor hormones, myometrial tone increases and blood is shunted away from the uteroplacental vascular bed. Therefore, the very hormone secreted by the fetal-placental unit to meet its needs has, under these circumstances, caused a greater need. In response, the fetal-placental unit senses a greater need and increases secretion of pressor hormones, thus producing a positive feed back loop as described by Page (12). This would initiate Page’s “inner vicious circle,” which is self-perpetuating. Symmonds (6) described a similar scenario that would initiate Page’s “inner vicious circle.” He postulated that a relative increase in angiotensin II or a decrease in local vasodilator prostaglandins would cause an increase in vascular tone and likewise would initiate Page’s “inner vicious circle .” The three factors necessary in women predisposed towards pre-eclampsia change with time
161
PRE-ECLAMPSIA: A HYPOTHESIS FOR ITS ETIOLOGY
during the pregnancy. The uterus enlarges and the surface area increases. The ability of the uteroplacental vascular bed and the ability to supply the needed nutrients and oxygen change with position, dietary and nutritional status, oxygenation, and hematocrit of the maternal blood. At the same time, the needs of the fetal placental unit are modest during the first few weeks of gestation and continue to increase till about midway through pregnancy. During the second half of pregnancy, the needs of the fetal placental unit level off as the normal fetus attains a rate of growth of approximately 125 g/wk. conditions conducive to the development of pre-eclampsia
The above stated interactions between genetic predisposition and the three factors would account for the increased tendency of women carrying twins and primiparous women to develop pre-eclampsia. With twins, the increased needs of the fetal placenta1 unit(s) taxes the uteroplacental vascular system to meet the needs. Thus, factors 2 and 3 are more likely to be met. Primigravid uteri have a less vascularized uterus. Therefore, uteroplacental blood supply may be greater in the multipara than the primigravida. Trophoblastic disease causes a rapid rate of growth during the first trimester. Therefore, the blood supply is taxed to a greater degree during the first trimester and beginning of the second trimester (22). Conclusions
adjunct to calcium channel blockers. Also the therapy must be started early in pregnancy since it has been shown that the decreased blood volume characteristic of pre-eclamptic patients develops long before clinical signs such as hypertension or edema become apparent (43). This and other approaches might avoid reaching the critical point that Page delineated until the betaz-receptors in the uterus become dominant or until the fetus can safely be delivered. And finally, a trial of large doses of a progesterone analog should be used to reduce the number of alpha!-adrenergic receptors of arterioles and myometrium. This approach would increase the possibility of a beta?-receptor dominance in the uterus and arterioles. Acknowledgement This work was supported in part by the Fraternal Order of Eagles and the American Heart Association and its Virginia Affiliate.
References 1. Pritchard J A. McDonald P C. Maternal adaptation to pregnancy. p 181 in Williams* Obstetrics. 17th ed. (J A Pritchard, N F Grant. P C McDonald. eds) AppletonCenturv-Crofts. New York. 1976. 2. Moore’K L. The Developing Human. 2nd ed. Saunders. Philadelphia, 1977. 3. Ureland K. Metacalfe J. Circulatory changes in pregnancy. Clinical Obstetrics and Gynecology 18-42, 1975. 4. Assali N S, Douglass R A. Baird W W, Nickolson D B, Syemoto R. Measurement of uterine blood flow and uterine metabolism: IV. Results in normal pregnancy. American Journal of Obstetrics and Gynecology 66: 246, 1953.
Our research is aimed at determining if. the alpha*-receptors of the pre-eclamptic uterus and arterioles are characteristically and/or duantitiatively different than the normal gravid uterus. If the above hypothesis proves to be valid, it will provide a more informed approach to therapy which could be aimed at diminishing the effect of the three factors that provoke the disease process in predisposed women. An approach to Factor 3 might be to increase the hematocrit of pregnant women, which enhances oxygen carrying capacity, and to introduce supplemental elemental nutrition intravenously. Of course, these would be adjunctive to bed rest in left lateral decubitus position with nasal oxygen. Also. the use of calcium channel blockers should. as mentioned before, be investigated in clinical trials. MgS04 may prove to be only an
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MEDICAL HYPOTHESES
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