journal or unnicai anaocrmuiogy aim meiuuuiisiii
Printed in U.S.A.
Copyright © 1978 by The Endocrine Society
Effect of Prostaglandin Synthetase Inhibitors on Pressor Response to Angiotensin II in Human Pregnancy* ROYICE B. EVERETT, RICHARD J. WORLEY, PAUL C. M A C D O N A L D , AND NORMAN F. GANT The Cecil H. and Ida Green Center for Reproductive Biology Sciences and the Department of Obstetrics and Gynecology, University of Texas Southwestern Medical School and St. Paul Hospital, Dallas, Texas 75235 ABSTRACT. Pregnant women destined to develop pregnancy-induced hypertension (PIH) lose refractoriness to the pressor effects of infused angiotensin II (AII) several weeks before the onset of hypertension. This loss of refractoriness to A-II is unrelated to plasma renin activity or circulating levels of A-II. In animal studies it has been shown that the prostaglandins are important mediators of vascular reactivity. Specifically, the uterine blood flow appears to vary directly with prostaglandin E concentrations in uterine venous effluent. The present study was designed to evaluate the effects of prostaglandin synthetase inhibitors on the pressor effects of A-II in human pregnancy. The "effective A-II pressor dose"
(nanograms of A-II • kg ' • min ' necessary to cause a 20 mm Hg rise in diastolic pressure) was determined in 14 pregnant women before and after treatment with either 25 mg indomethacin or 600 mg aspirin given twice, 6 h apart. The effective pressor dose required before treatment [22.7 ± 3.4 ngkg~'min~' (mean ± SE)] was significantly greater than that after treatment [8.7 ± 1.2 ngkg~'min~' (P < 0.001)]. The refractoriness to A-II observed in normal human pregnancy may be mediated in part by the action of prostaglandins or related substances produced in the arteriole. (J Clin Endocrinol Metab 46: 1007, 1978)
N
rise in diastolic pressure) before and after rapid plasma volume expansion in normal pregnant women. Volume expansion was effected by the rapid iv infusion of solutions of normal saline or 6% dextran. From an analysis of the results obtained in this study it was concluded that in late human pregnancy, neither endogenous A-II plasma levels nor plasma volume deficits are the principal determinants of the blunted A-II pressor response characteristic of normal human pregnancy. This concept gained further support from the results of the studies of Cunningham et al. (5) who found that pregnant women who underwent rapid blood volume expansion with infusions of high hematocrit blood (a volume expansion which is maintained over a long period of time) also experienced no change in the amount of A-II required to elicit a 20-mm Received June 8,1977. Address all correspondence and requests for reprints Hg rise in their diastolic blood pressure. Based to: N. F. Gant, M.D., Department of Obstetrics and Gyne- on these observations, we have suggested that cology, University of Texas Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, Texas 75235. the impeded pressor response to A-II infusions * This study was supported in part by USPHS Grant which accompanies normal pregnancy is the HD-08360. The results reported in this study were pre- result of increased vascular refractoriness to sented in part at the Annual Meeting of the Society for A-II. In women with PIH and in those graviGynecologic Investigation, Tucson, AZ, March 23-25, das destined to develop PIH, the normal preg1977.
ORMAL pregnant women develop an altered response to the pressor effects of infused angiotensin II (A-II) (1-3); however, this refractoriness to A-II is lost during pregnancies which are complicated by pregnancyinduced hypertension [PIH (2, 3)]. Moreover, as early as the 23rd week of gestation, an augmented pressor response to A-II infusions is observed in pregnant women who are normotensive but who are destined to develop PIH (3). In order to elucidate the nature of the difference in the pressor responses to A-II infusions between those pregnant women who remain normal and those who later develop PIH, Gant et al. (4) studied the "effective AII pressor dose" (nanograms of AII • kg"1 • min"1 necessary to cause a 20 mm Hg
1007
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1008
JCE&M • 1978 V0U6 • No 6
COMMENTS
nancy associated refractoriness to A-II pressor effects is lost. Therefore, a critical question is posed; specificially, what causes the vessel refractoriness to A-II that accompanies normal human pregnancy? McGiff and coworkers (6, 7) have shown that prostaglandins are potent mediators of vascular reactivity in several different organs under a variety of conditions. Moreover, Terragno et al. (8) found that in late canine pregnancy, uterine blood flow is related to the levels of prostaglandin E (PGE) in uterine venous blood. These investigators also observed that the iv infusion of A-II into pregnant dogs was associated with an increase in uterine blood flow and an increase in the levels of PGE in uterine venous blood. On the other hand, when prostaglandin synthesis was inhibited by indomethacin treatment, a decrease in uterine blood flow and in uterine venous concentrations of PGE was observed. In studies of pregnant monkeys, Franklin et al. (9) found that intrarterial infusions of A-II were associated with an increase in PGE levels in uterine venous blood; whereas after indomethacin pretreatment, there was no increase in PGE concentration in uterine venous blood in response to A-II infusions. Recently, Vane (10) reported the finding of a direct relationship between prostaglandin efflux from the kidney and renal blood flow. Indeed, when prostaglandin synthesis was inhibited by indomethacin treatment, renal blood flow decreased. From results of studies in the pregnant rabbit, Venuto et al. (11) concluded that uterine venous blood PGE concentrations were directly proportional to uterine blood flow, as indomethacin treatment was associated with a fall in uterine venous blood PGE concentration and uterine blood flow (11). The present study was designed to assess, indirectly, whether prostaglandins or prostaglandin-related substances might be involved in the control of vascular response to A-II during human pregnancy. The results of the present study are consistent with the view that prostaglandins serve, at least in part, to blunt pressor response to infused A-II in normal pregnant women.
Materials and Methods Informed volunteers' (written consent was obtained from each of the volunteers in these studies) for this study were obtained from the inpatient hospital population of the obstetric service of Parkland Memorial Hospital. Each woman was 28 weeks or later in gestation, had been normotensive throughout pregnancy, had no history of hypertension, and was eating her choice of food available from the hospital menu. Blood pressure measurements, utilizing the onset of the first (systolic) and fifth (diastolic) sounds of Korotkoff, were taken at 5-min intervals for at least 15 min or until the diastolic blood pressure was constant. Throughout the time of study, the subjects were kept in the left lateral recumbent position. An iv infusion was begun which contained 1 fig A-II (Ciba Pharmaceutical, Summit, NJ; (l-L-asparaginyl-5-L-valyl angiotensin octapeptide)/ml in a solution of 5% dextrose in water. This solution was administered at a constant rate with the aid of a Harvard infusion pump (Model 975, Harvard Apparatus Co., Milles, MA). The administered dose was increased in small increments every 5 min until a rise in diastolic blood pressure of 20 mm Hg was obtained. To confirm that this was the effective pressor dose, the A-II infusion was stopped and the diastolic blood pressure was allowed to return to its baseline value. The infusion was then restarted at the previously effective pressor dose and a repeat increase of 20 mm Hg in diastolic blood pressure was required to confirm the validity of the effective pressor dose. The effective pressor dose was considered to be the least amount of A-II [nanograms infused per kg BW/min (nanograms per kg per min)] which caused a 20 mm Hg rise in diastolic pressure. After establishing the effective pressor dose of AII before treatment, each subject was given one 25mg capsule of indomethacin (Indocin; Merck, Sharp, and Dohme) or 0.65 g of aspirin at 6-h intervals. Two hours after the second dose of indomethacin or aspirin, the effective pressor dose of A-II was determined in the same manner as before treatment. Between sets of A-II infusions, patients were allowed to maintain their usual hospital activities and diet restrictions were not imposed. The patients were receiving no cardiovascular medications or other drugs known to affect prostaglandin production.
Results Eleven pregnant women were studied before and after the administration of 25 mg
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 23 November 2015. at 03:36 For personal use only. No other uses without permission. . All rights reserved.
COMMENTS TABLE 1. Effective pressor dose of A-II before and after indomethacin treatment (A-II, nanograms per kg per min) Subject A
B
Before treatment 25.0" 25.5
C
7.7
D
25.0 52.7 12.7 19.2 17.5
E F
G H I J K
9.8
After treatment 12.7" 13.0 2.8 6.5
13.7 4.6 9.8 4.5 6.9 9.2 3.5
12.9 13.9 A P value of
Printed in U.S.A.
Copyright © 1978 by The Endocrine Society
Effect of Prostaglandin Synthetase Inhibitors on Pressor Response to Angiotensin II in Human Pregnancy* ROYICE B. EVERETT, RICHARD J. WORLEY, PAUL C. M A C D O N A L D , AND NORMAN F. GANT The Cecil H. and Ida Green Center for Reproductive Biology Sciences and the Department of Obstetrics and Gynecology, University of Texas Southwestern Medical School and St. Paul Hospital, Dallas, Texas 75235 ABSTRACT. Pregnant women destined to develop pregnancy-induced hypertension (PIH) lose refractoriness to the pressor effects of infused angiotensin II (AII) several weeks before the onset of hypertension. This loss of refractoriness to A-II is unrelated to plasma renin activity or circulating levels of A-II. In animal studies it has been shown that the prostaglandins are important mediators of vascular reactivity. Specifically, the uterine blood flow appears to vary directly with prostaglandin E concentrations in uterine venous effluent. The present study was designed to evaluate the effects of prostaglandin synthetase inhibitors on the pressor effects of A-II in human pregnancy. The "effective A-II pressor dose"
(nanograms of A-II • kg ' • min ' necessary to cause a 20 mm Hg rise in diastolic pressure) was determined in 14 pregnant women before and after treatment with either 25 mg indomethacin or 600 mg aspirin given twice, 6 h apart. The effective pressor dose required before treatment [22.7 ± 3.4 ngkg~'min~' (mean ± SE)] was significantly greater than that after treatment [8.7 ± 1.2 ngkg~'min~' (P < 0.001)]. The refractoriness to A-II observed in normal human pregnancy may be mediated in part by the action of prostaglandins or related substances produced in the arteriole. (J Clin Endocrinol Metab 46: 1007, 1978)
N
rise in diastolic pressure) before and after rapid plasma volume expansion in normal pregnant women. Volume expansion was effected by the rapid iv infusion of solutions of normal saline or 6% dextran. From an analysis of the results obtained in this study it was concluded that in late human pregnancy, neither endogenous A-II plasma levels nor plasma volume deficits are the principal determinants of the blunted A-II pressor response characteristic of normal human pregnancy. This concept gained further support from the results of the studies of Cunningham et al. (5) who found that pregnant women who underwent rapid blood volume expansion with infusions of high hematocrit blood (a volume expansion which is maintained over a long period of time) also experienced no change in the amount of A-II required to elicit a 20-mm Received June 8,1977. Address all correspondence and requests for reprints Hg rise in their diastolic blood pressure. Based to: N. F. Gant, M.D., Department of Obstetrics and Gyne- on these observations, we have suggested that cology, University of Texas Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, Texas 75235. the impeded pressor response to A-II infusions * This study was supported in part by USPHS Grant which accompanies normal pregnancy is the HD-08360. The results reported in this study were pre- result of increased vascular refractoriness to sented in part at the Annual Meeting of the Society for A-II. In women with PIH and in those graviGynecologic Investigation, Tucson, AZ, March 23-25, das destined to develop PIH, the normal preg1977.
ORMAL pregnant women develop an altered response to the pressor effects of infused angiotensin II (A-II) (1-3); however, this refractoriness to A-II is lost during pregnancies which are complicated by pregnancyinduced hypertension [PIH (2, 3)]. Moreover, as early as the 23rd week of gestation, an augmented pressor response to A-II infusions is observed in pregnant women who are normotensive but who are destined to develop PIH (3). In order to elucidate the nature of the difference in the pressor responses to A-II infusions between those pregnant women who remain normal and those who later develop PIH, Gant et al. (4) studied the "effective AII pressor dose" (nanograms of AII • kg"1 • min"1 necessary to cause a 20 mm Hg
1007
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 23 November 2015. at 03:36 For personal use only. No other uses without permission. . All rights reserved.
1008
JCE&M • 1978 V0U6 • No 6
COMMENTS
nancy associated refractoriness to A-II pressor effects is lost. Therefore, a critical question is posed; specificially, what causes the vessel refractoriness to A-II that accompanies normal human pregnancy? McGiff and coworkers (6, 7) have shown that prostaglandins are potent mediators of vascular reactivity in several different organs under a variety of conditions. Moreover, Terragno et al. (8) found that in late canine pregnancy, uterine blood flow is related to the levels of prostaglandin E (PGE) in uterine venous blood. These investigators also observed that the iv infusion of A-II into pregnant dogs was associated with an increase in uterine blood flow and an increase in the levels of PGE in uterine venous blood. On the other hand, when prostaglandin synthesis was inhibited by indomethacin treatment, a decrease in uterine blood flow and in uterine venous concentrations of PGE was observed. In studies of pregnant monkeys, Franklin et al. (9) found that intrarterial infusions of A-II were associated with an increase in PGE levels in uterine venous blood; whereas after indomethacin pretreatment, there was no increase in PGE concentration in uterine venous blood in response to A-II infusions. Recently, Vane (10) reported the finding of a direct relationship between prostaglandin efflux from the kidney and renal blood flow. Indeed, when prostaglandin synthesis was inhibited by indomethacin treatment, renal blood flow decreased. From results of studies in the pregnant rabbit, Venuto et al. (11) concluded that uterine venous blood PGE concentrations were directly proportional to uterine blood flow, as indomethacin treatment was associated with a fall in uterine venous blood PGE concentration and uterine blood flow (11). The present study was designed to assess, indirectly, whether prostaglandins or prostaglandin-related substances might be involved in the control of vascular response to A-II during human pregnancy. The results of the present study are consistent with the view that prostaglandins serve, at least in part, to blunt pressor response to infused A-II in normal pregnant women.
Materials and Methods Informed volunteers' (written consent was obtained from each of the volunteers in these studies) for this study were obtained from the inpatient hospital population of the obstetric service of Parkland Memorial Hospital. Each woman was 28 weeks or later in gestation, had been normotensive throughout pregnancy, had no history of hypertension, and was eating her choice of food available from the hospital menu. Blood pressure measurements, utilizing the onset of the first (systolic) and fifth (diastolic) sounds of Korotkoff, were taken at 5-min intervals for at least 15 min or until the diastolic blood pressure was constant. Throughout the time of study, the subjects were kept in the left lateral recumbent position. An iv infusion was begun which contained 1 fig A-II (Ciba Pharmaceutical, Summit, NJ; (l-L-asparaginyl-5-L-valyl angiotensin octapeptide)/ml in a solution of 5% dextrose in water. This solution was administered at a constant rate with the aid of a Harvard infusion pump (Model 975, Harvard Apparatus Co., Milles, MA). The administered dose was increased in small increments every 5 min until a rise in diastolic blood pressure of 20 mm Hg was obtained. To confirm that this was the effective pressor dose, the A-II infusion was stopped and the diastolic blood pressure was allowed to return to its baseline value. The infusion was then restarted at the previously effective pressor dose and a repeat increase of 20 mm Hg in diastolic blood pressure was required to confirm the validity of the effective pressor dose. The effective pressor dose was considered to be the least amount of A-II [nanograms infused per kg BW/min (nanograms per kg per min)] which caused a 20 mm Hg rise in diastolic pressure. After establishing the effective pressor dose of AII before treatment, each subject was given one 25mg capsule of indomethacin (Indocin; Merck, Sharp, and Dohme) or 0.65 g of aspirin at 6-h intervals. Two hours after the second dose of indomethacin or aspirin, the effective pressor dose of A-II was determined in the same manner as before treatment. Between sets of A-II infusions, patients were allowed to maintain their usual hospital activities and diet restrictions were not imposed. The patients were receiving no cardiovascular medications or other drugs known to affect prostaglandin production.
Results Eleven pregnant women were studied before and after the administration of 25 mg
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 23 November 2015. at 03:36 For personal use only. No other uses without permission. . All rights reserved.
COMMENTS TABLE 1. Effective pressor dose of A-II before and after indomethacin treatment (A-II, nanograms per kg per min) Subject A
B
Before treatment 25.0" 25.5
C
7.7
D
25.0 52.7 12.7 19.2 17.5
E F
G H I J K
9.8
After treatment 12.7" 13.0 2.8 6.5
13.7 4.6 9.8 4.5 6.9 9.2 3.5
12.9 13.9 A P value of
