Donate Help Contact The AHA Sign In Home
American Heart Association
Hypertension
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Hypertension. 1997;30:1247-1252

This Article
Right arrow Abstract Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Broughton Pipkin, F.
Right arrow Articles by Baker, P. N.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Broughton Pipkin, F.
Right arrow Articles by Baker, P. N.

(Hypertension. 1997;30:1247-1252.)
© 1997 American Heart Association, Inc.

Articles

Angiotensin II Has Depressor Effects in Pregnant and Nonpregnant Women

Fiona Broughton Pipkin; Philip N. Baker

From the Department of Obstetrics and Gynecology, D Floor, East Block, Queen's Medical Centre, University Hospital, Nottingham, NG7 2 UH England.

Correspondence to F. Broughton Pipkin, Professor of Perinatal Physiology, Department of Obstetrics and Gynaecology, D Floor, East Block, Queen's Medical Centre, University Hospital, Nottingham, NG7 2UH, England. E-mail Fiona.Broughton-Pipkin{at}nottingham.ac.uk


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Abstract Studies in anesthetized animals suggest that angiotensin II evokes a depressor as well as a pressor effect, which becomes evident on cessation of infusion. We have studied 18 nonpregnant and 8, 23, and 22 women in the first, second, and third trimesters of pregnancy to determine whether such an effect is present in conscious women, whether it is dose dependent, and whether it is influenced by pregnancy. Angiotensin II was infused intravenously in doubling concentrations at 10-minute intervals until a pressor effect of {approx}20 mm Hg was observed. The infusion was stopped, and blood pressure was monitored at 2-minute intervals for 30 minutes. There was a significant diastolic depressor effect after stopping angiotensin II in the nonpregnant women and those in the second and third trimesters of pregnancy. Individual women required differing doses of angiotensin II to evoke the standardized pressor response. It was thus possible to examine the depressor response in each group in relation to infused doses of angiotensin II. In nonpregnant women and in those in the second and third trimesters of pregnancy, the depressor response was dose dependent (P<.001). At any given dose, the depressor response deepened as pregnancy progressed (P<.001). Basal plasma prostacyclin concentrations rise in pregnancy, and angiotensin II can stimulate prostacyclin synthesis. This might mediate the depressor effect. In conclusion, the diminished pressor response to angiotensin II in normal pregnancy may be partly due to an increasing depressor effect of the hormone.


Key Words: angiotensin II • renin-angiotensin system • blood pressure • pregnancy, humans


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Angiotensin II (Ang II) evokes rises in arterial pressure both acutely and chronically, the latter occurring with the long-term infusion of initially subpressor doses.1 It is an extremely potent vasoconstrictor and also has central pressor effects.2 3 However, Ang II is also known to be a vasodilator in some circulations, including the cerebral4 and coronary resistance arterioles.5 A majority of the "classic" actions of Ang II are mediated via angiotensin type 1 (AT1) receptors.6 Under some circumstances, usually in association with the administration of high-dose Ang II to anesthetized animals, Ang II has been shown to exert a biphasic effect on the blood pressure, an initial pressor response being followed by a depressor effect on cessation of administration.7 8 This effect has been found to be mediated via the AT2 receptor.8 However, barbiturate anesthesia is associated with decreased renal blood flow in dogs, an effect minimized by administration of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker.9 It is also associated with a 50% rise in plasma Ang II concentration in humans.10 This hinders the interpretation of such studies.

It has been known for nearly 30 years that pressor responsiveness to Ang II is reduced in normotensive pregnancy, whereas that to noradrenaline is not.11 This suggested the downregulation of Ang II receptors. However, the density of Ang II receptors in mesenteric and uterine arteries has been reported not to differ in nonpregnant and near-term ewes12 ; the Bmax in human uterine arteries is also reported as being unchanged during pregnancy.13 It is not ethically possible to obtain repeated vascular biopsies from pregnant women. The direct study of AT1 receptors in human systemic resistance vessels in pregnancy has thus not been performed. A possible explanation for the decrease in pressor response to Ang II in human pregnancy would be an increased synthesis and/or release of prostacyclin (PGI2) or another vasodilator in response to Ang II. Ang II can release arachidonic acid metabolites such as PGI2 from vascular smooth muscle cell cultures.14 The acute administration of PGI2 results in a significant fall in pressor response to Ang II in second trimester human pregnancy.15 In vitro Ang II evokes significant increases in PGI2 release from the uterine arteries of pregnant but not nonpregnant sheep.16 This effect is mediated through the AT1 receptor.17 No significant increase was observed in the omental vasculature.16

In the course of experiments to investigate possible modulators of the pressor effect of Ang II in human pregnancy,15 18 19 we had repeatedly observed, but not studied or reported on, a fall in both systolic and diastolic pressure to below basal levels on stopping the infusion of Ang II, which was most pronounced during the first 10 minutes. The objectives of this study were therefore to determine (1) whether a significant depressor effect attributable to Ang II was indeed consistently noted in unanesthetized humans; (2) whether any such effect was dose-dependent, indicating indirectly a receptor-mediated rather than a nonspecific effect; and (3) whether any such effect was influenced by pregnancy.


*    Methods
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Patients
A total of 71 women were studied. None had any known metabolic or cardiovascular disease, and none were taking regular medication. Eighteen were nonpregnant nullipara women recruited from students and staff (group 0) with regular menstrual cycles. They were studied at 9.1±1.3 days after the start of their last menstrual period. The remaining 53 were pregnant. Thirty-one women studied in the first (n=8; group 1) or second (n=23; group 2) trimester of pregnancy subsequently underwent therapeutic termination of pregnancy after counseling by a consultant gynecologist unconnected with the project. An additional 22 were studied in the third trimester of continuing pregnancies (group 3). The protocol was approved by the Hospital Committee on Ethics, and all subjects gave informed written consent for participation. Table 1Down summarizes some basal data for the four groups.


View this table:
[in this window]
[in a new window]
  		Table 1. Some Basal Data Relating to the Four Groups of Women Studied

Infusion Protocol
The pressor sensitivity to Ang II varies widely in pregnancy. We therefore aimed to achieve a standard pressor response to 20 mm Hg above basal levels using doubling doses of Ang II from 4 ng/kg · min-1. Nonpregnant women are more sensitive than pregnant women to Ang II, usually exhibiting a 20-mm Hg pressor response at 4 ng/kg · min-1. However, to allow comparison of possible dose as well as baroreflex effects in pregnant and nonpregnant women, doses of up to 16 ng/kg · min-1 Ang II were given to nonpregnant women. Up to 64 ng/kg · min-1 were given to pregnant women.

The protocol used was as described previously18 with only minor modifications. It is described in brief below.

The subjects lay supine throughout the experiment; a pillow was placed under the pregnant subjects to support a right lateral tilt. An indwelling cannula (Venflon 18G, Viggo AB) was placed in the right antecubital fossa through which saline solution was infused continuously at approximately 30 drops per minute. Arterial blood pressure was measured at 2-minute intervals throughout the experiment from the left arm using a Dinamap automatic blood pressure recorder (Critikon Ltd).

Arterial blood pressure was allowed to stabilize for a minimum of 30 minutes after setting up, until random fluctuations in diastolic blood pressure had been within 6 mm Hg for 10 minutes. Ang II (Hypertensin, Ciba) was then infused intravenously through a needle connection into the indwelling cannula of the right arm so that it was flushed in by the saline infusion. The Ang II was made up freshly each day from dry ampules of 2.5 mg; the stock solution was then stored on ice. This was infused with a Vickers pump (Vickers Medical Ltd). The Ang II infusion was discontinued after the last planned infusion step or earlier if a 20-mm Hg rise in diastolic blood pressure had been achieved. A final period of 30 minutes recovery and stabilization of blood pressure then followed.

Calculations
The mean basal systolic and diastolic blood pressures were calculated over the 10 minutes immediately before the Ang II infusion was begun. Pressor and depressor effects were calculated by comparison with this for each patient.

Data are presented as arithmetic mean±SEM. Between- and within-group comparisons were made by ANOVA, with post hoc testing by Scheffé's method, using the Statistical Package for the Social Sciences, version 3X.


*    Results
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 *Results
down arrowDiscussion
 down arrowReferences
 
As expected, the basal systolic and diastolic pressures were significantly lower in the second trimester than at other gestations (Table 1Up; P<.001 and P<.002, respectively). Table 2Down shows the mean maximum pressor responses evoked in the four study groups, with the associated mean maximal dose of infused Ang II. There was no overall difference in maximum evoked systolic response between the groups. However, the maximum diastolic pressor response was significantly less in the third trimester than at other gestations (P<.01).


View this table:
[in this window]
[in a new window]
  		Table 2. Rise in Pressure and Dose of Angiotensin II

Fig 1Down summarizes the change in systolic pressure during the 30 minutes after stopping Ang II infusion in the four study groups. There was no evidence of any depressor effect in any group, with statistically significant rises above basal being maintained in most groups (P<.001 for all except group 3). There was a significant effect (P<.0001; ANOVA) of gestation group on the level of this rise; patients in the third trimester showed the least rise. Fig 2Down shows the change in diastolic pressure over the same period. The nonpregnant patients and those in the second and third trimesters showed significant and maintained falls in diastolic pressure throughout this period. Again, there was an effect of gestation age, with the response being greatest in the third trimester (group 3; P<.01).



View larger version (20K):
[in this window]
[in a new window]
  		Figure 1. There was no systolic depressor effect after stopping Ang II infusion. There was, however, a significant effect of gestation age on the overall changes observed (P<.0001; ANOVA). The number of subjects in each group is shown in parentheses. Bars, SEM.



View larger version (19K):
[in this window]
[in a new window]
  		Figure 2. There was a gestation-dependent diastolic depressor effect of Ang II; the response in the third trimester was significantly lower than that in the other three groups (P<.01). Bars, SEM.

The comparable maximum evoked pressor effect in the four groups was achieved by significantly different doses of Ang II (Table 2Up). We therefore considered only data from subjects exposed to a maximum dose of 16 ng Ang II/kg · min-1.

Table 3Down shows the maximum evoked pressor effect in these patients. There was again no evidence of a systolic depressor effect, but the diastolic pressure had fallen to significantly below basal (P<.05) by 6 to 8 minutes after cessation of infusion in all groups except group 1 and was significantly reduced overall in these groups (P<.02; Fig 3Down). There was no evidence for an effect of gestation per se. However, when a comparable analysis was performed on data from subjects receiving 32 ng Ang II/kg · min-1, not only were significant depressor effects again demonstrated in the second and third trimesters (P<.001 for both), but there was also a significant effect of gestation age (Fig 4Down; P<.001 overall).


View this table:
[in this window]
[in a new window]
  		Table 3. Evoked Rise in Pressure by Groups



View larger version (22K):
[in this window]
[in a new window]
  		Figure 3. There was a significant diastolic depressor effect in all groups except the first trimester (F=2.689; P<.05 for the group difference). Dose used was 16 ng/kg · min-1 for all groups. Bars, SEM.



View larger version (20K):
[in this window]
[in a new window]
  		Figure 4. At a standardized dose of 32 ng Ang II/kg · min-1, significant diastolic depressor effects were observed overall in the second and third trimesters (P<.001 for both). The differences in effect between the gestation groups were also significant (P<.001). Bars, SEM.

Comparison of Figs 3Up and 4Up suggested a dose-dependent depressor effect at each gestation stage. This was confirmed for the nonpregnant subjects (Fig 5Down; P<.001 comparing maximal doses of 8 and 16 ng/kg · min-1) and in the third trimester, comparing maximal doses of 16, 32, and 64 ng/kg · min-1 (P<.001; Fig 6Down). Interestingly, at this gestation, the highest necessary dose of Ang II was also associated with a significant systolic depressor effect (P<.001); there was a significant difference between the effects of the three doses (P<.001).



View larger version (17K):
[in this window]
[in a new window]
  		Figure 5. There was a dose-related diastolic depressor effect of Ang II in the nonpregnant subjects (P<.001). Bars, SEM.



View larger version (18K):
[in this window]
[in a new window]
  		Figure 6. There was a statistically highly significant dose-related diastolic depressor effect of Ang II in the third trimester (P<.001). Bars, SEM.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
Studies involving human volunteers have both advantages and disadvantages. In these experiments, the subjects were conscious and very cooperative; there were no anesthetic effects. It was, however, not ethically possible to make direct intra-arterial measurements of blood pressure. The blood pressure monitoring system we used was fully automated, removing observer bias, and no subject complained of discomfort from the frequent measurement of blood pressure. It should also be noted that at the highest dose of Ang II, the response of the systolic and diastolic pressure showed quite marked spikes in some pregnant women, which prevented us from evoking an absolutely comparable diastolic pressor response in each group (Table 2Up). Twelve nonpregnant women received doses of 16 ng Ang II/kg · min-1 to provide direct dose exposure comparability with the most sensitive pregnant patients. This is a higher dose than that usually given outside pregnancy. However, the dose-response curve to Ang II had reached a maximum plateau at this dose, such that the mean systolic and diastolic responses at 8 and 16 ng Ang II/kg · min-1 were the same (systolic, 19.1±1.8 and 19.5±1.2 mm Hg; diastolic, 22.0±2.5 and 19.4±1.7 mm Hg, respectively).

A fall in blood pressure to levels below basal on cessation of the infusion of a potent pressor agent could be due either to a transient disequilibrium in baroreflex response or to a longer-acting, receptor-mediated depressor effect, initially masked by the pressor effect. Acutely raising plasma Ang II concentrations for a minimum of 30 minutes can evoke a degree of central resetting of the blood pressure. Rapid baroreceptor resetting can be observed in animals after as little as 30 minute infusion of a pressor agent.21 By standardizing pressor responses as far as we were able in human subjects, we attempted to minimize differences in baroreflex response. However, because Ang II exerts direct effects on the baroreceptors,22 an effect at this level cannot be ruled out.

The elegant studies of Scheuer and Perrone8 suggest strongly that in the anesthetized rat, the depressor effect after the bolus injection of Ang II is genuinely agonist mediated via AT2 receptors. The data presented here support the hypothesis of an agonist-mediated response. Both in nonpregnant (Fig 5Up) and pregnant (Fig 6Up) subjects, the depressor effect was significantly dose related. The duration of effect was also greater at higher doses. Thus, in the third trimester, the depressor effect after 16 ng/kg · min-1 was ended by 12 minutes after stopping the infusion (Fig 6Up), whereas in the groups requiring 32 and 64 ng/kg · min-1 to evoke a 20-mm Hg rise in pressure, the depressor effect was still apparent at the end of the experiment.

In the original observations of the depressor effect of Ang II,7 it was shown that the simultaneous administration of cyclooxygenase inhibitors potentiated the pressor effects and abolished the depressor effects of Ang II. We have shown previously15 that infused PGI2 blunts the pressor response to Ang II in human pregnancy. However, Ang II has been reported to not significantly stimulate prostacyclin synthesis by ovine omental arteries in pregnancy.16 In any case, Ang II in the circulation of pregnant and nonpregnant women has a half-life of around 50 seconds,23 whereas the observed depressor effect was of much longer duration. It could therefore be supposed that a biologically active metabolite of Ang II had been produced by degradation, which has a long half-life in the circulation. Ang II is degraded in vivo by a variety of amino peptidases, and some C- and N-terminal fragments have biological activity. Amino peptidase concentrations are raised in human pregnancy,24 but the metabolic clearance rate of Ang II appears to be largely unchanged.23 25 The [desAsp1]Ang II fragment (angiotensin 2-8), Ang III, has only about one third the pressor activity of Ang II in humans.26 Assays of sufficient sensitivity to identify this fragment show that in the nonpregnant subjects, it is present at about one fifth of the concentration of Ang II.27 28 The only study of such sensitivity including pregnant women29 reported a similar proportion in five pregnant women. Both Ang II and Ang III have been reported to be depressors on direct central administration in low doses.30

The N-terminal fragment [desPhe8]Ang II (Ang-[1-7]) can be synthesized in vivo and in vitro by the degradation of either Ang I or Ang II by endopeptidases such as prolyl or neutral endopeptidase 24.11 (enkephalinase).31 32 Ang-(1-7) stimulates prostaglandin synthesis in cultured vascular endothelial cells33 and human astrocytes34 and stimulates renal prostacyclin release from the isolated perfused rat kidney.35 It has also been reported to evoke the release of nitric oxide from porcine coronary artery rings36 and from feline mesenteric vasculature.37 It is thus not surprising that it should appear to act as a vasodilator and depressor agent both peripherally37 38 and centrally.21 22 There appears to be no published information concerning Ang-(1-7) concentrations during pregnancy or comparative rates of Ang II metabolism to its various fragments. The rate of further breakdown of the large fragments is also unknown at this time, although human placental subcellular fractions have been reported to break down Ang-(2-8) rapidly.24 Ang-(1-7) may perhaps be a more likely candidate as a depressor fragment than Ang-(2-8) in view of its known depressor effect.8 Basal PGI2 synthesis is also enhanced in normal pregnancy.39 Because Ang-(1-7) appears to exert its depressor effect partly through stimulation of the vasodilator prostanoids, this might contribute to the greater depressor effect seen in pregnancy (Fig 2Up). Interestingly, Ang-(1-7) has been reported to directly antagonize the pressor effects of Ang II in spontaneously hypertensive rats.40

Ang II normally exerts a negative feedback on renin release, and we have shown previously that this effect is maintained in human pregnancy.19 It is thus possible that the relatively high plasma concentrations of Ang II reached during infusion suppressed renin release to such an extent that preinfusion concentrations of endogenous Ang II had not been reattained by the end of the experiment. We have no data with which to test this hypothesis.

One other possibility can be suggested. Mesenteric vascular Ang II receptors are downregulated in rabbit pregnancy41 ; rabbit systemic vascular Ang II receptors are of the AT1 subtype.42 However, uterine and mesenteric Ang II vascular smooth muscle receptors from sheep are not downregulated in pregnancy.12 43 The Bmax in human uterine vessels has also been reported as being unchanged in pregnancy,13 although there appear to be no studies of the Ang II receptors in human mesenteric vessels in pregnancy. The observation that uterine vascular smooth muscle AT2 receptors are not downregulated in human pregnancy,13 without information on other systemic vessels, does not necessarily close the question because the responses of pregnant human uterine and other systemic vasculature differ markedly to various agonists.44

In conclusion, we have shown that on ending an Ang II infusion, there is a depressor effect in nonpregnant and pregnant women. This effect increases with gestation age and may partly explain the blunted pressor response to Ang II in normal pregnancy.


*    Acknowledgments
 
Dr Baker was supported by the British Heart Foundation. We acknowledge with thanks the gift of Hypertensin (angiotensin II amide) from Ciba.

Received May 31, 1996; first decision July 11, 1996; accepted April 24, 1997.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 up arrowDiscussion
 *References
 

  1. Brown AJ, Casals-Stenzel J, Gofford S, Lever AF, Morton JJ. Comparison of fast and slow pressor effects of angiotensin II in the conscious rat. Am J Physiol.. 1981;241:H381-H388.[Abstract/Free Full Text]
  2. Lever AF. The fast and the slowly developing pressor effect of angiotensin II. In: Robertson JIS, Nicholls MG, eds. The Renin-Angiotensin System. London, UK: Gower Medical Publishing; 1993:28.1-28.9.
  3. Squire IB, Reid JL. Interactions between the renin-angiotensin system and the autonomic nervous system. In: Robertson JIS, Nicholls MG, eds. The Renin-Angiotensin System. London, UK: Gower Medical Publishing; 1993:37.1-37.16.
  4. Tamaki K, Saku Y, Ogata J. Effects of angiotensin and atrial natriuretic peptide on the cerebral circulation. J Cereb Blood Flow Metab.. 1992;12:318-325.[Medline] [Order article via Infotrieve]
  5. Myers PR, Katwa LC, Tanner M, Morrow C, Guarda E, Parker JL. Effect of angiotensin II on canine and porcine coronary epicardial and resistance arteries. J Vasc Res.. 1994;31:338-346.[Medline] [Order article via Infotrieve]
  6. Timmermans PBMWM, Wong PC, Chiu AT, Herblin WF, Benfield P, Carini DJ, Lee RJ, Wexler RR, Saye JAM, Smith RD. Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev.. 1993;45:205-251.[Medline] [Order article via Infotrieve]
  7. Rowe BP, Nasjletti A. Biphasic blood pressure response to angiotensin II in the conscious rabbit: relation to prostaglandins. J Pharmacol Exp Ther.. 1983;225:559-563.[Abstract/Free Full Text]
  8. Scheuer DA, Perrone MH. Angiotensin type 2 receptors mediate depressor phase of biphasic pressure response to angiotensin. Am J Physiol.. 1993;264:R917-R923.[Abstract/Free Full Text]
  9. Burger BM, Hopkins T, Tulloch A, Hollenberg NK. The role of angiotensin in the canine renal vascular response to barbiturate anesthesia. Circ Res.. 1976;38:196-202.[Abstract/Free Full Text]
  10. Broughton Pipkin F, Waldon BA. Ketamine, hypertension and the renin-angiotensin system. Clin Exp Hyp. 1983;A5:875-883.
  11. Talledo OE, Chesley LC, Zuspan FP. Renin angiotensin system in normal and toxaemic pregnancies, III: differential sensitivity to angiotensin II and norepinephrine in toxaemia of pregnancy. Am J Obstet Gynecol.. 1968;100:218-221.
  12. Makanjee HR, Shaul PW, Magness RR, Rosenfeld CR. Angiotensin II vascular smooth-muscle receptors are not down-regulated in near-term pregnant sheep. Am J Obstet Gynecol.. 1991;165:1641-1648.[Medline] [Order article via Infotrieve]
  13. Cox BE, Word A, Rosenfeld C. Angiotensin II receptor characteristics and subtype expression in uterine arteries and myometrium during pregnancy. J Clin Endocrinol Metab.. 1996;81:49-58.[Abstract]
  14. Leung KH, Chang RS, Lotti VJ, Roscoe WA, Smith RD, Timmermans PB, Chiu AT. AT1 receptors mediate the release of prostaglandins in porcine smooth muscle cells and rat astrocytes. Am J Hypertens.. 1992;5:648-656.[Medline] [Order article via Infotrieve]
  15. Broughton Pipkin F, Morrison R, O'Brien PMS. Prostacyclin attenuates both the pressor and adrenocortical response to angiotensin II in human pregnancy. Clin Sci.. 1989;76:529-534.[Medline] [Order article via Infotrieve]
  16. Magness RR, Osei-Boaten K, Mitchell MD, Rosenfeld CR. In vitro prostacyclin production by ovine uterine and systemic arteries: effects of angiotensin II. J Clin Invest.. 1985;76:2206-2212.
  17. Cox BE, Rosenfeld CR, Kalinyak JE, Magness RR, Shaul PW. Tissue specific expression of vascular smooth muscle, angiotensin II receptor subtypes during ovine pregnancy. Am J Physiol.. 1996;271:H212-H221.[Abstract/Free Full Text]
  18. Broughton Pipkin F, Hunter JC, Turner SR, O'Brien PMS. Prostaglandin E2 attenuates the pressor response to angiotensin II in pregnant, but not non-pregnant, humans. Am J Obstet Gynecol.. 1982;142:168-176.[Medline] [Order article via Infotrieve]
  19. Broughton Pipkin F, Morrison R, O'Brien PMS. The effect of prostaglandin E1 upon the pressor and hormonal response to exogenous angiotensin II in human pregnancy. Clin Sci.. 1987;72:351-357.[Medline] [Order article via Infotrieve]
  20. Burnier M, Centeno G, Grouzmann E, Walker P, Waeber B, Brunner HR. In vitro effects of DuP753, a nonpeptide angiotensin II receptor antagonist, on human platelets and rat vascular smooth muscle cells. Am J Hypertens.. 1991;4:438-443.[Medline] [Order article via Infotrieve]
  21. Moreira ED, Ida F, Oliveira VLL, Krieger EM. Rapid resetting of the baroreceptors in renal hypertensive rats. Hypertension. 1990;15(suppl I):I-40-I-44.
  22. Ferrario CM, Barnes KL, Block CH, Brosnihan KB, Diz DI, Khosla MC, Santos RAS. Pathways of angiotensin formation and function in the brain. Hypertension. 1990;15(suppl I):I-13-I-19.
  23. Magness RR, Cox K, Rosenfeld CR, Gant NF. Angiotensin II metabolic clearance rate and pressor responses in non-pregnant and pregnant women. Am J Obstet Gynecol.. 1994;171:668-679.[Medline] [Order article via Infotrieve]
  24. Mizutani S, Akiyama H, Kurauchi O, Taira H, Narita O, Tomoda Y. In vitro degradation of angiotensin II (A-II) by human subcellular fractions, pregnancy sera and purified placental aminopeptidases. Acta Endocrinol.. 1985;110:135-139.
  25. Broughton Pipkin F, Hunter JC, Turner SR, O'Brien PMS. The effect of prostaglandin E2 upon the biochemical response to infused angiotensin II in human pregnancy. Clin Sci.. 1984;66:399-406.[Medline] [Order article via Infotrieve]
  26. Carey RM, Vaughan ED, Peach MJ, Ayers CR. Activity of des-Asp1-angiotensin II in man. J Clin Invest.. 1978;61:20-31.
  27. Nussberger J, Brunner D, Waeber B, Brunner HR. Specific measurement of angiotensin metabolites and in vitro generated angiotensin II in plasma. Hypertension.. 1986;8:476-482.[Abstract/Free Full Text]
  28. Campbell DJ, Kladis A. Simultaneous radioimmunoassay of six angiotensin peptides in arterial and venous plasma of man. J Hypertens.. 1990;8:167-172.
  29. Semple PF, Boyd AS, Dawes PM, Morton JJ. Angiotensin II and its heptapeptide (2-8), hexapeptide (3-8), and pentapeptide (4-8) metabolites in arterial and venous blood of man. Circ Res.. 1976;39:671-678.[Abstract/Free Full Text]
  30. Tseng CJ, Chou LL, Ger LP, Tung CS. Cardiovascular effects of angiotensin III in brainstem nuclei of normotensive and hypertensive rats. J Pharmacol Exp Ther.. 1994;268:558-564.[Abstract/Free Full Text]
  31. Yamamoto K, Chappell MC, Brosnihan KB, Ferrario CM. In vivo metabolism of angiotensin I by neutral endopeptidase (EC 3.4.24.11) in spontaneously hypertensive rats. Hypertension.. 1992;19:692-696.[Abstract/Free Full Text]
  32. Santos RA, Brosnihan KB, Jacobsen DW, diCorleto PE, Ferrario CM. Production of angiotensin-(1-7) by human vascular endothelium. Hypertension. 1992;19(suppl II):II-56-II-61.
  33. Jaiswal N, Diz DI, Chappell MC, Khosla MC, Ferrario CM. Stimulation of endothelial cell prostaglandin production by angiotensin peptides. Hypertension. 1992;19(suppl II):II-49-II-55.
  34. Jaiswal N, Tallant EA, Diz DI, Khosal MC, Ferrario CM. Subtype 2 angiotensin receptors mediate prostaglandin synthesis in human astrocytes. Hypertension.. 1991;17:1115-1120.[Abstract/Free Full Text]
  35. Hilchey SD, Bell-Quilley CP. Association between the natriuretic actions of angiotensin-(1-7) and selective stimulation of renal prostaglandin I2 release. Hypertension.. 1995;25:1238-1244.[Abstract/Free Full Text]
  36. Porsti I, Bara AT, Busse R, Hecker M. Release of nitric oxide by angiotensin (1-7) from porcine coronary endothelium: implications for a novel angiotensin receptor. Br J Pharmacol.. 1994;111:652-654.[Medline] [Order article via Infotrieve]
  37. Osei SY, Ahima RS, Minkes RK, Weaver JP, Khosla MC, Kadowitz PJ. Differential responses to angiotensin (1-7) in the feline mesenteric and hindquarters vascular beds. Eur J Pharmacol.. 1993;234:35-42.[Medline] [Order article via Infotrieve]
  38. Benter IF, Ferrario CM, Morris M, Diz DI. Antihypertensive actions of angiotensin (1-7) in spontaneously hypertensive rats. Am J Physiol.. 1995;269:H313-319.[Abstract/Free Full Text]
  39. Fitzgerald DJ, Entman SS, Mulloy K, Fitzgerald GA. Decreased prostacyclin biosynthesis preceding the clinical manifestation of pregnancy-induced hypertension. Circulation.. 1987;75:956-967.[Abstract/Free Full Text]
  40. Benter IF, Diz DI, Ferrario CM. Pressor and reflex sensitivity is altered in spontaneously hypertensive rats treated with angiotensin- (1-7). Hypertension.. 1995;26:1138-1144.[Abstract/Free Full Text]
  41. Brown GP, Venuto RC. Angiotensin II receptor alterations during pregnancy in rabbits. Am J Physiol.. 1986;251:E58-E64.[Abstract/Free Full Text]
  42. Noda M, Shibouta Y, Inada Y, Ojima M, Wada T, Sanada T, Kubo K, Kohara Y, Naka T, Nishikawa K. Inhibition of rabbit aortic angiotensin II (AII) receptor by CV-11974, a new non-peptide AII antagonist. Biochem Pharmacol.. 1993;46:311-318.[Medline] [Order article via Infotrieve]
  43. Cox BE, Ipson MA, Shaul PW, Kamm KE, Rosenfeld CR. Myometrial angiotensin II receptor subtypes change during ovine pregnancy. J Clin Invest.. 1993;92:2240-2248.
  44. Ashworth JR, Baker PN, Warren AY, Johnson IR. Altered endothelium-dependent relaxation in myometrial but not systemic resistance arteries in normal pregnancy and in pre-eclampsia. Br J Obstet Gynaecol.. 1996;103:482-483.



This article has been cited by other articles:


Home page
 J. Am. Soc. Nephrol.Home page
S. B. Ahmed, A. K. Kang, K. D. Burns, C. R. J. Kennedy, V. Lai, D. C. Cattran, J. W. Scholey, and J. A. Miller
Effects of Oral Contraceptive Use on the Renal and Systemic Vascular Response to Angiotensin II Infusion
J. Am. Soc. Nephrol., March 1, 2004; 15(3): 780 - 786.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
B. P. Rowe and B. Dixon
Angiotensin III Depressor Action in the Conscious Rabbit Is Blocked by Losartan but not PD 123319
Hypertension, January 1, 2000; 35(1): 130 - 134.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Broughton Pipkin, F.
Right arrow Articles by Baker, P. N.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Broughton Pipkin, F.
Right arrow Articles by Baker, P. N.

Hypertension Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search
Copyright © 1997 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited.