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Endocrinology, doi:10.1210/en.2003-0009
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Endocrinology Vol. 144, No. 8 3338-3343
Copyright © 2003 by The Endocrine Society

Pregnancy Enhances the Angiotensin (Ang)-(1–7) Vasodilator Response in Mesenteric Arteries and Increases the Renal Concentration and Urinary Excretion of Ang-(1–7)

Liomar A. A. Neves, Aleck F. Williams, David B. Averill, Carlos M. Ferrario, Michael P. Walkup and K. Bridget Brosnihan

The Hypertension and Vascular Disease Center (L.A.A.N., A.F.W., D.B.A., C.M.F., K.B.B.), and Public Health Sciences (M.P.W.), Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1932

Address all correspondence and requests for reprints to: K. Bridget Brosnihan, Ph.D., The Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157-1032. E-mail: bbrosnih{at}wfubmc.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The vasoactive effect of angiotensin (Ang)-(1–7) in mesenteric resistance arteries together with its plasma and kidney concentration and urinary excretion was assessed in pregnant and virgin rats. Mesenteric arteries (230–290 µm) were mounted in a pressurized myograph system and Ang-(1–7) concentration-dependent response curves (10-10–10-5 M) were determined in arteries preconstricted with endothelin-1 (10-7 M). The Ang-(1–7) response was investigated in vessels with and without pretreatment with the Ang-(1–7) antagonist [D-[Ala7]-Ang-(1–7)] (10-7 M). Ang-(1–7) caused a significantly enhanced, concentration-dependent dilation of mesenteric vessels (EC50 = 2.7 nM) from pregnant compared with virgin female rats. D-[Ala7]-Ang-(1–7) eliminated the vasodilator effect of Ang-(1–7). There was no significant change in plasma concentration of Ang-(1–7) in pregnant animals. On the other hand, 24 h urinary excretion and kidney concentration of Ang-(1–7) were significantly higher in pregnant animals. The increased mesenteric dilation to Ang-(1–7) with enhanced kidney concentration and 24 h urinary excretion rate of Ang-(1–7) suggests an important role for this peptide in cardiovascular regulation during pregnancy.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
PREGNANCY IS A physiological condition characterized by an increased hypervolemia, increased cardiac output, and a decreased total peripheral resistance (1). Characteristically, pregnant subjects are normotensive or slightly hypotensive. There is a progressive increase in the activity of the renin-angiotensin system (RAS), evident by a marked increase in circulating concentration of angiotensinogen, renin activity, and angiotensin II (Ang II) (1, 2). Although the mechanism that accounts for normal blood pressure in the face of increased RAS activity remains to be established, little consideration has been given to the presence and role of Ang-(1–7), a vasodilator component of this system, during pregnancy. Valdes et al. (3) showed that urinary excretion of Ang-(1–7) rises progressively throughout normal pregnancy, reaching levels that are 20-fold higher by the end of gestation compared with normal menstrual cycle. Similarly, Merrill et al. (4) reported that plasma Ang-(1–7) concentration is also increased in normotensive pregnant women at the third trimester compared with nonpregnant subject.

To explore further the role of Ang-(1–7) in pregnancy, we assessed the vasodilator capability of Ang-(1–7) in mesenteric resistance arteries together with the concentration of Ang-(1–7) in plasma and kidney and its urinary excretion in pregnant and virgin rats.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Timed pregnant and age-matched virgin female Sprague Dawley rats were obtained from Charles River Laboratories, Inc. (Wilmington, MA) and housed individually under a 12-h light, 12-h dark cycle in an AAALAC-approved facility. All protocols were approved by the Animal Care and Use Committee of Wake Forest University School of Medicine and are in compliance with NIH guidelines.

Surgical procedure
Two days before experiments, the animals were placed in metabolic cages. Urine was collected for 24 h in 1 ml of 1 N hydrochloric acid for determination of Ang concentrations. After urine collection, at d 19 of pregnancy or equivalent in virgin female rats, the animals were killed by decapitation. Trunk blood was collected for determination of the circulating concentration of the RAS components and 17ß-estradiol. A vaginal smear was obtained from the virgin female rats and vaginal cytology was used to determine the stage of the estrous cycle. The mesenteric bed was immediately removed and placed in cold (4 C) physiological salt solution with the following composition (in mmol/liter: KCl, 4.8; CaCl2, 2.0; KH2PO4, 1.2; MgSO4, 1.2; dextrose, 11; NaCl, 118; and NaHCO3, 25). Kidneys were quickly removed, frozen on dry ice, and stored at -80 C until determination of the angiotensin peptides.

Isolated mesenteric artery preparation
Arteries with an outer diameter of 230–290 µm were identified, carefully dissected, and cleaned of adherent adipose tissue. Isolated artery segments with a length of 2–3 mm were transferred to an arteriograph chamber (Living System Instrumentation, Burlington, VT) (5). The artery segment was cannulated at each end and maintained at an intraluminal pressure of 40 mm Hg. Only leak-free preparations that maintained a stable intraluminal pressure were included. Prewarmed buffer (37 ± 0.5 C) equilibrated with 21% O2: 5% CO2: 74% N2 (pH 7.4) was circulated through the vessel chamber at a rate of 38 ml/min; the same gas mixture flowed under the superfusion gas cover. The chamber was set on the stage of an inverted microscope with a video camera attached to the viewing tube. The vessel image was projected on a television monitor and continuous measurement of the lumen diameter was made using a Living Systems Instrumentation video dimension analyzer system (Burlington, VT). Signals from a pressure servo system and video dimension analyzer were simultaneously collected by a computer data acquisition system (WinDaq, DATAQ Instruments Inc., Akron, OH), and analyzed by WinDaq Waveform Browser (DATAQ Instruments Inc.). All drugs were added to a buffer reservoir and the buffer was recirculated. Dosages were expressed as the final cumulative molar concentration in the buffer solution, assuming zero metabolism. Each mesenteric artery was initially constricted with 50 mmol/liter KCl to demonstrate appropriate vascular smooth muscle responses, followed by exposure to 10-5 M acetylcholine to demonstrate intact endothelial-dependent relaxation. Vessels that did not constrict by 50% to KCl and did not dilate by 80% when acetylcholine was applied were excluded from further study. After the viability of the vessel had been determined, the vessel was washed and allowed to equilibrate for 30 min before the beginning of the experiment. Only one artery was used for each concentration response curve; however, several arteries were taken from each rat for the different agonist/antagonist combinations studied or the time control. At the end of each experiment, 10-5 M acetylcholine was added to each vessel to reaffirm the presence of viable endothelium; vessels that did not dilate by at least 80% were excluded from the analysis.

Experimental protocol
After an equilibration period, the vessels were preconstricted to 34% of their resting diameter with 10-7 M endothelin-1 (ET-1). All studies included a time control group, in which the luminal diameter of preconstricted vessels was recorded every 3 min for 21 min, i.e. the total time of the experiment. In a second group of vessels, Ang-(1–7) at progressively increasing cumulative concentrations (10-10–10-5 M) was applied to the ET-1 preconstricted vessel. Vessels were exposed to each peptide concentration for 3 min before the next concentration was added, and the maximal dilation was recorded during each 3-min period. In a third group, vessels were perfused with 10-7 M [D-Ala7]-Ang-(1–7) (D-Ala), a specific Ang-(1–7) antagonist (6), for 30 min before the concentration-response curve for Ang-(1–7) was obtained. For each vessel, dilation at any given peptide concentration was expressed as the difference in lumen diameter from maximum ET-1 constriction divided by the difference between baseline and ET-1 constriction. The time control was subtracted from the measured Ang-(1–7) dilator responses in the presence and absence of D-Ala (see Fig. 4Go).



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  		FIG. 4. The spontaneous relaxation of the time control was subtracted from all responses. The Ang-(1–7) (10-10–10-5 M) dilator response is compared in mesenteric vessels from virgin (A) and 19 d pregnant (B) Sprague Dawley rats before and after pretreatment with 10-7 M D-[Ala7)]-Ang-(1–7). Differences among the means were evaluated using one-way ANOVA followed by Newman-Keuls or Dunn’s multiple comparisons test. *, P < 0.05 compared with Ang-(1–7) alone.

 
Assays
Angiotensin peptides.
Trunk blood was collected in a cocktail of proteases inhibitors as previously described (7). Frozen tissues were rapidly weighed and homogenized as described by Allred et al. (8). Plasma, urine, and tissue homogenates were extracted using Sep-Pak columns as described previously (8, 9, 10). The eluate was divided for three RIAs [Ang I, Ang II, and Ang-(1–7)] and the solvent evaporated. Recoveries of radiolabeled angiotensin added to the plasma and urine samples were determined during the extraction. Recovery of radiolabeled peptide averaged more than 65%; and results were corrected for recovery. Ang I was measured using a modification of commercially available NEN Life Science Products RIA kit (Rianen Dupont, Billerica, MA). Ang II was measured using the Alpco Diagnostics kit (Windham, NH). Ang-(1–7) was measured using the antibody produced by our laboratory (9, 10). The minimum detectable levels of the assays were 1.25 pg/ml for Ang I, 0.8 pg/ml for Ang II, and 2.5 pg/ml for Ang-(1–7). The intra- and interassay coefficients of variation for Ang I RIA are 18 and 22%, for Ang II are 12 and 22%, and for Ang-(1–7) are 8 and 20%, respectively.

Plasma renin concentration.
Plasma renin concentration (PRC) was measured under conditions of excess exogenous substrate from nephrectomized rats. The samples were incubated at 37 C and 0 C for 1.5 h at pH 6.5 and the difference in Ang I generated at the two temperatures was used as a measure of renin activity and expressed as nanomoles per milliliter per hour. The generated Ang I was quantified by RIA (DiaSorin, Inc., Stillwater, MN).

Angiotensin-converting enzyme (ACE) activity.
ACE was measured using radioactive tripeptide, 3H-Hip-Gly-Gly, as substrate and incubating the serum at pH 8.0 for 60 min at 37 C (Alpco). The 3H-Hip generated was used as a measure of ACE activity and expressed as micromoles per minute per liter.

17ß-Estradiol.
Serum 17ß-estradiol was measured by RIA using a commercially available kit (Polymedco, Inc., Cortlandt Manor, NY). Serum samples were ethanol extracted and redissolved in buffer before assay. The sensitivity of the assay is 4.7 pg/ml. The intra- and interassay coefficients of variation were 8.3 and 10%, respectively.

Angiotensinogen.
Plasma samples containing EDTA and PMSF were incubated with exogenously added hog renin (Sigma, St. Louis, MO) at pH 6.5 for 90 min. The Ang I formed was quantitated by the RIA as described above.

Creatinine.
The creatinine concentration in the urine was obtained using a colorimetric assay from Sigma Diagnostics (St. Louis, MO). The sensitivity of the assay is 1 mg/dl of creatinine.

Statistical analysis
General linear models were used to estimate mean percentage dilation across time while controlling for correlations among measurements and artery segments from the same animal. These models were fit using maximum likelihood; comparisons between means were performed using the Wald test (11). Responses at each concentrations of Ang-(1–7) were compared by one-way ANOVA followed by Newman-Keuls or Dunn’s multiple comparisons test when significant differences existed between groups. Unpaired Student’s t test was used to compare vessel diameter before and after ET-1 and also to compare plasma, kidney, and urinary measurements. P < 0.05 was considered statistically significant. A logarithmic transformation of the angiotensin peptide data was performed before analysis to normalize the group variances. All values are presented as mean ± SEM.

Reagents and chemicals
The chemicals used were from Sigma unless otherwise noted. Ang-(1–7) and D-(Ala)7-Ang-(1–7) were obtained from Bachem, Inc. (Torrance, CA). These peptides were dissolved in water at an initial concentration of 10-2 M, aliquoted, and stored at -20 C until use. ET-1 was obtained from Novabiochem (La Jolla, CA) and dissolved in 50:50 ethanol:water solution at an initial concentration of 10-4 M and stored at -20 C. On the day of the experiment, the agonists and antagonists were diluted in Krebs-Henseleit solution to achieve the desired final concentration.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Basal characterization of virgin and pregnant Sprague Dawley rats
Table 1Go shows the baseline values for both virgin and pregnant rats. Virgin animals were at the diestrus phase of the estrus cycle as indicated by cytology and resting plasma 17ß-estradiol concentration, which were nearly 5-fold lower than those found in pregnant animals. Urinary flow was significantly increased during late pregnancy (P < 0.01) without a change in creatinine excretion. Pregnancy was associated with significant increases in plasma angiotensinogen (57%) and PRC (271%). Serum ACE activity was decreased by 20% in pregnant animals. There was no significant change in plasma concentration of Ang I, Ang II, and Ang (1–7) at d 19 of pregnancy.


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  		TABLE 1. Basal characterization of virgin female and d 19 pregnant rats

 
Figures 1Go and 2Go show the urinary excretion and kidney angiotensin concentrations measured in virgin and pregnant animals (d 19). In agreement with previous finding (3), 24 h urinary excretion of the angiotensin peptides was significantly increased in pregnant animals, reaching levels that were increased by 93% (Ang I), 44% (Ang II), and 60% [Ang-(1–7)] of values found in virgin rats. Kidney Ang I and Ang-(1–7) concentrations were significantly increased in pregnant animals compared with virgin female. The Ang I and Ang-(1–7) concentrations were increased by 7- and 5-fold, respectively (P < 0.05; Fig. 2Go). There was no significant change in kidney Ang II concentration of pregnant and virgin females.



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  		FIG. 1. Twenty-four-hour urinary excretion of angiotensins [Ang I, Ang II, and Ang-(1–7)] in d 19 pregnant and virgin Sprague Dawley rats. Values are expressed as mean ± SEM. Differences between the means were evaluated using Student’s t test. *, P < 0.01, virgin vs. pregnant.

 


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  		FIG. 2. Kidney angiotensin concentration in d 19 pregnant and virgin Sprague Dawley rats. Values are expressed as mean ± SEM. Differences between the means were evaluated using Student’s t test. *, P < 0.05, virgin vs. pregnant.

 
Effect of Ang-(1–7) on vascular reactivity
In isolated mesenteric resistance arteries, superfusion of 10-7 M ET-1 significantly reduced the luminal diameter by 71.9 ± 0.1% (from 245.0 ± 3.5 to 68.9 ± 2.5 µm, P < 0.001, n = 38). There was no significant difference in baseline diameter among the groups, and neither was there a significant difference in the diameter after ET-1 administration among the groups. Addition of progressively higher concentrations of Ang-(1–7) (10-10–10-5 M) was without effect in mesenteric vessels isolated from virgin female rats at the diestrus phase of the estrus cycle (P = 0.88 compared with the time control, Fig. 3AGo). In contrast, in pregnant animals Ang-(1–7) (10-10–10-5 M) caused significant dilation of the mesenteric vessels compared with the time control (P < 0.001; Fig. 3BGo) and virgin animals (P = 0.01) (Fig. 3Go, A vs. B). Upon removing the influence of the spontaneous dilation of the time control, Fig. 4BGo shows that Ang-(1–7) reached a plateau at 10-6 M and displayed an EC50 of 2.7 nM in vessels from pregnant animals. Pretreatment of the vessels with the Ang-(1–7) receptor antagonist, D-Ala, completely blocked the Ang-(1–7)-induced dilation in pregnant rats (P < 0.05; Fig. 4BGo), and was without effect in virgin rats (Fig. 4AGo).



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  		FIG. 3. Mesenteric arteries from virgin (A) and d 19 pregnant (B) Sprague Dawley rats were preconstricted with ET-1 (10-7 M) and lumen diameter was monitored for 21 min (time control) or after addition of Ang-(1–7) (10-10–10-5 M). The responses are expressed as the percent dilation relative to the contractions induced by ET-1. Differences among the means were evaluated using a random and fixed effect general linear model (SAS Institute, Cary, NC). *, P < 0.001 compared with time control.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We have shown for the first time that mesenteric vascular reactivity to Ang-(1–7), the vasodilator component of the RAS, is increased during late pregnancy compared with virgin animals in the diestrus phase of the estrus cycle. The specificity of the response was verified by complete blockade after administration of the Ang-(1–7) selective antagonist, D-Ala. The increases in plasma angiotensinogen concentration and PRC were not accompanied by elevations in circulating concentrations of Ang I, Ang II, and Ang-(1–7). However renal concentration of Ang I and Ang-(1–7) and 24-h urinary excretion of Ang I, Ang II, and Ang-(1–7) were elevated. The absence of changes in angiotensin peptide concentrations in plasma but not in the kidney may reflect either increased local formation or an increase uptake of circulating peptides in tissues.

Our study provides evidence that animals during d 19 of pregnancy have a marked dilatory response to Ang-(1–7). This contrasts with the absence of a dilatory response in virgin animals that were known to be in diestrus by cytological staining and serum 17ß-estradiol concentration. The virgin animals have serum 17ß-estradiol concentrations that are slightly above the detectable level of the assay (<20 pmol/liter), whereas pregnant animals have an estradiol concentration nearly 5-fold greater than the virgin controls. In previous studies, we showed that estrogen replacement also increases Ang-(1–7) vasodilator responses in ovariectomized animals (12). The mesenteric vascular reactivity to Ang-(1–7) in ovariectomized animals without estrogen replacement in that study resembled the findings in the females in diestrus, suggesting that estrogen is playing a primary role in the enhancement of the Ang-(1–7) response. Estrogen has been proposed to be a potential mediator of pregnancy-induced vascular changes by up-regulating endothelial nitric oxide synthase expression (13, 14) and increasing nitric oxide-mediated vasodilation (15). Because nitric oxide has been reported to mediate Ang-(1–7) vasodilation in coronary and mesentery vessels (16, 17), it is likely that it is a mediator of the enhanced Ang-(1–7) response during pregnancy. However, further studies are required to evaluate the mechanism of this response in pregnancy because other mediators, namely prostacyclin, endothelial-derived hyperpolarizing factor, and bradykinin are also potential candidates that have been shown to be involved in the Ang-(1–7) vascular response (16, 17, 18) and some of these agents are also influenced by estrogen (19, 20, 21).

In the present experiments, pretreatment of resistance arteries from pregnant animals with D-Ala completely abolished the vasodilation evoked by Ang-(1–7). These results agree with previous studies demonstrating that Ang-(1–7) acts in the vasculature at a specific Ang-(1–7) receptor (16, 17, 22, 23). Studies using in vitro receptor autoradiography of mesentery arteries showed that 125I-[Sar1Thr8] Ang II binding in the presence of losartan and PD123319 was blocked by Ang-(1–7) or D-Ala (24). Further support for the specificity of this receptor was provided by binding studies using membranes from cultured bovine aortic endothelial cells showing that D-Ala competed for 125I-Ang-(1–7) binding (25, 26).

The significant increase in 24 h urinary excretion of Ang I, Ang II, and Ang-(1–7) in pregnant rats reported in this study is in accordance with increased urinary excretion of Ang II and Ang-(1–7) in pregnant human subjects reported by Valdes et al. (3). Because the increases in both Ang I (93%) and Ang-(1–7) (60%) excretion were greater than the increase in urine flow rate (46%) that accompanied pregnancy, it is unlikely that the increase of urinary excretion of Ang I and Ang-(1–7) is due only to the increase in diuresis, but reflect active secretion of the peptides into the urine. On the other hand, urinary excretion of Ang II (44%) most likely reflects the increase in urine flow.

Ang-(1–7) and Ang I concentrations were elevated in the kidney without changes in the Ang II concentration; this may indicate a differential regulation of the enzymes of the RAS during pregnancy. In this study, we showed that PRC was increased with pregnancy and serum ACE was decreased. In other studies, we have shown that kidney ACE is down-regulated when estrogen is elevated (27). The lack of change of kidney Ang II thus might be explained by the balance of change in these enzymes. However, it is know that other enzymes also participate in the metabolism of Ang II, including chymase (28) and ACE2 (29). The regulation of these enzymes during pregnancy and their participation in the production of Ang II is unknown during pregnancy. In addition, because ACE is also capable of degrading Ang-(1–7), (30) a decrease in its activity could also contribute to a decrease degradation of Ang-(1–7) that would contribute to the increased Ang-(1–7) concentration. Because other enzymes have been shown to participate in Ang-(1–7) metabolism, further studies are necessary to investigate the metabolic pathway of Ang-(1–7) formation during pregnancy.

In the present study, we found no change in plasma concentration of Ang I, Ang II, and Ang-(1–7) at d 19 of pregnancy. This was unexpected in light of the increases in PRC and plasma angiotensinogen concentration. However, our findings confirm studies reported by others in rats. Yang et al. (31) reported no difference in plasma Ang II at d 14–17 of pregnancy and Conrad et al. (32) showed no difference in plasma Ang II at d 18 compared with 12 d postpartum. Conrad et al. (32) also showed that PRA was significantly elevated at d 6, 12, and 20 gestation. An insight into the lack of increase in plasma Ang II in their and our study was revealed when Yang et al. (31) reported that creatinine clearance was increased during pregnancy. This finding suggests that there may be enhanced filtration of Ang peptides during pregnancy. An increased clearance from the circulation would tend to reduce circulating angiotensin peptides and thus would be consistent with our findings. Another consideration to be taken into account is the half-lives of the peptides between nonpregnant and pregnant rats. The half-lives of the peptides varies from 30 sec for Ang I and 49 sec for Ang II, whereas it is less than 10 sec for Ang-(1–7) (33, 34). The effect of pregnancy on the half-lives of the angiotensin peptides has not been studied.

In conclusion, we found evidence that Ang-(1–7) is increased in the kidney and urine and that the mesenteric resistance vessels have enhanced vasodilatory capacity to Ang-(1–7) during pregnancy. These findings are consistent with the likelihood that Ang-(1–7) may play an important role in cardiovascular regulation during pregnancy.


   Footnotes
 
This work was supported in part by National Institutes of Health (NIH) Grants NHLBI-P01-HL-58952, NICHD HD-42631, and a venture grant from Wake Forest University School of Medicine. A.F.W. is a Post-baccalaureate Research Education Program scholar who is supported by NIH Grant GM-64249.

Abbreviations: ACE, Angiotensin-converting enzyme; Ang, angiotensin; ET, endothelin; PRC, plasma renin concentration; RAS, renin-angiotensin system.

Received January 6, 2003.

Accepted for publication April 10, 2003.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. August P, Lenz T, Ales KL, Druzin ML, Edersheim TG, Hutson JM, Muller FB, Laragh JH, Sealey JE 1990 Longitudinal study of the renin-angiotensin-aldosterone system in hypertensive pregnant women: deviations related to the development of superimposed preeclampsia. Am J Obstet Gynecol 163:1612–1621[Medline]
  2. Brown MA, Wang J, Whitworth JA 1997 The renin-angiotensin-aldosterone system in pre-eclampsia. Clin Exp Hypertens 19:713–726
  3. Valdes G, Germain AM, Corthorn J, Berrios C, Foradori AC, Ferrario CM, Brosnihan KB 2001 Urinary vasodilator and vasoconstrictor angiotensins during menstrual cycle, pregnancy, and lactation. Endocrine 16:117–122[CrossRef][Medline]
  4. Merrill DC, Karoly M, Chen K, Ferrario CM, Brosnihan KB 2002 Angiotensin-(1–7) in normal and preeclamptic pregnancy. Endocrine 18:239–245[CrossRef][Medline]
  5. Halpren W, Osol G, Coy GS 1984 Mechanical behavior of pressurized in vitro prearteriolar vessels determined with a video system. Ann Biomed Eng 12:463–479[CrossRef][Medline]
  6. Santos RAS, Campagnole-Santos MJ, Baracho NCV, Fontes MAP, Silva LCS, Neves LAA, Oliveira DR, Caligiorne SM, Rodrigues ARV, Gropen Jr C, Carvalho WS, Silva ACSE, Khosla MC 1994 Characterization of a new angiotensin antagonist selective for angiotensin-(1–7): evidence that the actions of angiotensin-(1–7) are mediated by specific angiotensin receptors. Brain Res Bull 35:293–398[CrossRef][Medline]
  7. Kohara K, Tabuchi Y, Senanayake P, Brosnihan KB, Ferrario CM 1991 Reassessment of plasma angiotensins measurement: effects of protease inhibitors and sample handling procedures. Peptides 12:1135–1141[CrossRef][Medline]
  8. Allred AJ, Chappell MC, Ferrario CM, Diz DI 2000 Differential actions of renal ischemic injury on the intrarenal angiotensin system. Am J Physiol Renal Physiol 279:F636–F645
  9. Senanayake PS, Smeby RR, Martins AS, Moriguchi A, Kumagai H, Ganten D, Brosnihan KB 1998 Adrenal, kidney, and heart angiotensins in female murine Ren-2 transfected hypertensive rats. Peptides 19:1685–1694[CrossRef][Medline]
  10. Nakamoto H, Ferrario CM, Fuller SB, Robaczwski DL, Winicov E, Dean RH 1995 Angiotensin-(1–7) and nitric oxide interaction in renovascular hypertension. Hypertension 25:796–802[Abstract/Free Full Text]
  11. 1992 SAS/STAT Software: changes and enhancements, release 6.06. SAS Technical Report P-229. Cary, NC: SAS Institute
  12. Neves L, Aschner J, Smith T, Espeland M, Averill DB, Ferrario CM, Brosnihan KB 2000 Estrogen modulates Ang-(1–7) vasodilation in mesenteric resistance vessels. J Hypertens 18:S76
  13. Weiner CP, Lizasoain I, Baylis SA, Knowles RG, Charles IG, Moncada S 1994 Induction of calcium-dependent nitric oxide synthases by sex hormones. Proc Natl Acad Sci USA 91:5212–5216[Abstract/Free Full Text]
  14. Weiner CP, Knowles RG, Moncada S 1994 Induction of nitric oxide synthases early in pregnancy. Am J Obstet Gynecol 171:838–843[Medline]
  15. Williams DJ, Vallance PJ, Neild GH, Spencer JA, Imms FJ 1997 Nitric oxide-mediated vasodilation in human pregnancy. Am J Physiol 272:H748–H752
  16. Brosnihan KB, Li P, Ferrario CM 1996 Angiotensin-(1–7) dilates canine coronary arteries through kinins and nitric oxide. Hypertension 27:523–528[Abstract/Free Full Text]
  17. Fernandes L, Fortes ZB, Nigro D, Tostes RC, Santos RA, Carvalho MHC 2001 Potentiation of bradykinin by angiotensin-(1–7) on arterioles of spontaneously hypertensive rats studied in vivo. Hypertension 37:703–709[Abstract/Free Full Text]
  18. Osei SY, Ahima RS, Minkes RK, Weaver JP, Khosla MC, Kadowitz PJ 1993 Differential responses to angiotensin-(1–7) in the feline mesenteric and hindquarters vascular beds. Eur J Pharmacol 234:35–42[CrossRef][Medline]
  19. Valdes G, Figueroa CD, Corthorn J 1996 Temporospatial changes of kallikrein-like enzymes during the estrous cycle and pregnancy in the rat uterus. Biol Reprod 55:236–245[Abstract]
  20. Ylikorkala O, Puolakka J, Viinikka L 1984 Vasoconstrictory thromboxane A2 and vasodilatory prostacyclin in climacteric women: effect of oestrogen-progestogen therapy. Maturitas 5:201–205[CrossRef][Medline]
  21. Seillan C, Ody C, Russo-Marie F, Duval D 1983 Differential effects of sex steroids on prostaglandin secretion by male and female cultured piglet endothelial cells. Prostaglandins 26:3–12[CrossRef][Medline]
  22. Ferrario CM, Chappell MC, Tallant EA, Brosnihan KB, Diz DI 1997 Counterregulatory actions of angiotensin-(1–7). Hypertension 30:535–541[Abstract/Free Full Text]
  23. Porsti I, Bara AT, Busse R, Hecker M 1994 Release of nitric oxide by angiotensin-(1–7) from porcine coronary endothelium: implications for a novel angiotensin receptor. Br J Pharmacol 111:652–654[Medline]
  24. Iyer SN, Chappell MC, Averill DB, Diz DI, Ferrario CM 1998 Vasodepressor actions of angiotensin-(1–7) unmasked during combined treatment with lisinopril and losartan. Hypertension 31:699–705[Abstract/Free Full Text]
  25. Tallant EA, Lu X, Weiss RB, Chappell MC, Ferrario CM 1997 Bovine aortic endothelial cells contain an angiotensin-(1–7) receptor. Hypertension 29:388–392[Abstract/Free Full Text]
  26. Iyer SN, Yamada K, Diz DI, Ferrario CM, Chappell MC 2000 Evidence that prostaglandins mediate the antihypertensive actions of angiotensin-(1–7) during chronic blockade of the renin-angiotensin system. J Cardiovasc Pharmacol 36:109–117[CrossRef][Medline]
  27. Gallagher PE, Li P, Lenhart JR, Chappell MC, Brosnihan KB 1999 Estrogen regulation of angiotensin-converting enzyme mRNA. Hypertension 33:323–328[Abstract/Free Full Text]
  28. Urata H, Boehm KD, Philip A, Kinoshita A, Gabrovsek J, Bumpus FM, Husain A 1993 Cellular localization and regional distribution of an angiotensin II-forming chymase in the heart. J Clin Invest 91:1269–1281
  29. Crackower MA, Sarao R, Oudit GY, Yagil C, Kozieradzki I, Scanga SE, Oliveira-dos-Santo AJ, da Costa J, Zhang L, Pei Y, Scholey J, Bray MR, Ferrario CM, Backx PH, Manoukian AS, Chappell MC, Yagil Y, Penninger JM 2002 Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature 417:822–828[CrossRef][Medline]
  30. Allred AJ, Diz DI, Ferrario CM, Chappell MC 2000 Pathways for angiotensin-(1–7) metabolism in pulmonary and renal tissues. Am J Physiol 279:F841–F850
  31. Yang Y, Macdonald GJ, Duggan KA 2001 Effects of nitric oxide synthase inhibition on angiotensin receptors and metabolism in the pregnant hypertensive rat. Clin Sci (Lond) 100:319–326[Medline]
  32. Conrad KP, Morganelli PM, Brinck-Johnsen T, Colpoys MC 1989 The renin-angiotensin system during pregnancy in chronically instrumented, conscious rats. Am J Obstet Gynecol 161:1065–1072[Medline]
  33. Iyer SN, Chappell MC, Brosnihan KB, Ferrario CM 1998 Role of AT1 and AT2 receptors in the plasma clearance of angiotensin II. J Cardiovasc Pharmacol 31:464–469[CrossRef][Medline]
  34. Yamada K, Iyer SN, Chappell MC, Ganten D, Ferrario CM 1998 Converting enzyme determines the plasma clearance of angiotensin-(1–7). Hypertension 98:496–502




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