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(Hypertension. 2003;42:781.)
© 2003 American Heart Association, Inc.

Scientific Contributions

Estrogen or the AT1 Antagonist Olmesartan Reverses the Development of Profound Hypertension in the Congenic mRen2.Lewis Rat

Mark C. Chappell; Patricia E. Gallagher; David B. Averill; Carlos M. Ferrario; K. Bridget Brosnihan

From the Hypertension and Vascular Disease Center, Wake Forest University Health Sciences, Winston-Salem, NC.

Correspondence to Mark C. Chappell, PhD, Hypertension and Vascular Disease Center, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC 27157-1095. E-mail mchappel{at}wfubmc.edu

	Abstract

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The influence of estrogen on the regulation of cardiovascular function remains a controversial and complex area of investigation. We assessed the effects of estrogen depletion in the congenic mRen(2).Lewis rat, established from the back-cross of the original (mRen2)-27 transgenic onto the Lewis inbred strain. Ovariectomy of heterozygous mRen(2).Lewis at 4 to 5 weeks resulted in a progressive increase in blood pressure compared with the sham surgery congenics at weeks 6 to 11. At 11 weeks, the ovariectomized mRen(2).Lewis (OVX) systolic blood pressure averaged 195±3.7 mm Hg versus 141±4.0 mm Hg for sham. Plasma Angiotensin (Ang) II, serum ACE activity, plasma renin concentration, as well as urinary excretion of Ang II, 8-isoprostane F₂, and endothelin-1 were elevated; however, renal mRNA levels of eNOS were suppressed after ovariectomy. Estrogen replacement reduced blood pressure below both the sham and OVX by 11 weeks (125±2.9 mm Hg, n=7, P<0.01 versus OVX and sham). Moreover, the AT₁ receptor antagonist olmesartan (CS866; week 12 to 16) essentially normalized blood pressure to 113±5.4 mm Hg (n=6, P<0.01 versus OVX and sham). The attenuation of the hypertension was still evident 7 weeks after complete withdrawal of treatment (124±4.1 mm Hg at week 23). In summary, the OVX mRen.2.Lewis exhibited a rapid and sustained increase in blood pressure. Estrogen or olmesartan lowered pressure by a similar extent. We conclude that the ovary exerts considerable influence on the regulation of the blood pressure in the mRen2.Lewis strain, possibly by limiting activation of the renin-angiotensin system.

Key Words: angiotensin II • angiotensin-converting enzyme • estrogen • rats, transgenic • hypertension, genetic

	Introduction

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It is well recognized that ovarian hormones, particularly estrogen, exhibit a protective role on the cardiovascular system. After menopause, there is increased arterial pressure and higher rates of hypertension, renal disease, cardiovascular events, and mortality rates in women. However, recent clinical studies have questioned the beneficial effects of hormone replacement therapy (estrogen/progestin), particularly the actions that influence the cardiovascular system.¹ Indeed, one arm of the Women’s Health Initiative (WHI) study with the combined therapy was halted prematurely because of negative outcomes, although the estrogen replacement group has continued at the present time. In light of the clinical data, the protective actions of estrogen would appear to be in contrast to the hormone’s effects on several components of the renin-angiotensin system (RAS)—one of the key regulatory systems for the control of blood pressure and cardiovascular pathologies. Specifically, estrogen stimulates the expression of angiotensinogen from the liver, kidney, and other tissues, as well as increases renin activity.^2,3 However, estrogen has also been shown to suppress components of the RAS, including ACE and the AT₁ receptor, perhaps achieving an overall balance to attenuate the development of hypertension and progression of other cardiovascular events.^4–7

Various hypertensive models have marked gender differences in the expression of hypertension. Although the majority of the studies have focused on the relation of androgens to the development of blood pressure,^8–10 there clearly remains strong evidence for the contribution of estrogens or their metabolites in cardiovascular regulation.¹¹ For example, homozygous and heterozygous (mRen2)-27 male rats have blood pressures 100 and 50 mm Hg higher, respectively, than their female littermates.¹² We and other groups extensively use the (mRen2)-27 transgenics to study the mechanisms of renin overexpression and the development of hypertension. However, to eliminate the variability of the outbred SD background, (mRen2)-27 transgenics were back-crossed into the inbred Lewis rat, creating the new mRen(2).Lewis strain. After 9 generations, characterization of the mRen(2).Lewis rat revealed essentially the same degree of hypertension as the original transgenics, but the congenics lacked the malignant hypertension and the inability to concentrate urine.¹³ Of particular interest, the mRen(2).Lewis strain also demonstrates a significant gender difference in the development of hypertension. Therefore, in the present studies, we tested the hypothesis that early depletion of estrogen in the congenic mRen(2).Lewis rats influences the development of blood pressure and the expression of the circulating and renal RAS components, as well as related mediators, including endothelin-1 and the reactive oxygen species (ROS) metabolite 8-isoprostane F₂. In addition, we determined the influence of both estrogen replacement and selective blockade with the AT₁ antagonist olmesartan on blood pressure in the ovariectomized mRen(2).Lewis strain.

	Methods

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Heterozygous male and female mRen(2).Lewis rats were obtained from the Hypertension and Vascular Disease Center Transgenic colony at 5 weeks of age, and either a bilateral ovariectomy or sham surgery was performed on the female littermates. A separate group of ovariectomized (OVX)-mRen(2).Lewis was implanted with a 3-week 17ß-estradiol pellet (1.0 mg pellet) subcutaneously after the ovariectomy and again 3 weeks later. These groups were killed at 11 weeks to assess both circulating and tissue RAS components as well as 17ß-estradiol serum levels. Two additional groups of OVX-mRen(2).Lewis rats were either treated with the AT₁ antagonist olmesartan (1 mg/kg per day OS) for 4 weeks (weeks 12 to 16) to assess the influence of RAS blockade during the period of established hypertension or used as age-matched control animals. At the end of 16 weeks, the drug was completely removed from the drinking water and the rats were monitored for an additional 7 weeks. Finally, age-matched normotensive Lewis rats (Harlan Labs) were ovariectomized, and blood pressure was determined from week 5 to week 17. Systolic blood pressure (SBP) was measured in trained rats (mean of 5 determinations per data point) before and after treatment with a Narco Biosystems device. Animals were fed a powdered rat chow (Purina Mills) to provide a daily intake of 17 and 28 mEq of sodium and potassium, respectively, per 100 g of body weight. At the end of the study, animals were euthanized by decapitation without anesthesia, and tissues were rapidly removed for analysis. Rats were maintained on a 12-hour light/dark cycle (6 AM on, 6 PM off) at constant temperature and humidity in a facility approved by the Association for Assessment and Accreditation of Laboratory Animal Care. All animal experiments were performed in accordance with protocols of the Institutional Animal Care and Use Committee of Wake Forest University School of Medicine.

The concentration of Angiotensin (Ang) II was determined in the plasma, urine, and kidneys from control and treated rats, as described by Allred et al.¹⁴ Urine was collected over a 24-hour period into 4% acetic acid and BHT. Excretion of 8-isoprostane F₂ (Cayman Chemicals) and endothelin-1 (ALPCO Diagnostics) were determined according to instructions for each assay kit. Serum estradiol concentrations were determined by RIA with a kit from Adaltis Italia S.P.A. Serum ACE activity was determined with the synthetic substrate Hip-His-Leu in the presence and absence of the ACE inhibitor lisinopril (10 µmol/L).¹⁴ Plasma renin concentration (PRC) was determined by addition of exogenous angiotensinogen (nephrectomized rat plasma) incubated at either pH 6.5 (rat renin) or pH 8.5 (mouse renin).

Total RNA was isolated from the renal cortex and medulla of each rat with TRIzol (Invitrogen) and then amplified with or without AMV reverse transcriptase, as described by Gallagher et al.⁵ Primer pairs were eNOS forward 5'-CTGCTGCCCGAGATATCTTC-3' and reverse 5'-AAGTAAGRGAGAGCCTGGCGCA-3', yielding a 435-bp fragment; ACE forward 5'-TTGACGTGAGCAACTTCCAG-3' and reverse 5'-GGCTGCAGCTCCTGGTATAG-3', yielding a 421-bp fragment; and EF1 forward 5'-GGAATGGTGACAACATGCTG-3' and reverse 5'-CGTTGAAGCCTACATTGTCC-3', yielding a 347-bp fragment. Amplification conditions were 60-second denaturation at 94°C, annealing for 60 seconds at 60°C for ACE or 62°C for eNOS, and extension at 72°C for 30 cycles followed by a final extension at 72°C for 5 minutes. EF₁ primers were added after 10 cycles were completed. Products were separated on 6% polyacrylamide gels, and band intensities were quantified by phosphorimage analysis. The mRNA concentration was expressed as the ratio of eNOS or ACE to the control EF₁ to account for variations in the RT-PCR assay. We use EF₁ because Ang II is known to regulate other "control" genes such as GADPH.

Statistical Analysis
All measurements are expressed as mean±SEM. Comparisons between the sham, ovariectomized, and treated rats were evaluated by ANOVA and the Dunnett post hoc analysis (StatMate). All other data were analyzed by the Student unpaired t test, and figures were constructed with GraphPad Prism plotting and statistical software. A probability value of <0.05 was required for statistical significance.

	Results

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Compared with the sham mRen(2).Lewis rats, the OVX congenics had an elevated blood pressure as early as week 6 (109±3.0 mm Hg versus 129±4.2 mm Hg) (Figure 1). Although the sham SBP plateaued by week 9 (139±2.5 mm Hg versus 141±3.9 mm Hg at week 11), the OVX-mRen(2).Lewis continued to have a higher blood pressure at week 9 (171±4.0 mm Hg) through week 11 (195±3.7 mm Hg). The estrogen replacement group also had a greater increase in blood pressure than the sham rats up to week 7 (139±2.3 mm Hg versus 115±3.9 mm Hg for Sham, P<0.01) and was similar to the OVX rats (145±3.7 mm Hg, 7 weeks). However, by week 9, the blood pressure began to decline (135±2.9 mm Hg) and was significantly lower (125±2.9 mm Hg, P<0.05) than either the Sham or OVX-Ren(2).Lewis at 11 weeks. Although not shown, ovariectomy of the normotensive Lewis rats did not alter blood pressure (intact Lewis: 112±9.3 mm Hg, n=5 versus OVX-Lewis: 118±6.7 mm Hg, n=3; both groups at 12 weeks of age). Furthermore, the blood pressures in the OVX-mRen(2).Lewis rat were similar to that of the male mRen(2).Lewis at 11 weeks (205±9 mm Hg, n=5), suggesting that estrogen depletion at this age abolishes the gender difference in the mRen(2).Lewis rat. Finally, in the female mRen(2).Lewis rats, serum estradiol levels at 11 weeks averaged 88±17 pg/mL for sham, <5.0 pg/mL in the OVX group, and 194±79 pg/mL with estrogen replacement.

View larger version (26K): [in this window] [in a new window]   Figure 1. Effects of ovariectomy (OVX) and estrogen (E2) replacement on development of blood pressure in mRen(2).Lewis rat. SBP was determined from weeks 6 through 11. Data are mean±SEM; *P<0.05 vs sham; #P<0.05 vs OVX+E2 (n=6 to 7).

As shown in Figure 2A, estrogen depletion in the mRen(2).Lewis increased PRC approximately 2-fold compared with either the sham or estrogen-treated groups. Measurement of mouse PRC revealed a similar level to that of rat renin after ovariectomy and estrogen replacement (Figure 2B). Serum ACE activity was also significantly higher in the OVX-mRen(2).Lewis as compared with the other two groups, although the estrogen-treated animals tended to have the lowest ACE activity (Figure 2C), consistent with the lower blood pressure in this group (see Figure 1). Also consistent with an increased activity of both renin and ACE, the circulating levels of Ang II were elevated to a similar degree compared with intact and estrogen-treated groups (Figure 2D). We also determined the free plasma concentration of 8-isoprostane F₂ as an index of ROS but did not observe a difference between the OVX and estrogen-treated groups (26.8±4.6 fmol/mL versus 36.5±8.2 fmol/mL, respectively).

View larger version (29K): [in this window] [in a new window]   Figure 2. Effects of ovariectomy (OVX) and estrogen (E2) replacement on circulating RAS in mRen(2).Lewis rat. Samples were taken from rats killed at the end of week 11. A, Rat plasma renin concentration (PRC); B, mouse PRC; C, serum ACE activity; D, plasma Ang II concentration. Data are mean±SEM, **P<0.01 vs OVX+E2 or sham; n=6 to 7.

In terms of the renal RAS, urinary excretion and cortical tissue levels of Ang II were significantly increased in the OVX-mRen(2).Lewis rats (Figures 3A and 3B). The urinary excretion of both endothelin-1 (ET-1) and 8-isoprostane F₂ were also elevated in the OVX group in comparison to either the sham or estrogen-treated rats (Figures 3C and 3D). Consistent with the increase in serum ACE activity and renal Ang II, both cortical and medullary levels of ACE mRNA were significantly higher in the OVX group as compared with the estrogen group (Figure 3E). Finally, we assessed mRNA levels of eNOS in the OVX-mRen(2).Lewis and the estrogen replacement group. The mRNA levels for eNOS (expressed as a ratio to EF₁) were reduced 42% [0.273±0.016 U versus 0.466±0.073 U, P<0.01, n=6 to 7] in the renal medulla of the OVX-mRen(2).Lewis as compared with the estrogen-treated group. The overall cortical expression of eNOS was significantly lower than that in the medulla; however, estrogen depletion had no effect on cortical eNOS levels [OVX: 0.123±0.013 U versus OVX+E2: 0.103±0.011 U, P>0.05, n=6 to 7].

View larger version (24K): [in this window] [in a new window]   Figure 3. Effects of ovariectomy (OVX) and estrogen (E2) replacement on renal angiotensin, endothelin-1, and isoprostane systems in mRen(2).Lewis rat. Tissue and urine samples were taken at the end of week 11. A, Renal cortex Ang II concentration; B, daily excretion of Angiotensin II; C, daily excretion of endothelin-1; D, daily excretion of isoprostane; E, mRNA levels of ACE in renal cortex and medulla. Data are mean±SEM, **P<0.01 or *P<0.05 vs OVX+E2 or sham; n=6 to 7.

As shown in Figure 4, oral administration of olmesartan (1 mg/kg per day) for 2 weeks to 12-week OVX-mRen(2).Lewis rats substantially reduced blood pressure and, by 4 weeks, blood pressure was not different than the untreated normotensive female Lewis rats of similar age (113±5.4 mm Hg, n=6 versus 118±7 mm Hg for Lewis, n=5). In addition, we determined the blood pressure in this group of rats after the cessation of olmesartan treatment (week 16) for 7 weeks. By the end of week 23, the systolic blood pressures in the olmesartan-treated OVX-mRen(2).Lewis were still substantially reduced as compared with either that before treatment at 12 weeks (124±4.1 mm Hg versus 201±11 mm Hg, P<0.01) or a separate group of age-matched untreated OVX-mRen(2).Lewis at 16 weeks (190±9 mm Hg, n=5) and 23 weeks (208±12 mm Hg) but not different from that of the 16-week OVX-mRen(2).Lewis group receiving olmesartan (Figure 4).

View larger version (18K): [in this window] [in a new window]   Figure 4. Effect of AT1 antagonist olmesartan on SBP in ovariectomized (OVX) mRen(2).Lewis rat. Olmesartan (OLM, 1 mg/kg per day) was administered for 4 weeks to OVX-mRen(2).Lewis rats (12 weeks) with established hypertension. At week 16, drug treatment ceased and blood pressure was assessed for an additional 7 weeks (23 weeks of age). Data are mean±SEM; **P<0.01 vs 12-week OVX rats, n=6.

	Discussion

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In the present study, we characterized the effects of estrogen depletion on the development of blood pressure and expression of the circulating and renal components of the RAS in the female mRen(2).Lewis rat—a monogenetic strain that overexpresses the mouse renin 2 gene. Similar to other hypertensive models and the original (mRen2)-27 transgenic strain, the mRen(2).Lewis rats exhibit a significant gender difference in the expression of blood pressure. Indeed, the systolic blood pressure in the heterozygous female mRen(2).Lewis rat is 40 to 50 mm Hg lower than male littermates. However, in contrast to estrogen depletion in young SHR, our findings reveal a significant effect of estrogen depletion on the development and maintenance of blood pressure in the mRen(2).Lewis rats.⁸ Indeed, estrogen depletion essentially abolished the gender difference in blood pressure that normally exists between the male and female mRen(2).Lewis rats. Low-dose estrogen (estradiol) replacement reversed the course of the development of hypertension and lowered blood pressure below that of the intact mRen(2).Lewis rat. Furthermore, chronic treatment with the AT₁ receptor antagonist olmesartan normalized the blood pressure in the ovariectomized mRen(2).Lewis. These findings clearly support recent studies that also found a protective role for estrogen in the development of hypertension in the Dahl S model maintained on either a low¹⁵ or high salt¹⁶ diet and the SHR fed a phytoestrogen-free high salt diet.¹⁷

Previous studies in female (mRen2)-27 rats, the founder strain for the congenic mRen(2).Lewis rats, revealed differences in the blood pressure response after ovariectomy. Bachman et al¹⁸ reported that ovariectomy in 16-week heterozygous (mRen2)-27 reduced blood pressure by 20 mm Hg. The reduction in blood pressure was associated with a fall in both PRA and Ang II, as well as reduced expression of rat and mouse renin mRNA levels in the kidney.¹⁸ Although the effects of estrogen replacement were not determined in this study, the lower PRA after ovariectomy is consistent with a stimulatory effect of estrogen on renin. In contrast, Brosnihan et al¹⁹ found that ovariectomy had little effect on blood pressure in 12-week (mRen2)-27, but estrogen replacement reduced blood pressure as well as decreased ACE activity and mRNA levels of the enzyme in the lung, aorta, and kidney. In addition, the reduction in ACE was associated with a differential expression of plasma Ang peptides, reduced Ang II, and increased Ang-(1-7) that most likely reflects the ability of ACE to form Ang II and degrade Ang-(1-7).²⁰ Similar to the latter study, the present results revealed increased plasma Ang II and serum ACE activity as well as increased rat PRC after ovariectomy. Moreover, estrogen replacement reversed the changes in these parameters as well as attenuated the development of hypertension. Apart from the background of the (mRen2)-27 transgenics (Sprague-Dawley versus Lewis), the major difference in the present study was that ovariectomy was performed at an earlier age before the establishment of hypertension. Interestingly, ovariectomy in the SHR as early as 3 weeks does not alter the development of blood pressure or exacerbate the hypertension.⁸ Indeed, androgens are thought to mediate the expression of hypertension in this model.¹⁰ In this regard, Baltatu et al²¹ recently reported that the androgen antagonist flutamide reduced blood pressure as well as attenuated the development of cardiac and renal injury in female (mRen2)-27 transgenics. The influence of androgen blockade in the mRen(2).Lewis rat is currently not known. It is possible that estrogen may well have a modulatory influence on the actions of androgens in this model, although studies on the effects of the testosterone antagonist in intact or estrogen depleted mRen(2).Lewis are necessary to address this issue.

Additional evidence that estrogen may influence the RAS and the development of hypertension in the mRen(2).Lewis are the results that blood pressure was normalized after 4-week treatment with the AT₁ receptor antagonist olmesartan. Indeed, systolic blood pressures in the olmesartan-treated OVX-mRen(2).Lewis group were not different from that of either the intact or OVX-Lewis rat. Estrogen reduces the expression of the AT₁ receptor in the vasculature, adrenal gland, and kidney, as well as inhibits the AT₁-dependent actions of Ang II in vascular smooth muscle cells.^4,6 The effects of increased expression of Ang II and the AT₁ receptor after estrogen depletion may be further enhanced by the reduced capacity of eNOS in the kidney. Cowley and colleagues²² showed that reduced NO production in the renal medulla significantly influences blood pressure in the Dahl S rats. The influence of NOS may also explain the delayed effects of exogenous estrogen to attenuate the development of hypertension in the OVX-mRen(2).Lewis rats. Rahimian et al²³ observed that 3 weeks of estrogen treatment was required to restore NO activity after ovariectomy. This treatment period corresponds to the time point for the development of blood pressure to diverge in the present study. Studies are in progress to determine whether the treatment of ovariectomized mRen(2).Lewis with olmesartan restores the renal expression of eNOS. Regarding the influence of other mediators, we do not know whether alterations in the renal excretion of ET-1 and isoprostanes are directly influenced by estrogen or an activated Ang II–AT₁ axis. Ang II–dependent hypertension is associated with both increased ET-1 and activated ROS.^24–28 Furthermore, RAS blockade and estrogen attenuate expression of both systems.^28–32 However, the issue of enhanced renal ET-1 is complicated by the presence of both ET-A and ET-B receptors in the kidney that mediate opposing actions.³³ Thus, the balance of these two receptors may dictate whether increased ET-1 contributes to or counters the increase in blood pressure after estrogen depletion. In addition, the effects of estrogen depletion may encompass increased ROS in the kidney that may further diminish the bioavailability of NO.^32,34 Additional studies to assess whether the blockade of these two systems contributes to the increase in blood pressure or alters renal status in the mRen(2).Lewis rat are also in progress.

Finally, an unanticipated finding of the present study was the persistent effect of olmesartan treatment on blood pressure once the antagonist was withdrawn. In the ovariectomized mRen(2).Lewis, the systolic pressures were still markedly reduced (-36%) at 7 weeks after cessation of olmesartan administration and were not different than the blood pressures determined at the end of the 4-week treatment period (-42%). Previous studies, all performed in the SHR, clearly showed that RAS blockade with either an ACE inhibitor or ARB exhibits similar effects, provided that treatment is initiated at an early age (3 to 4 weeks) before the development of hypertension.^35–38 Furthermore, the long-lasting effects are generally not shared by other anti-hypertensive drugs despite a similar reduction in pressure during the treatment period.^39–41 In contrast, studies in the Milan and Lyon hypertensive rats revealed that RAS blockade had no persistent effect on blood pressure despite marked improvements in indexes of vascular and renal injury.^42–43 To our knowledge, the present study is the first to demonstrate a substantial effect on blood pressure after cessation of AT₁ receptor blockade in adult females with established hypertension and in a hypertensive model other than the SHR.³⁸ Future studies are necessary to ascertain the mechanism and the duration of the persistent effects of olmesartan in the mRen(2).Lewis rat. In this regard, it will also be of interest to determine whether cessation of estrogen treatment in the ovariectomized mRen(2).Lewis rat also exhibits a persistent effect on blood pressure similar to that of the AT₁ antagonist.

Perspectives
The role of estrogen to influence the cardiovascular system, particularly in a hypertensive setting, is complex. The mRen(2).Lewis strain represents a model of monogenetic Ang II–dependent hypertension in which estrogen depletion has a profound influence on the development of blood pressure, most likely through attenuating activation of the RAS and other downstream mediators. The early influence of estrogen in the current studies may be more relevant to the status of estrogen in the premenopausal versus postmenopausal period. Kaplan and colleagues⁴⁴ have demonstrated that reduced levels of estrogen arising from stress in the premenopausal period are associated with increased incidence of cardiovascular disease. Thus, the early loss or reduction of estrogen may play a more significant role in the setting and progression of cardiovascular disease than estrogen loss in the postmenopausal state.⁴⁵

	Acknowledgments

 
This work was supported by in part by grants from the National Heart, Lung, and Blood Institute, NIH (HL-51952), a grant-in-aid from the American Heart Association, and the Sankyo Pharmaceutical Corporation.

Received May 12, 2003; first decision May 30, 2003; accepted June 25, 2003.

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