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(Hypertension. 1997;29:494.)
© 1997 American Heart Association, Inc.

State-of-the-Art-Lecture

Gonadal Hormones Modulate Deoxycorticosterone-Salt Hypertension in Male and Female Rats

Joan T. Crofton; Leonard Share

From the Department of Physiology and Biophysics, University of Tennessee, Memphis.

Correspondence to Joan T. Crofton, Department of Physiology and Biophysics, University of Tennessee, Memphis, 894 Union Ave, Memphis, TN 38163 E-mail jcrofton{at}physiol.utmem.edu

	Abstract

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We have shown previously that, in rats with deoxycorticosterone (DOC)-salt hypertension, arterial blood pressure rises more rapidly and reaches a higher level in male than in female rats and that the course of the hypertension was ameliorated by gonadectomy in male rats and exacerbated by gonadectomy in female rats. The present investigation was undertaken to examine the role of the gonadal steroid hormones in modulating the course of DOC-salt hypertension in the rat. Our previous findings with respect to the effects of gender and gonadectomy on DOC-salt hypertension were confirmed in this study. Chronic treatment with gonadal steroids was begun 1 week before the start of the DOC-salt protocol. 17ß-Estradiol attenuated the course of the hypertension in intact male rats and in gonadectomized females. Testosterone exacerbated the development of the hypertension in gonadectomized male rats but was without effect in intact females. Progesterone alone had no effect on the hypertension in ovariectomized rats but when given to ovariectomized rats in combination with estradiol transiently prevented the ameliorating effect of the estradiol. These effects of the gonadal steroid hormones could not be attributed to effects of saline intake. Thus, these findings demonstrate that the gonadal steroid hormones play an important role in modulating the pathogenesis of DOC-salt hypertension in the rat. It is suggested that the effects of the gonadal hormones on the course of the hypertension may be due to modulation of the cardiovascular and renal actions of vasopressin, since vasopressin is required for this model of hypertension.

Key Words: gender differences • sex steroids • DOC-salt hypertension

	Introduction

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The incidence of hypertension is higher in men than in premenopausal women.¹ Similarly, we have shown that the development of deoxycorticosterone (DOC)-salt hypertension is sexually dimorphic. Thus, the rate of increase in arterial blood pressure and the level to which it rises are greater in male than in female rats.^2–4 It is likely that these differences are due to the actions of the gonadal steroid hormones, since gonadectomy attenuated the hypertension in male rats and exacerbated it in females.⁴ The role of the individual gonadal steroid hormones in the hypertensive processes, however, has not been characterized. The experiments presented here were undertaken to deal with this issue. We have determined in male and female rats the effect of gonadectomy, with and without gonadal steroid hormone treatment, on the development of DOC-salt hypertension. We have also determined the effects of treatment of intact male rats with estradiol and intact female rats with testosterone.

	Methods

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Male and female Sprague-Dawley rats were gonadectomized or sham gonadectomized by the supplier (Harlan Sprague Dawley, Indianapolis, Ind) when they were 3 weeks old. They were shipped to us at age 4 to 5 weeks and were housed in animal quarters with controlled lighting (10 hours on, 14 hours off) and temperature (23°C to 24°C). The rats were given food (Purina Laboratory Chow) and tap water ad libitum. When the rats were 7 to 8 weeks old, they were unilaterally nephrectomized under ether anesthesia. At that time they were given a subcutaneous implant of gonadal steroid-containing slow-release pellets (Innovative Research of America). Gonadectomized males were given testosterone (10 mg) or a cholesterol placebo (10 mg). Gonadectomized females were given 17ß-estradiol (0.5 mg), progesterone (10 mg), 17ß-estradiol (0.5 mg) plus progesterone (10 mg), or a cholesterol placebo (10 mg). Intact males were given 17ß-estradiol (0.5 mg) or a cholesterol placebo (10 mg), and intact females were given testosterone (10 mg) or a cholesterol placebo (10 mg). These doses of estradiol and progesterone in ovariectomized rats would provide plasma concentrations of estradiol that were approximately 4 times those seen in proestrus and concentrations of progesterone similar to those in proestrus⁵; the dose of testosterone in gonadectomized males would result in plasma testosterone levels similar to those in intact males (communication from Innovative Research of America). One week later, the rats were divided into two groups. One group was given weekly subcutaneous injections of DOC (Percorten Pivalate, Ciba, 30 mg/kg), and 1% saline replaced the drinking water. The rats in the second group continued to drink tap water and were given weekly subcutaneous injections of 0.9% NaCl (1.2 mL/kg) as the vehicle for the DOC.

One week after unilateral nephrectomy and at weekly intervals thereafter, systolic blood pressure (SBP) was measured by tail plethysmography, using a Physiograph Six-B (Narco Biosystems). During this procedure, the rats were lightly anesthetized with ether and rested on a slightly warmed heating pad. After the measurement of SBP at week 1, the steroid pellets were removed and replaced with fresh pellets. Fluid intake was measured for the 24-hour period that preceded each weekly measurement of SBP. Body weight was measured just before each measurement of SBP.

The data were analyzed by one-way and two-way analyses of variance. Where appropriate, significant differences were isolated by the Fisher LSD test. Data are presented as mean±SEM.

	Results

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In rats treated with DOC and given a salt supplement, SBP increased more rapidly and to a higher level (P<.01) in males than in females ( Fig 1). Thus, by the end of the first week of treatment, SBP had increased significantly (P<.01) in males but was unchanged in females. At the end of weeks 2 and 3, the increases in SBP in male rats was approximately twice those in females (P<.05 to .01).

View larger version (40K): [in this window] [in a new window]   FIG 1. Systolic blood pressure (SBP) in intact and gonadectomized (GX) male and female rats treated with DOC and drinking 1% saline. Control measurements (C) were made just before the start of treatment. Asterisks above the bars indicate within-group differences from C. Asterisks within the brackets and between the bars indicate differences between groups.

Castration of males treated with DOC and salt greatly attenuated the course of the hypertension (P<.05 to .01), which remained similar to that seen in intact DOC-salt-treated females (Fig 1). Treatment of gonadectomized males with testosterone restored the development of the hypertension to levels similar to those in intact males (Fig 2), but this effect did not become apparent until the third week of the experiment.

View larger version (45K): [in this window] [in a new window]   FIG 2. Effect on systolic blood pressure (SBP) of treatment of intact male DOC-salt-hypertensive rats with estradiol (E) and gonadectomized (GX) male hypertensive rats with testosterone (T). The data for untreated intact and gonadectomized hypertensive males are repeated from Fig 1 for comparison purposes. Asterisks above the bars indicate within-group differences from control (C). Asterisks within the brackets and between the bars indicate differences between groups.

In female rats, ovariectomy greatly enhanced the development of DOC-salt hypertension (Fig 1, P<.05 to .01). Indeed, by the end of 3 weeks of treatment with DOC and salt, the increase in SBP was similar to that in intact DOC-salt males. When DOC-salt-hypertensive ovariectomized rats were treated with estradiol, the increases in SBP were reduced to levels similar to those in intact DOC-salt-hypertensive females, whereas treatment with progesterone did not alter the course of the hypertension in ovariectomized rats (Fig 3). When ovariectomized DOC-salt rats were given both progesterone and estradiol, the progesterone prevented the ameliorating action of estradiol on the development of hypertension for the first 2 weeks, but in the third week of the hypertension, SBP was at a level similar to that in the intact DOC-salt-hypertensive females (Fig 3).

View larger version (53K): [in this window] [in a new window]   FIG 3. Effect on systolic blood pressure (SBP) of treatment of intact female DOC-salt-hypertensive rats with testosterone (T) and gonadectomized (GX) female hypertensive rats with estradiol (E), progesterone (P), and estradiol plus progesterone (EP). The data for untreated intact and gonadectomized hypertensive females are repeated from Fig 1 for comparison purposes. Asterisks above the bars indicate within-group differences from control (C). Asterisks within the brackets and between the bars indicate differences between groups.

Treatment of intact males, given DOC and salt, with estradiol reduced the development of the hypertension to levels similar to those seen in gonadectomized hypertensive males (Fig 2). On the other hand, when intact DOC-salt—hypertensive females were treated with testosterone, there was no significant effect on the course of the hypertension (Fig 3).

All male rats treated with the vehicle for DOC and given tap water to drink (Table 1) remained normotensive, and treatment with estradiol, castration, and treatment of castrated males with testosterone were without effect on SBP. Similarly, female rats given the DOC vehicle and drinking tap water (Table 1) remained normotensive, although there was a transient increase in SBP of 17 mm Hg (P<.01) in the first week of this treatment in the intact females given testosterone.

View this table: [in this window] [in a new window]   TABLE 1. Systolic Blood Pressure in Male and Female Rats Receiving the Vehicle for Deoxycorticosterone and Drinking Water

In intact male and female rats, fluid intake corrected for body weight (Table 2) was increased twofold to threefold by treatment with DOC and substitution of saline for drinking water (P<.01), and there were no differences between males and females. In rats treated with DOC and drinking saline, gonadectomy in males and females, treatment of gonadectomized males and intact males with testosterone, and treatment of ovariectomized rats with progesterone were without effect on saline intake, compared with intact hypertensive rats (Table 2). On the other hand, treatment of gonadectomized females and intact males with estradiol caused a further increase in saline intake (P<.01). During the first 2 weeks of observation, saline intake in hypertensive ovariectomized rats treated with both estradiol and progesterone was similar to that in ovariectomized hypertensive rats treated with estradiol alone, but in the third week of observation, saline intake in the ovariectomized rats treated with both estradiol and progesterone fell toward levels seen in ovariectomized rats that were untreated or given only progesterone (Table 2).

View this table: [in this window] [in a new window]   TABLE 2. Fluid Consumption in DOC-Salt Hypertensive Rats

Gonadectomy resulted in an increase in body weight in females (Fig 4). This effect was reversed by treatment with estradiol. Treatment of intact females with testosterone (Fig 4) resulted in small but significant increases in body weight (P<.01). In intact male rats, treatment with estradiol reduced body weight (Fig 5; P<.01).

View larger version (65K): [in this window] [in a new window]   FIG 4. Effect on body weight of treatment of intact female DOC-salt—hypertensive rats with testosterone (T) and gonadectomized (GX) female hypertensive rats with estradiol (E), progesterone (P), and estradiol plus progesterone (EP). Asterisks above the bars indicate within-group differences from control (C). Asterisks within the brackets and between the bars indicate differences between groups.

View larger version (51K): [in this window] [in a new window]   FIG 5. Effect on body weight of treatment of intact male DOC-salt—hypertensive rats with estradiol (E) and gonadectomized (GX) male hypertensive rats with testosterone (T). Asterisks above the bars indicate within-group differences from control (C). Asterisks within the brackets and between the bars indicate differences between groups.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
We had found previously that in rats treated with DOC and given saline to drink, arterial pressure rises faster and to a higher level in male than in female rats^2–4 and that gonadectomy attenuated the development of hypertension in male rats and exacerbated it in female rats.⁴ This suggested that the gonadal steroid hormones can affect the course of this model of hypertension. The findings in the present report indicate that this is indeed the case. Thus, in DOC-salt—hypertensive rats, the effects of gonadectomy were reversed by chronically treating males with testosterone and females with estradiol. Additionally, chronic treatment of intact male DOC-salt—hypertensive rats with estradiol retarded the development of the hypertension. Similarly, it has been observed that estrogen treatment attenuated the hypertension in cockerels made hypertensive by treatment with DOC and salt⁶ and in the spontaneously hypertensive rat,^7,8 whereas testosterone treatment increased the hypertension in the spontaneously hypertensive rat.⁹ In contrast to these findings, Bunag¹⁰ has reported that pretreatment of female rats with Enovid, a mixture of mestranol and norethynodrel, exacerbated DOC-salt hypertension. It is difficult to explain this report in the light of the findings reported here and by others.

The effects of gonadectomy and of testosterone and estradiol on the hypertension in the present experiments could not be due to differences in saline intake. Testosterone was without effect on saline intake. Estradiol increased saline intake, but this would be expected to increase the hypertension rather than decrease it, as observed in these experiments.

The mechanisms by which estrogen and testosterone affect the development of DOC-salt hypertension are, however, uncertain. There are receptors for androgen and estrogen in centers in the brain stem involved in blood pressure regulation.^11,12 Since there is considerable evidence that the sympathetic nervous system is an important pathogenetic factor in DOC-salt hypertension,^13–16 the gonadal steroid hormones could act at these centers to modulate the activity of the sympathetic nervous system. Consistent with this possibility is our observation³ that the sensitivity of the heart rate component of the baroreceptor reflex is reduced to a greater extent in male than in female DOC-salt—hypertensive rats. Receptors for the gonadal steroid hormones are also found in centers in the brain involved in vasopressin release.^17,18 However, although vasopressin is essential for the production of DOC-salt hypertension,^19,20 and although plasma levels of vasopressin are elevated in the hypertensive animals,^2–4 differences in plasma levels of vasopressin are not responsible for the gender-dependent difference in the development of the hypertension or the effects of gonadectomy on that development, since plasma vasopressin concentrations in DOC-salt—hypertensive rats were unaffected by either gender or gonadectomy.^2–4

DOC-salt hypertension is dependent on both the vasoconstrictor and antidiuretic actions of vasopressin, mediated by V₁ and V₂ receptors, respectively. Thus, DOC-salt hypertension is reduced by treatment with either V₁ or V₂ receptor antagonists.^16,19,21 Indeed, chronic combined treatment with V₁ and V₂ antagonists almost completely prevented the development of the hypertension.²¹ It is likely that estrogen attenuates this form of hypertension by reducing the pressor and antidiuretic actions of vasopressin. Both of these actions of vasopressin are greater in male than in female rats in the nonestrous phases of the estrous cycle,^3,22,24 and both of these gender differences are dependent on estrogen.^25,26

The mechanisms by which estrogen attenuates the pressor response to vasopressin are uncertain. One possibility is that estrogen, by means of its actions on centers in the brain involved in cardiovascular regulation, can decrease the gain of the baroreceptor reflex. Indeed, we have found (Y.-X. Wang, unpublished observations, 1996) that the sensitivity of the heart rate component of the baroreceptor reflex is greater in nonestrous female rats than in males. There is also considerable evidence that estrogen can act directly on the vasculature to modify the response to vasoactive agents, but the nature of this response is controversial. On the one hand, acute treatment with 17ß-estradiol decreased the contractile response of rat tail artery strips to vasopressin.²⁷ On the other hand, treatment of intact female rats with estradiol, compared with untreated ovariectomized rats, resulted in an increase in the vasoconstrictor action of vasopressin in the isolated perfused mesenteric vascular bed.²⁸

It is likely that estrogen attenuates the antidiuretic action of vasopressin by a direct action on the collecting duct. V₂ receptor density and the ability of vasopressin to stimulate cAMP synthesis are lower in renal collecting duct cells obtained from female than from male rats,²⁹ and in cultured renal medullary cells, estradiol decreased the ability of vasopressin to stimulate cAMP production.³⁰

To the extent that increased activity of the sympathetic nervous system contributes to DOC-salt hypertension, modulation by estrogen of the vasoconstrictor action of catecholamines could contribute to the sexual dimorphism in DOC-salt hypertension, but here too the reports are controversial. The vasoconstriction action of norepinephrine or phenylephrine was decreased by estradiol in rat aortic rings³⁰ and rat tail artery strips²⁷ and was increased by estradiol in preparations of the rat mesenteric vascular bed.^31,32 In intact male rats, acute treatment with estradiol reduced the pressor response to norepinephrine.²⁷

Another possibility to be considered is that estradiol, by increasing hepatic synthesis of plasma proteins that could bind DOC, could ameliorate DOC-salt hypertension by decreasing the bioavailability of DOC. However, since the dose of DOC used in these experiments was greatly in excess, it seems highly unlikely that any increase in plasma binding protein concentration could have been sufficiently large to have had an impact on the course of the hypertension.

Our observation that gonadectomy in male rats attenuated DOC-salt hypertension and that this effect was reversed by treatment with testosterone indicates that testosterone in male rats exacerbates this form of hypertension. This effect cannot be due to modulation of the actions of vasopressin by testosterone, since gonadectomy in males was without effect on either the pressor²⁵ or antidiuretic²⁴ responses to vasopressin. However, since increased activity of the sympathetic nervous system is a contributing factor to DOC-salt hypertension, testosterone may exacerbate the hypertension by increasing the pressor response to catecholamines.^33–35

It is perhaps not surprising that chronic treatment of intact male rats with estradiol attenuated the development of DOC-salt hypertension. Many of the experiments demonstrating a vascular action of estradiol were carried out in male rats,^27,32,36 indicating that there are vascular estrogen receptors in male rats. Similarly, estrogen binding was demonstrated in catecholamine-containing neurons of the brain stem in male as well as in female rats.^11,12 If estradiol increased the synthesis of plasma proteins that bind testosterone, the availability of testosterone could have been decreased, and this could have attenuated the hypertension.

The failure of testosterone to affect the development of DOC-salt hypertension in female rats suggests that they lack testosterone receptors in relevant sites in the vasculature or central nervous system.

Body weight was lower in intact males and gonadectomized females chronically treated with estradiol than in untreated intact males and gonadectomized females, respectively. Although the hypertension was attenuated in the estradiol-treated rats, we are unaware of data that support an influence of growth rate or body mass on the development or severity of hypertension in rats. Indeed, the body weight was higher in intact hypertensive females chronically treated with testosterone, but the development and severity of the hypertension was similar to that in untreated intact females.

Testosterone can be converted to estrogen in both male and female rats by the enzyme aromatase. It is unlikely that this was a significant factor in the responses to testosterone treatment in the hypertensive gonadectomized males. Body weight did not fall, whereas treatment with estradiol lowered body weight, and more importantly SBP was increased to levels seen in intact hypertensive males. On the other hand, conversion of testosterone to estrogen could have been a factor in the failure of testosterone to exacerbate the hypertension in intact females. Indeed, SBP was lower in the second week of the DOC-salt regimen in intact females treated with testosterone than in untreated females.

Progesterone alone had no effect on the development of DOC-salt hypertension in ovariectomized rats. However, when progesterone was given to ovariectomized rats in combination with estradiol, the ameliorating action of estradiol on the hypertension was prevented for the first 2 weeks of the experiment. The fall in SBP in the third week of the experiment to a level similar to that in intact hypertensive females was associated with a fall in saline intake; in the preceding 2 weeks, saline intake was elevated due to the influence of the estradiol. There does not, however, appear to be a direct relationship between saline intake and the magnitude of DOC-salt hypertension. Thus, for example, treatment of gonadectomized female and intact male DOC-salt—hypertensive rats with estradiol attenuated the hypertension and increased saline intake. One can only speculate that the ability of progesterone to prevent transiently the ameliorating action of estradiol on the hypertension may be due to an effect of progesterone on estrogen receptors or postreceptor events at sites involved in the development of DOC-salt hypertension.

In conclusion, the gender difference in the development of DOC-salt hypertension in the rat can be attributed to the gonadal steroid hormones. Estrogen attenuates the hypertension, whereas, in male rats, testosterone exacerbates the hypertension. It seems likely that the effects of estrogen result at least in part from modulation of the antidiuretic and pressor actions of vasopressin, both of which contribute importantly to DOC-salt hypertension. It is possible that the effects of testosterone on the hypertension, as well as, in part, the effects of estrogen, result from modulation of the sympathetic nervous system, at the level of the central nervous system or the vasculature.

	Acknowledgments

 
This research was supported by USPHS grants HL-19209 and HL-12990 from the National Heart, Lung, and Blood Institute.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Blood Pressure of Persons 6-74 Years of Age in the United States. National Center for Health Statistics, Advance Data, Vital and Health Statistics, No. 1; 1976 .

2. Ouchi Y, Share L, Crofton JT, Iitake K, Brooks DP. Sex differences in the development of deoxycorticosterone-salt hypertension in the rat. Hypertension. 1987; 9 : 172 –177.[Abstract/Free Full Text]

3. Ouchi Y, Share L, Crofton JT, Iitake K, Brooks DP. Sex differences in pressor responsiveness to vasopressin and baroreflex function in DOC-salt hypertensive rats. J Hypertens. 1988; 6 : 381 –387.[Medline] [Order article via Infotrieve]

4. Crofton JT, Share L, Brooks DP. Gonadectomy abolishes the sexual dimorphism in DOC-salt hypertension in the rat. Clin Exp Hypertens A. 1989; AI : 1249 –1261.

5. Barron WH, Schrieber J, Lindheimer MD. Effect of ovarian steroids on osmoregulation and vasopressin secretion in the rat. Am J Physiol. 1986; 250 : E352 –E361.[Medline] [Order article via Infotrieve]

6. Stamler J. Estrogen inhibition of corticoid hypertension in chickens. Circulation. 1954; 10 : 896 –901.[Medline] [Order article via Infotrieve]

7. Iams SG, Wexler BC. Retardation in the development of spontaneous hypertension in SH rats by gonadectomy. J Lab Clin Med. 1977; 90 : 997 –1003.[Medline] [Order article via Infotrieve]

8. Hoeg JM, Willis LR, Weinberger MH. Estrogen attenuation of the development of hypertension in spontaneous hypertension rats. Am J Physiol. 1977; 233 : H369 –H373.[Medline] [Order article via Infotrieve]

9. Cambotti LJ, Cole FE, Gerall AA, Frohlich ED, MacPhee AA. Neonatal gonadal hormones and blood pressure in the spontaneously hypertensive rat. Am J Physiol. 1984; 247 : E258 –E264.[Medline] [Order article via Infotrieve]

10. Bunag RD. Exaggeration of experimental hypertension in rats by contraceptive steroids (Enovid). Endocrinology. 1976; 98 : 1315 –1320.[Abstract/Free Full Text]

11. Heritage AS, Stumpf WE, Sar M, Grant LD. Brain stem catecholamine neurons are target sites for sex steroid hormones. Science. 1980; 207 : 1377 –1379.[Abstract/Free Full Text]

12. Heritage AS, Stumpf WE, Sar M, Grant LD.[³H]Dihydrotestosterone in catecholamine neurons of rat brain stem: combined localization by autoradiography and formaldehyde-induced fluorescence. J Comp Neurol. 1981; 200 : 289 –307.[Medline] [Order article via Infotrieve]

13. Bouvier M, de Champlain J. Increased apparent norepinephrine release rate in anesthetized DOCA-salt hypertensive rats. Clin Exp Hypertens A. 1985; A7 : 1629 –1645.

14. Bouvier M, de Champlain J. Increased sympathoadrenal tone and adrenal medulla reactivity in DOCA-salt hypertensive rats. J Hypertens. 1986; 4 : 157 –163.[Medline] [Order article via Infotrieve]

15. Matsuguchi H, Schmid PG. Acute interaction of vasopressin and neurogenic mechanisms in DOC-salt hypertension. Am J Physiol. 1982; 242 : H37 –H43.[Medline] [Order article via Infotrieve]

16. Mento PF, Wang HH, Sawyer WH. Contributions of vasopressin and other pressor systems to DOC-salt hypertension in rats. Proc Soc Exp Biol Med. 1984; 175 : 58 –63.[Medline] [Order article via Infotrieve]

17. Sar M, Stumpf WE. Distribution of androgen target cells in rat forebrain and pituitary after [3H]dihydrotestosterone administration. J Steroid Biochem Mol Biol. 1977; 8 : 1131 –1135.

18. Sar M, Stumpf WE. Combined autoradiography and immunohistochemistry for simultaneous localization of radioactively labeled steroid hormones and antibodies in the brain. J Histochem Cytochem. 1981; 29 : 161 –166.[Medline] [Order article via Infotrieve]

19. Crofton JT, Share L, Shade RE, Lee-Kwon WJ, Manning M, Sawyer WH. The importance of vasopressin in the development and maintenance of DOC-salt hypertension in the rat. Hypertension. 1979; 1 : 31 –38.[Abstract/Free Full Text]

20. Saito T, Yajima Y. Involvement of AVP in development and maintenance of hypertension in rats. In: Yoshida S, Share L, Yagi K, eds. Antidiuretic Hormone. Baltimore, Md: University Park Press; 1980; 215 –226.

21. Okada H, Suzuki H, Kanno Y, Saruta T. Effect of nonpeptide vasopressin receptor antagonists on developing, and established DOCA-salt hypertension in rats. Clin Exp Hypertens. 1995; 17 : 469 –483.[Medline] [Order article via Infotrieve]

22. Crofton JT, Ratliff DL, Brooks DP, Share L. The metabolic clearance rate of and pressor responses to vasopressin in male and female rats. Endocrinology. 1986; 118 : 1777 –1781.[Abstract/Free Full Text]

23. Crofton JT, Share L, Brooks DP. Pressor responsiveness to and secretion of vasopressin during the estrous cycle. Am J Physiol. 1988; 255 : R1041 –R1048.[Medline] [Order article via Infotrieve]

24. Wang Y-X, Crofton JT, Liu H, Brooks DP, Share L. Effects of gonadectomy on sexually dimorphic antidiuretic action of vasopressin in conscious rats. Am J Physiol. 1994; 267 : R536 –R541.[Medline] [Order article via Infotrieve]

25. Toba K, Crofton JT, Inoue M, Share L. Effects of vasopressin on arterial blood pressure and cardiac output in male and female rats. Am J Physiol. 1991; 261 : R1118 –R1125.[Medline] [Order article via Infotrieve]

26. Wang Y-X, Crofton JT, Liu H, Sato K, Brooks DP, Share L. Estradiol attenuates the antidiuretic action of vasopressin in ovariectomized rats. Am J Physiol. 1995; 268 : R951 –R957.[Medline] [Order article via Infotrieve]

27. Shan J, Resnick LM, Liu Q-Y, Wu X-C, Barbagallo M, Pang PKT. Vascular effects of 17ß-estradiol in male Sprague-Dawley rats. Am J Physiol. 1994; 266 : H967 –H973.[Medline] [Order article via Infotrieve]

28. St-Louis J, Parent A, Lariviere R, Schiffrin EL. Vasopressin responses and receptors in the mesenteric vasculature of estrogen-treated rats. Am J Physiol. 1986; 251 : H885 –H889.[Medline] [Order article via Infotrieve]

29. Wang Y-X, Edwards RM, Nambi P, Stack EJ, Pullen M, Share L, Crofton JT, Brooks DP. Sex difference in the antidiuretic activity of vasopressin in the rat. Am J Physiol. 1993; 265 : R1284 –R1290.[Medline] [Order article via Infotrieve]

30. Hatano T, Ogawa K, Kanda K, Seo H, Matsui N. Effect of ovarian steriods on cyclic adenosine 3':5'-monophosphate production stimulated by arginine vasopressin in rat renal monolayer cultured cells. Endocrinol Jap. 1988; 35 : 267 –274.[Medline] [Order article via Infotrieve]

31. Colucci WS, Gimbrone MA, McLaughlin MK, Halpern W, Alexander RW. Increased vascular catecholamine sensitivity and -adrenergic receptor affinity in female and estrogen-treated male rats. Circ Res. 1982; 50 : 805 –811.[Free Full Text]

32. Vargas R, Delaney M, Farhat MY, Wolfe R, Rego A, Ramwell PW. Effect of estradiol 17ß on pressor responses of rat mesenteric bed to norepinephrine, K+, and U-46619. J Cardiovasc Pharmacol. 1995; 25 : 200 –206.[Medline] [Order article via Infotrieve]

33. Baker PJ, Ramey ER, Ramwell PW. Androgen-mediated sex differences of cardiovascular responses in rats. Am J Physiol. 1978; 235 : H242 –H246.[Medline] [Order article via Infotrieve]

34. Bhargava KP, Dhawan KN, Saxena RC. Enhancement of noradrenaline pressor responses in testosterone-treated cats. Br J Pharmacol Chemother. 1967; 31 : 26 –31.[Medline] [Order article via Infotrieve]

35. Greenberg S, Heitz DC, Long JP. Testosterone-induced depression of adrenergic activity in the perfused canine hind limb. Soc Exp Biol Med. 1972; 142 : 883 –888.

36. Thomas G, Ito K, Zikic E, Bhatti T, Han C, Ramwell PW. Specific inhibition of the contraction of the rat aorta by estradiol 17ß. J Pharmacol Exp Ther. 1995; 273 : 1544 –1550.[Abstract/Free Full Text]

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				B. Xue, J. Pamidimukkala, and M. Hay Sex differences in the development of angiotensin II-induced hypertension in conscious mice Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2177 - H2184. [Abstract] [Full Text] [PDF]

				J. Pamidimukkala, B. Xue, L. G. Newton, D. B. Lubahn, and M. Hay Estrogen receptor-{alpha} mediates estrogen facilitation of baroreflex heart rate responses in conscious mice Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1063 - H1070. [Abstract] [Full Text] [PDF]

				C. Hinojosa-Laborde, T. Craig, W. Zheng, H. Ji, J. R. Haywood, and K. Sandberg Ovariectomy Augments Hypertension in Aging Female Dahl Salt-Sensitive Rats Hypertension, October 1, 2004; 44(4): 405 - 409. [Abstract] [Full Text] [PDF]

				C. Yallampalli, S.B. Kondapaka, P. Lanlua, S.J. Wimalawansa, and P.R.R. Gangula Female Sex Steroid Hormones and Pregnancy Regulate Receptors for Calcitonin Gene-Related Peptide in Rat Mesenteric Arteries, but Not in Aorta Biol Reprod, April 1, 2004; 70(4): 1055 - 1062. [Abstract] [Full Text] [PDF]

				J. Sainz, A. Osuna, R. Wangensteen, J. de Dios Luna, I. Rodriguez-Gomez, J. Duarte, J. M. Moreno, and F. Vargas Role of sex, gonadectomy and sex hormones in the development of nitric oxide inhibition-induced hypertension Exp Physiol, March 1, 2004; 89(2): 155 - 162. [Abstract] [Full Text] [PDF]

				J. Pamidimukkala and M. Hay 17{beta}-Estradiol inhibits angiotensin II activation of area postrema neurons Am J Physiol Heart Circ Physiol, October 1, 2003; 285(4): H1515 - H1520. [Abstract] [Full Text] [PDF]

				D. Javeshghani, R. M. Touyz, M. R. Sairam, A. Virdis, M. F. Neves, and E. L. Schiffrin Attenuated Responses to Angiotensin II in Follitropin Receptor Knockout Mice, a Model of Menopause-Associated Hypertension Hypertension, October 1, 2003; 42(4): 761 - 767. [Abstract] [Full Text] [PDF]

				O. Baltatu, C. Cayla, R. Iliescu, D. Andreev, and M. Bader Abolition of End-Organ Damage by Antiandrogen Treatment in Female Hypertensive Transgenic Rats Hypertension, March 1, 2003; 41(3): 830 - 833. [Abstract] [Full Text] [PDF]

				O. Baltatu, C. Cayla, R. Iliescu, D. Andreev, C. Jordan, and M. Bader Abolition of Hypertension-Induced End-Organ Damage by Androgen Receptor Blockade in Transgenic Rats Harboring the Mouse Ren-2 Gene J. Am. Soc. Nephrol., November 1, 2002; 13(11): 2681 - 2687. [Abstract] [Full Text] [PDF]

				N. Tamaya-Mori, K. Uemura, and A. Iguchi Gender Differences in the Dietary Lard-Induced Increase in Blood Pressure in Rats Hypertension, May 1, 2002; 39(5): 1015 - 1020. [Abstract] [Full Text] [PDF]

				R. K. Dubey, S. Oparil, B. Imthurn, and E. K. Jackson Sex hormones and hypertension Cardiovasc Res, February 15, 2002; 53(3): 688 - 708. [Abstract] [Full Text] [PDF]

				R. K. Dubey and E. K. Jackson Genome and Hormones: Gender Differences in Physiology: Invited Review: Cardiovascular protective effects of 17{beta}-estradiol metabolites J Appl Physiol, October 1, 2001; 91(4): 1868 - 1883. [Abstract] [Full Text] [PDF]

				F. L. David, M. H. C. Carvalho, A. L.N. Cobra, D. Nigro, Z. B. Fortes, N. A. Reboucas, and R. C.A. Tostes Ovarian Hormones Modulate Endothelin-1 Vascular Reactivity and mRNA Expression in DOCA-Salt Hypertensive Rats Hypertension, September 1, 2001; 38(3): 692 - 696. [Abstract] [Full Text] [PDF]

				J. F. Reckelhoff Gender Differences in the Regulation of Blood Pressure Hypertension, May 1, 2001; 37(5): 1199 - 1208. [Abstract] [Full Text] [PDF]

				R. K. Dubey and E. K. Jackson Estrogen-induced cardiorenal protection: potential cellular, biochemical, and molecular mechanisms Am J Physiol Renal Physiol, March 1, 2001; 280(3): F365 - F388. [Abstract] [Full Text] [PDF]

				Z. Li and M. Hay 17-beta -Estradiol Modulation of Area Postrema Potassium Currents J Neurophysiol, September 1, 2000; 84(3): 1385 - 1391. [Abstract] [Full Text] [PDF]

				X.-R. He, W. Wang, J. T. Crofton, and L. Share Effects of 17beta -estradiol on the baroreflex control of sympathetic activity in conscious ovariectomized rats Am J Physiol Regulatory Integrative Comp Physiol, August 1, 1999; 277(2): R493 - R498. [Abstract] [Full Text] [PDF]

				M. L Kuroski de Bold Estrogen, natriuretic peptides and the renin-angiotensin system Cardiovasc Res, March 1, 1999; 41(3): 524 - 531. [Abstract] [Full Text] [PDF]

				P. R. R. Gangula, H. Zhao, S. Supowit, S. Wimalawansa, D. DiPette, and C. Yallampalli Pregnancy and steroid hormones enhance the vasodilation responses to CGRP in rats Am J Physiol Heart Circ Physiol, January 1, 1999; 276(1): H284 - H288. [Abstract] [Full Text] [PDF]

				X.-R. He, W. Wang, J. T. Crofton, and L. Share Effects of 17beta -estradiol on sympathetic activity and pressor response to phenylephrine in ovariectomized rats Am J Physiol Regulatory Integrative Comp Physiol, October 1, 1998; 275(4): R1202 - R1208. [Abstract] [Full Text] [PDF]

				S. A Doggrell and L. Brown Rat models of hypertension, cardiac hypertrophy and failure Cardiovasc Res, July 1, 1998; 39(1): 89 - 105. [Full Text] [PDF]

				D. L. Lange, J. R. Haywood, and C. Hinojosa-Laborde Role of the Adrenal Medullae in Male and Female DOCA-Salt Hypertensive Rats Hypertension, January 1, 1998; 31(1): 403 - 408. [Abstract] [Full Text] [PDF]

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