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1 Departamento de Fisiología, Facultad de Medicina2 Departamento de Bioestadística, Facultad de Medicina3 Departamento de Farmacología, Facultad de Farmacia, Universidad de Granada, Spain4 Servicio de Nefrología, Unidad Experimental, Hospital Virgen de las Nieves, Granada, Spain
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Abstract |
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(Received 15 September 2003;
accepted after revision 3 December 2003)
Corresponding author F. Vargas: Departamento de Fisiología, Facultad de Medicina, E-18012, Granada, Spain. E-mail: fvargas{at}ugr.es
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Introduction |
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Previous studies in spontaneous and secondary types of hypertension provided abundant evidence that gonadectomy alters the course of hypertension (Masubuchi et al. 1982; Malyusz et al. 1985; Crofton et al. 1989; Chen & Meng, 1991; Reckelhoff et al. 1999). Sex differences in BP have been attributed to protection of the female by oestrogens (Sasaki et al. 2000), or the prohypertensive activities of testosterone (Reckelhoff et al. 1998b). Oestrogen can have rapid effects on vascular cells, activating nitric oxide synthase in a non-genomic manner (Chen et al. 1999). It can also have long-term effects, due at least in part to increases in the expression of genes for nitric oxide synthase (Weiner et al. 1994). Therefore, these studies seem to indicate that oestrogens protect against hypertension via NO.
NO synthesis is inhibited by arginine analogues such as NG.-nitro-L-arginine methyl ester (L-NAME) (Rees et al. 1990), and it is well known that the long-term oral administration of this inhibitor induces dose- and time-dependent arterial hypertension and renal injury, in which the renin–angiotensin system (RAS) plays an important role (Zatz & Baylis, 1998; Fortepiani et al. 1999; De Gracia et al. 2000).
In a preliminary experiment, we observed that there is sex-dependent dimorphism in the development of L-NAME-dependent hypertension in the rat (Sáinz et al. 2000). The aim of the present study was to further explore this phenomenon by analysing the influence of sex hormones focusing our investigation on blood pressure (BP), plasma renin activity (PRA), cardiac hypertrophy and proteinuria. For this purpose, we studied the effects of gonadectomy and of oestrogen and testosterone in gonadectomized male and female rats, respectively, on the sex-dependent dimorphism of this type of hypertension.
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Methods |
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Sixty male and female age-matched Wistar rats (13–14 weeks old) born and raised in the experimental animal service of the University of Granada were used in the present study. The experiments were performed according to European Union guidelines for the ethical care of animals. Male and female rats were randomly assigned to the different experimental groups (n= 10 in each group). The following studies were performed.
Experiment I: analysis of the influence of sex on the development of L-NAME-induced hypertension
The four experimental groups were: male and female controls and L-NAME-treated males and females.
Experiment II: analysis of the influence of gonadectomy on the dimorphism of L-NAME-induced hypertension
Orchidectomy and ovariectomy were performed under ether anaesthesia. Ovariectomized female and orchidectomized male rats were assigned to control or L-NAME groups. To determine whether sex steroids affect the dimorphic pattern of L-NAME-induced hypertension, male and female rats of each strain were surgically neutered to reduce levels of circulating sex hormones. Neutering reduced plasma testosterone and oestradiol concentrations below detectable levels.
Experiment III: analysis of the effects of the administration of testosterone and oestradiol
Administration of testosterone (1 mg kg–1 day–1 s.c.; George et al. 1991) to ovariectomized female and of 17ß-oestradiol (0.2 mg kg–1 week–1 s.c) to orchidectomized male rats (Chini et al. 1997) was investigated. These doses were selected because it has been reported that they achieve constant physiological levels of plasma hormones. The animals were assigned to control or L-NAME treatment groups. Serum testosterone levels were similar in intact males and ovariectomized females treated chronically with testosterone (male controls, 3.3 ± 0.35; androgenized females, 4.3 ± 0.52 ng ml–1). Serum oestradiol concentration was also similar in intact females (30.3 ± 6.7 pg ml–1) and oestrogenized males (27.8 ± 2.3 pg ml–1). Chronic treatment with gonadal steroids was begun 1 week before the start of the L-NAME protocol.
Experimental protocol
All animals had free access to standard rat chow and tap water or the saline solution. L-NAME was given in the drinking water at a concentration of 75 mg (100 ml)–1, resulting in a daily intake of approximately 65 mg kg–1 day–1 in male rats in all experiments. In female rats, the concentration of the NO inhibitor was adjusted according to the fluid intake to ensure that a similar dose was administered to both L-NAME groups.
Systolic blood pressure (SBP) was measured twice weekly by tail-cuff plethysmography in unanaesthetized rats. At least seven determinations were made every session and the mean of the lowest three values within 5 mmHg was used to obtain the SBP level. These treatments were maintained for 5 weeks and all rats of each group were then housed in metabolic cages with free access to food and their respective drinking fluids and urine was collected for analysis. Subsequently, all animals were anaesthetized with ethylic ether and the right femoral artery was cannulated to obtain direct BP measurements and blood samples. After a 24 h recovery period, BP was continuously measured for 60 min (TRA-021 transducer connected to a two-channel Letigraph 2000 recorder LETICA, Barcelona, Spain) in conscious rats. Values obtained during the last 30 min were averaged on a minute to minute basis to obtain the mean BP value. Blood samples were then taken. PRA, testosterone and oestradiol concentrations and standard biochemical variables were measured. Finally, the animals were killed and the weight of the left kidney and ventricle obtained.
Analytical techniques
PRA was measured following the method of Haber et al. (1969). The assay was performed with rat plasma obtained from blood collected in ice-chilled tubes containing sodium EDTA. Plasma was incubated at 37 °C and pH 7.4 with protease inhibitors (3.4 mM 8-hydroxyquinolone sulphate, 0.25 mM EDTA, 0.1 mM phenylmethylsulfonyl fluoride (PMSF), 1.6 mM dimercaprol and 5 mM sodium tetrathionate) for 2 h. The angiotensin I generated was measured using a radioimmunoassay kit purchased from CIS Bio International (Gif-Sur-Yvette Cedex, France). Testosterone and oestradiol were measured by electrochemiluminescence immunoassay (Roche Diagnostics, Mannheim, Germany). Plasma and urine electrolytes, and urea and creatinine concentrations were measured on the day in an autoanalyser (Beckman CX4, Breca, CA, USA). Proteinuria was measured using the method of Bradford (1976).
Statistical analysis
We compared the evolution of tail SBP over time using a nested design, with groups and days as fixed factors and rats as the random factor. When the overall difference was significant, Bonferroni's method with an appropriate error was used. The rest of the variables were compared at the end of the experiment with two-way analysis of variance and subsequent pairwise comparisons when group–sex interaction was present with the Bonferroni test.
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Results |
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In experiment I, both male and female rats became hypertensive in response to L-NAME administration, with a significant (P < 0.01) increase in the tail SBP of both groups as early as 6 days after onset of treatment (Fig. 1). However, hypertension developed to a higher level in the male rats. Thus, the tail SBP was higher in the male rats throughout the 5 weeks of the study. There were no differences in initial BP between any of the groups, nor were there any differences in BP over the 5 weeks of observation in the two control groups that drank tap water (Fig. 1). At the end of the 5-week treatment, the higher BP in male versus female L-NAME-treated rats was confirmed by direct measurement from the arterial catheter in conscious rats (Table 1).
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The time course of SBP in experiment III was similar to that observed in experiment II. Thus, initial tail SBP was again significantly decreased in female rats after 1 week of ovariectomy and final values were similar to those in male orchidectomized rats. Tail SBP was significantly increased in male L-NAME-treated rats in comparison with female L-NAME-treated rats at the three initial determinations. The rest of the time course evolution of SBP was similar in both male and female L-NAME groups, reaching a similar level of SBP at the end of the experimental period (Fig. 1). Final MAP values were again in agreement with the tail SBP measured at the last determination (Table 1).
Morphological variables
The values of morphological variables are summarized in Table 2. In Experiment I, final body weight (FBW) was greater in male than in female rats, as expected. The increase in body weight during the experimental period (
BW) was similar between the L-NAME-treated and control groups and this increase was markedly reduced in both female groups. Left ventricular weight (LVW) and left kidney weight (LKW) were reduced in both female groups relative to their respective BW. Relative (LVW/BW) left ventricular weight, used as an index of left ventricular hypertrophy, was significantly increased in female L-NAME-treated rats in comparison with female control and male L-NAME groups. The LVW/BW ratio correlated with SBP in female rats (r= 0.52, P < 0.05) but not in male rats. The administration of L-NAME did not significantly affect kidney weight (KW) in male or female rats and the kidney weight/body weight ratio (KW/BW) was similar in all four groups.
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BW in all experimental groups. The BW was half that of experiment I intact animals in both male groups and double this value in both female groups. LVW and LKW were reduced in male and female hypertensive and normotensive rats when compared with values from experiment I. The values of LVW/BW and LKW/BW ratios were reduced in all animals when compared with their respective groups of intact animals in experiment I. Relative left ventricular hypertrophy was observed in both male and female groups treated with L-NAME. The LVW/BW ratio correlated in both male and female groups with SBP (r= 0.50 and r= 0.51, P < 0.05; for male and female groups, respectively). The LKW/BW ratio was similar in all groups.
In experiment III, all experimental groups showed similar FBW. However, the BW of testosterone-treated female rats, both treated and not treated with L-NAME, was similar to that observed in untreated males, while the BW gain of oestradiol-treated male rats was similar to that of untreated female rats in experiment I. Relative left ventricular hypertrophy was only detected in female L-NAME-treated rats with respect to female control rats and correlated with SBP (r= 0.52, P < 0.05). In this experiment, the LVW/BW and KW/BW ratios of all groups were similar to those of the intact animals in experiment I and were therefore significantly increased with respect to the gonadectomized animals in experiment II.
Plasma renin activity
Among the intact animals of experiment I, PRA was significantly increased in the male L-NAME-treated rats compared to the male controls. In contrast, PRA was not significantly modified in female L-NAME-treated rats compared to their controls (Table 1). PRA values were not significantly modified by L-NAME treatment in the male or female gonadectomized rats of experiment II. In experiment III, oestrogenized male control and L-NAME-treated rats showed levels of PRA similar to those in female rats, while androgenized female rats (control and L-NAME-treated) showed PRA values similar to those of untreated male control rats. There were no significant differences between L-NAME-treated (male and female) rats and their respective controls, but PRA was significantly increased in female androgenized L-NAME-treated rats compared with male oestrogenized L-NAME-treated rats (Table 1).
Proteinuria
In experiment I, proteinuria was significantly increased in male L-NAME-treated rats when compared with male or female controls and female L-NAME-treated rats (Fig. 2). Orchidectomy markedly reduced proteinuria in male controls and L-NAME treated rats. In contrast, proteinuria was not significantly modified in either treated or non-treated female rats when compared with intact rats, and the difference between L-NAME-treated male and female rats observed in experiment I disappeared. However, a significant difference persisted between orchidectomized male L-NAME-treated and orchidectomized male control rats. The administration of oestrogen to orchidectomized male rats maintained proteinuria at a low level and suppressed the difference between L-NAME-treated and non-treated rats. The administration of testosterone produced a marked increase in proteinuria in both L-NAME-treated and non-treated female rats, with no significant differences between the two groups.
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Discussion |
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The present paper shows that male rats develop higher blood pressures compared with females after L-NAME administration and that the level of hypertension produced is greater in the male rats, at least within the first 5 weeks. This study demonstrates that the sex-dependent dimorphic pattern of blood pressure in rats is present in response to NO blockade. Although numerous studies have suggested that oestrogen attenuates hypertension in females due to an enhancement of NO activity (Weiner et al. 1994; Chen et al. 1999; Sasaki et al. 2000), these present data agree with a preliminary report from our laboratory (Sáinz et al. 2000) and with data from Verhagen et al. (2000) using L-NNA, another NO synthase inhibitor. Nevertheless, these findings conflict with a report (Reckelhoff et al. 1998a) that showed no difference in BP between males and females treated with L-NAME for 2 weeks at a low dose (3–4 mg kg–1 day–1). However, the latter study only measured BP at one time point and under anaesthesia. Our data are in line with epidemiological, clinical and experimental reports that male subjects are more likely to develop hypertension than are females (Chen, 1996; Reckelhoff, 2001).
Gonadal hormones play a role in determining the different BP levels produced in males and females. According to the present results, gonadectomy attenuates the sex-dependent dimorphic pattern of BP in L-NAME-induced hypertension. Thus, orchidectomy of L-NAME-treated rats is associated with a reduction in BP to the levels found in females. Ovariectomy did not affect the level of BP reached in females, suggesting that the attenuated hypertension in female is not due to a protective effect of oestrogen. Our data are consistent with previous findings in SHRs (Chen & Meng, 1991; Reckelhoff et al. 1999) and secondary types of hypertension (Masubuchi et al. 1982; Malyusz et al. 1985; Crofton et al. 1989) showing that orchidectomy significantly attenuated the BP elevation in the male SHR, whereas ovariectomy had no effect on the development of hypertension in the female.
The oestrogenization of males and androgenization of females did not further modify the suppression of the dimorphic pattern of BP in L-NAME-dependent hypertension induced by gonadectomy. These results suggest that for NO blockade to develop its full hypertensive effect, the simultaneous presence of two factors is required: testosterone and the male phenotype. The failure of testosterone to affect the development of L-NAME-induced hypertension in ovariectomized female rats is consistent with previous data in the DOCA-salt model (Crofton & Share, 1997).
Testosterone induces hypertension in rats (Colby et al. 1970) and contributes to the exacerbation of hypertension in SHRs by reducing pressure-natriuresis and increasing PRA (Reckelhoff et al. 1998b). Thus, the testosterone of our male rats might have determined an additional shift to the right in the blunted pressure-natriuresis (Fortepiani et al. 1999) relationship of L-NAME-induced hypertension. However, testosterone did not increase BP in our ovariectomized rats, suggesting that sex-dependent genetic influences might determine a reduced pressor sensitivity to testosterone in female Wistar rats.
Plasma renin activity
Animal and human studies have shown that PRA or circulating renin levels are higher in male than in female mice (Nielsen et al. 1989), rats (Chen et al. 1992) and humans (Sealey et al. 1980). Other reports have demonstrated that androgens stimulate the RAS and that orchidectomy delays the development of spontaneous hypertension in males, in association with a significant decrease in plasma renin activity to the range found in females. Moreover, the testosterone treatment of ovariectomized female rats caused significant increases in BP and PRA (Katz & Roper, 1977; Ellison et al. 1989). All these data indicate that androgens promote the exacerbation of hypertension in male humans and animals through a mechanism involving the RAS.
Because PRA is greater in intact male L-NAME-induced hypertensive rats than in female rats, and neutering produced similar levels of PRA in all groups, we consider that renin may be involved in the male/female differences of this type of hypertension. There is considerable evidence suggesting that the RAS plays a major role in L-NAME-induced hypertension, and experiments have shown that blockade of the RAS prevents the development of hypertension in this model (Zatz & Baylis, 1998; Fortepiani et al. 1999; De Gracia et al. 2000).
Cardiac hypertrophy
In states of pressure-overload hypertrophy, such as hypertension or aortic stenosis, left ventricular hypertrophy is found more frequently and in more pronounced form in women than in men (Garavaglia et al. 1989). Animal studies have shown a similar difference between the sexes in ventricular remodelling in response to increased cardiac load, as also observed in humans (Devereux et al. 1987). In the present study, the absence of both sex hormones produced a reduction in renal and cardiac mass in both male and female rats, as shown by the reductions in the LVW/BW and LKW/BW ratios in all the experimental groups of experiment II. Both ratios were increased by the administration of oestradiol to males and of testosterone to females. These results suggest that both sex hormones have a trophic effect on the heart and the kidney. In contrast, Verhagen et al. (2000) showed that neutering had no significant effect on LVW/BW ratio in male normotensive WKY or hypertensive SHR. However, it must be borne in mind that SHR are genetically hypertensive, and different strains may have distinct sensitivity to the factors involved in the control of ventricular mass.
The intact female L-NAME-treated rats of experiment I showed a greater degree of cardiac hypertrophy than the males, despite having a lower BP. This dimorphic pattern disappeared with the gonadectomy of both males and females and with the androgenization of females or oestrogenization of males. These data indicate that female L-NAME-treated rats have a greater sensitivity to develop cardiac hypertrophy in response to an increased BP when oestrogen is present.
Proteinuria
Testosterone and oestrogen receptors have both been detected in the kidney (Davidoff et al. 1980), and sex hormones can directly influence many processes implicated in the pathogenesis of renal disease. Our male L-NAME-treated hypertensive rats showed an increased proteinuria that was not present in female rats. Experiments II and III analysed the effects of the gonadectomy and oestrogenization of males and the androgenization of females. The dimorphic pattern of proteinuria disappeared with the gonadectomy of the male and female rats and clearly demonstrated that testosterone induces the animals, males and females, to develop proteinuria, regardless of the level of BP. However, this hormone does not seem to play an essential role in the sensitization to develop proteinuria after L-NAME administration. Thus, ochidectomized male L-NAME-treated rats showed an increased proteinuria compared to controls but androgenized female L-NAME-treated rats did not show an increased proteinuria compared to controls. Therefore these results again suggest, as for its hypertensive effect, that testosterone and the male phenotype are required for L-NAME-induced hypertension to develop its full proteinuric effect. Oestrogen administration to orchidectomized male rats suppressed the differences between L-NAME-treated and control rats found in experiments I and II, suggesting that oestrogens provide some protection against chronic NO synthase inhibition-induced proteinuria.
In summary, the present results indicate that males are more sensitive to the pressor and proteinuric effects of chronic nitric oxide inhibition, whereas females are more sensitive to developing cardiac hypertrophy. Evidence is also provided that the renin–angiotensin system may play a role in the dimorphic patterns of BP and proteinuria in this type of hypertension.
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References |
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|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Bradford MM (1976). A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye-binding. Anal Biochem 72, 248–254.
Chen YF (1996). Sexual dimorphism of hypertension. Curr Opin Nephrol Hypertens 6, 181–185.
Chen YF & Meng QC (1991). Sexual dimorphism of blood pressure in spontaneously hypertensive rats is androgen dependent. Life Sci 48, 85–96.[CrossRef][Medline]
Chen YF, Naftilan AJ & Oparil S (1992). Androgen-dependent angiotensinogen and renin messenger RNA expression in hypertensive rats. Hypertension 19, 456–463.
Chen Z, Yuhanna IS, Galcheva-Gargova ZI, Karas RH, Mendelsohn ME & Shaul PW (1999). Estrogen receptor 
mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen. J Clin Invest 103, 401–406.[Medline]
Chini EN, de Toledo FG, Thompson MA & Dousa TP (1997). Effect of estrogen upon cyclic ADP ribose metabolism: ß-estradiol stimulates ADP ribosyl cyclase in rat uterus. Proc Natl Acad Sci U S A 94, 5872–5876.
Colby HD, Skelton FR & Brownie AC (1970). Testosterone-induced hypertension in the rat. Endocrinology 86, 1093–1101.[Medline]
Crofton JT & Share L (1997). Gonadal hormones modulate deoxycorticosterone-salt hypertension in male and female rats. Hypertension 29, 494–499.
Crofton JT, Share L & Brooks DP (1989). Gonadectomy abolishes the sexual dimorphism in DOC-salt hypertension in the rat. Clin Exp Hypertens A11, 1249–1261.
Davidoff M, Caffier H & Schiebler TH (1980). Steroid hormone binding receptors in the rat kidney. Histochemistry 69, 39–48.[CrossRef][Medline]
De Gracia MC, Osuna A, O'Valle F, Del Moral RG, Wangensteen R, García del Río C & Vargas F (2000). Deoxycorticosterone suppresses the effects of losartan in nitric oxide-deficient hypertensive rats. J Am Soc Nephrol 11, 1995–2000.
Devereux RB, Pickering TG, Alderman MH, Chien S, Borer JS & Laragh JH (1987). Left ventricular hypertrophy in hypertension. Prevalence and relationship to pathophysiologic variables. Hypertension 9 (Suppl. II), II-53–II-60.
Ellison KE, Ingelfinger JR, Pivor M & Dzau VJ (1989). Androgen regulation of rat renal angiotensinogen messenger RNA expression. J Clin Invest 83, 1941–1945.
Fortepiani LA, Rodrigo L, Ortiz MC, Cachofeiro V, Atucha NM, Ruilope LM, Lahera V & García-Estañ J (1999). Pressure natriuresis in nitric oxide-deficient hypertensive rats: effect of antihypertensive treatments. J Am Soc Nephrol 10, 21–27.
Garavaglia GE, Messerli FH, Schmeider RE, Nunez BD & Oren S (1989). Sex differences in cardiac adaptation to essential hypertension. Eur Heart J 10, 1110–1114.
George FW, Russell DW & Wilson JD (1991). Feed-forward control of prostate growth: dihydrotestosterone induces expression of its own biosynthetic enzyme, steroid 5-reductase. Proc Natl Acad Sci U S A 88, 8044–8047.
Haber ET, Koerner LB, Page B, Kilman B & Purnode A (1969). Application of radioimmunoassay for angiotensin I to the physiologic measurement of plasma renin activity in normal human subject. J Clin Endocrinol Metab 29, 1349–1355.[Medline]
Katz FH & Roper EF (1977). Testosterone effect on renin system in rats. Proc Soc Exp Biol Medical 155, 330–333.[Medline]
Malyusz M, Ehrens HJ & Wrigge P (1985). Effects of castration on the experimental renal hypertension of the rat. Nephron 40, 96–99.[Medline]
Masubuchi Y, Kumai T, Uematsu A, Komoriyama K & Hirai M (1982). Gonadectomy-induced reduction in blood pressure in adult spontaneously hypertensive rats. Acta Endocrinol (Copenh) 101, 154–160.
Nielsen AH, Johannessen A & Poulsen K (1989). Inactive plasma renin exhibits sex difference in mice. Clin Sci 76, 439–446.[Medline]
Ouchi Y, Share L, Crofton JT, Iitake K & Brooks DP (1987). Sex differences in the development of deoxycorticosterone-salt hypertension in the rat. Hypertension 9, 172–177.
Reckelhoff JF (2001). Gender differences in the regulation of blood pressure. Hypertension 37, 1199–1208.
Reckelhoff JF, Hennington BS, Moore AG, Blanchard EJ & Cameron J (1998a). Gender differences in the renal nitric oxide (NO) system. Dissociation between expression of endothelial NO synthase and renal hemodynamic response to NO synthase inhibition. Am J Hypertens 11, 97–104.[CrossRef][Medline]
Reckelhoff JF, Zhang H & Granger JP (1998b). Testosterone exacerbates hypertension and reduces pressure-natriuresis in male spontaneously hypertensive rats. Hypertension 31, 435–439.
Reckelhoff JF, Zhang H, Srivastava K & Granger JP (1999). Gender differences in hypertension in spontaneously hypertensive rats: role of androgens and androgen receptor. Hypertension 34, 920–923.
Rees DD, Palmer RM, Schulz R, Hodson HF & Moncada S (1990). Characterization of three inhibitors of endothelial nitric oxide synthase in vitro and in vivo. Br J Pharmacol 101, 746–752.[Medline]
Rowland NE & Fregly MJ (1992). Role of gonadal hormones in hypertension in the Dahl salt-sensitive rat. Clin Exp Hypertens A14, 367–375.
Sáinz J, Osuna A, Wangensteen R, Duarte J & Vargas F (2000). Influence of gender on the development of nitric oxide inhibition-induced hypertension. Hypertension 36, 660.
Sasaki T, Ohno Y, Otsuka K, Suzawa T, Suzuki H & Saruta T (2000). Oestrogen attenuates the increases in blood pressure and platelet aggregation in ovariectomized and salt-loaded Dahl salt-sensitive rats. J Hypertens 18, 911–917.[CrossRef][Medline]
Sealey JE, Atlas SA & Larga JH (1980). Prorenin and other large molecular weight forms of renin. Endocr Rev 1, 365–391.[CrossRef][Medline]
Selye H & Pentz EI (1943). Pathogenetical correlations between periarteritis nodosa, renal hypertension and rheumatic lesions. Can Med Assoc J 49, 264–272.
Skelton FR (1956). Adrenal regeneration hypertension and factors influencing its development. Arch Intern Med 98, 449–462.
Sturtevant FM (1958). The biology of metacorticoid hypertension. Ann Int Med 49, 1281–1293.
Verhagen AM, Attia DM, Koomans HA & Joles JA (2000). Male gender increases sensitivity to proteinuria induced by mild NOS inhibition in rats: role of sex hormones. Am J Physiol Renal Physiol 279, F664–670.
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 U S A 91, 5212–5216.
Zatz R & Baylis C (1998). Chronic nitric oxide inhibition model six years on. Hypertension 32, 958–964.
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