Sex differences in primary hypertension

Abstract

Men have higher blood pressure than women through much of life regardless of race and ethnicity. This is a robust and highly conserved sex difference that it is also observed across species including dogs, rats, mice and chickens and it is found in induced, genetic and transgenic animal models of hypertension. Not only do the differences between the ovarian and testicular hormonal milieu contribute to this sexual dimorphism in blood pressure, the sex chromosomes also play a role in and of themselves. This review primarily focuses on epidemiological studies of blood pressure in men and women and experimental models of hypertension in both sexes. Gaps in current knowledge regarding what underlie male-female differences in blood pressure control are discussed. Elucidating the mechanisms underlying sex differences in hypertension may lead to the development of anti-hypertensives tailored to one's sex and ultimately to improved therapeutic strategies for treating this disease and preventing its devastating consequences.

Figure 1

Blood pressure in men and women across the life span. Shown is SBP (left panels) and DBP (right panels) in white (upper panels) and black (lower panels) men (black bar) and women (white bar) from the Community Hypertension Evaluation Clinic program, which measured blood pressure in over 1 million people in the United States between 1973 to 1975. *p < 0.01 vs male (t-test). This figure was drawn using data from reference [21].

Figure 2

Prevalence of hypertension in men and women as a function of age. Shown is the prevalence of hypertension in non-Hispanic white (top panel), Mexican American (middle panel) and non-Hispanic black (bottom panel) man (black bar) and women (white bar) from 18 to > 70 years of age from data collected from the NHANES III examination between 1988-1991. This figure was drawn using data from reference [27].

Figure 3

Mean arterial pressure in female and male dogs. Shown is the MAP in female (n = 80) and male (n = 67) street dogs of unknown age. *p < 0.05 vs female (t-test). This figure was drawn using data from reference [33].

Figure 4

Blood pressure in male and female chickens across the life span. Shown is the SBP (top panel) and DBP (bottom panel) in male (black bar) and female (white bar) chickens at different developmental stages from chick (5-7 weeks; n = 7/group), young adult (27-29 weeks; n = 8/group) to full adult (75-80 weeks; n = 6/group). *p < 0.05 vs female, same age group (t-test). This figure was drawn using data from reference [34].

Figure 5

Sex differences in arterial blood pressure in experimental models of hypertension. Shown is the difference in arterial blood pressure between males and females in animal models of hypertension including Ang II infusion in MF1 mice (MF1+Ang II) [39]^a, aldosterone infusion in Sprague Dawley (SD) rats (SD+Aldo) [41]^a and L-NAME-treated Wistar rats (W+L-NAME) [44]^c. Salt-sensitive models include SD rats maintained on a 1% NaCl diet and infused with aldosterone (SD+Aldo-NaCl) [54]^a or deoxycorticosterone acetate (SD+DOCA-NaCl) [55]^c and, DOCA-NaCl treated Sabra salt-sensitive rats (SS+DOCA-NaCl) [60]^c and DS rats maintained on 8% NaCl (DS+NaCl) [57]^a. Fetal programming models of hypertension include rats subjected to intrauterine growth restriction (SD+IUGR) [64]^a and intrauterine nutrition restriction (W+IUNR) [65]^c, respectively. Genetic models include the SHR [170]^a, SPSHR [171]^c and New Zealand genetically hypertensive (NZGH) rat [172]^c. Transgenic models include the mRen2.Lewis rat [49]^c. Single gene knock out models of hypertension include the low density lipoprotein receptor (C57-LDL-R^-/-) [73]^c, cyclooxgenase-2 (129-COX-2^-/-) [74]^c and endothelial nitric oxide synthase (129/C57-eNOS^-/-) [76]^b on the C57BL/6, 129Sv and 129Sv/C57BL/6J background strains, respectively. *p < 0.05, male vs female (see cited references for experimental and statistical details of individual studies). Note, studies measuring MAP by radiotelemetry^a were preferentially cited over studies using indwelling catheters^b or those reporting SBP determined by tail plethysmography^c.

Figure 6

Effect of dietary sodium on the sex differences in MAP in the DS rat. Shown is the difference in MAP between males and females in the DS rat as a function of dietary sodium; p < 0.05, male vs female (2-way ANOVA, sex, time). This figure was drawn using data from reference [57].

Figure 7

Relationship between the magnitude of hypertension in Ang II and aldosterone infused males and the sex difference in MAP. Shown is the MAP in males after angiotensin II (top panel) or aldosterone (bottom panel)-induced hypertension as a function of the sex difference in MAP (male-female, mm Hg). The data and correlation coefficient (r²) were drawn using data from references [39,41].

Figure 8

Sex differences in QTL locations of salt-sensitive hypertension in the SS rat. Shown is the difference in MAP between the SS rat and rats in which SS alleles were introgressed into female (white bar) and male (black bar) salt-resistant rats (SR alleles) at the SS1a, SS1b and SS17 QTL locations. #p < 0.05 vs SS, same sex. This figure was drawn using data from reference [99].

Figure 9

Sex differences in the chromosome location of salt-sensitive hypertension in the DS rat. Shown is the difference in MAP between the DS rat and the salt-resistant Brown Norway (BN) rat or DS consomics in which chromosomes (C) 1, 5, 7, 13, 16 and 18 were substituted with the respective BN chromosomes in male (black bar) and female (white bar) rats. Note that the maximum difference in salt-sensitivity is expected to be between the DS and BN rats. #p < 0.05 vs DS, same sex. This figure was drawn using data from reference [101].

Figure 10

Effect of ovariectomy on salt-sensitivity. Shown is the difference in MAP between HS (8% NaCl) and LS diets 0.15-0.60% NaCl in the intact (white bar) and ovariectomized (Ovx) (striped bar) SHR [112] and DS rat [57]. §p < 0.05 vs Intact, same rat strain, same dietary sodium; †p < 0.05, HS vs LS, same rat strain, same gonadal state (see cited references for experimental and statistical details of individual studies).

Figure 11

Effect of gonadectomy on blood pressure in experimental models of hypertension. Top panel, Shown is the difference in blood pressure between ovariectomized (Ovx) and intact (Intact) females in animal models of hypertension including Ang II infusion in C57 mice (C57+Ang II) [38]^a, Wistar rats infused with L-NAME (W+L-NAME) [44]^c, SD rats treated with deocycorticosterone acetate and HS (SD+DOCA+NaCl) [54]^a, DS rats [57]^a and the SHR [112]^a maintained on a LS and HS diet and the mRen2.Lewis rat [111]^c. Bottom panel, Shown is the difference in blood pressure between orchiectomy (Orch) and intact (Intact) males in animal models of hypertension including C57+Ang II [38]^a, W+L-NAME [44]^c, SD+DOCA+NaCl [54]^a, DS maintained on a LS and HS diet [173]^a, SHR [146]^b and the SPSHR [145]^c. §p < 0.05 vs Intact, same sex (see cited references for experimental and statistical details of individual studies). Note, studies measuring MAP by radiotelemetry^a were preferentially cited over studies using indwelling catheters^b or those reporting SBP determined by tail plethysmography^c.

Figure 12

Generation of the four core genotype. The Sry gene was spontaneously deleted from the Y chromosome (Y^-) and transferred to an autosome resulting in the XY^-Sry male mouse. Breeding XX females with XY^-Sry males produces the four core genotype: XY^- and XX females and XY^-Sry and XXSry males. We refer to XX and XY^- as XX and XY-Females and XXSry and XY^-Sry as XX- and XY-Males throughout the text.

Figure 13

MAP and HR after Ang II infusion in GDX four core genotype mice. Shown are the mean ± SEM for MAP (A) and HR (B) two weeks after Ang II infusion at 200 ng/kg/min in the GDX four core genotype; XX-Female (white, n = 9), XY-Female (horizontal stripes, n = 9), XX-Male (diagonal stripes, n = 8) and XY-Male (black, n = 8). Two-Way ANOVA showed that the sex chromosomes account for 16% of the total variance (*p < 0.03 vs. XX, regardless of gonadal sex) on MAP whereas there was no gonadal sex effect (p = 0.58) nor any interaction between the sex chromosomes and gonadal sex (p = 0.90). There was no SCE (p = 0.55) or interaction between the sex chromosomes and gonadal sex (p = 0.13) on HR. Gonadal sex accounted for 31% of the total variance (#p < 0.001 vs female, regardless of sex chromosome complement) in HR. This data is republished from reference [39].