Female sex hormones protect against salt-sensitive hypertension but not essential hypertension

Abstract

Brinson KN, Rafikova O, Sullivan JC. Female sex hormones protect against salt-sensitive hypertension but not essential hypertension. Am J Physiol Regul Integr Comp Physiol 307: R149 -R157, 2014. First published May 14, 2014 doi:10.1152/ajpregu.00061.2014.-Initial studies found that female Dahl salt-sensitive (DS) rats exhibit greater blood pressure (BP) salt sensitivity than female spontaneously hypertensive rats (SHR). On the basis of the central role played by NO in sodium excretion and BP control, we further tested the hypothesis that blunted increases in BP in female SHR will be accompanied by greater increases in renal inner medullary nitric oxide synthase (NOS) activity and expression in response to a high-salt (HS) diet compared with DS rats. Gonad-intact and ovariectomized (OVX) female SHR and DS rats were placed on normal salt (NS; 0.4% salt) or HS (4% salt) diet for 2 wk. OVX did not alter BP in SHR, and HS diet produced a modest increase in BP. OVX significantly increased BP in DS rats on NS; HS further increased BP in all DS rats, although OVX had a greater increase in BP. Renal inner medullary NOS activity, total NOS3 protein, and NOS3 phosphorylated on serine residue 1177 were not altered by salt or OVX in either strain. NOS1 protein expression, however, significantly increased with HS only in SHR, and this corresponded to an increase in urinary nitrate/nitrite excretion. SHR also exhibit greater NOS1 and NOS3 protein expression than DS rats. These data indicate that female sex hormones offer protection against HS-mediated elevations in BP in DS rats but not SHR. We propose that the relative resistance to HS-mediated increases in BP in SHR is related to greater NOS expression and the ability to increase NOS1 protein expression compared with DS rats. nitric oxide; Dahl-salt sensitive rats; ovariectomy; spontaneously hypertensive rats SALT SENSITIVITY OF BLOOD pressure (BP) is associated with an increased risk for the development of hypertension and cardiovascular disease. Among women, the prevalence of salt sensitivity increases following both surgical and natural menopause (14, 38), suggesting that the loss of ovarian hormones renders women prone to salt sensitivity and increases their risk of developing hypertension (38). This is further supported by studies in experimental animals; surgical ovariectomy (OVX) increases the BP response to salt in many rat strains, including Dahl salt-sensitive (DS) and Dahl salt-resistant rats (59), mRen(2).Lewis rats (7), Sprague-Dawley rats treated with aldosterone (57), and spontaneously hypertensive rats (SHR) (10). These data suggest that female sex hormones are critical in influencing sodium handling and BP regulation; however, the mechanisms responsible continue to be investigated.Salt-sensitive hypertension has been linked to the reninangiotensin system, as well as a decrease in NO production and bioavailability (8,19,53). There is ample evidence in the literature supporting a role for increased ANG II and AT 1 receptor activation in female experimental an...

Blood Pressure, Sex, and Female Sex Hormones Influence Renal Inner Medullary Nitric Oxide Synthase Activity and Expression in Spontaneously Hypertensive Rats

“…Indeed, female SHRs have much greater NOS expression than Dahl salt‐sensitive rats; as a result, it is not surprising that the effect of OVX is more pronounced in SHRs. 50 Regardless, our results indicate that timing may be a critical determinant of post‐OVX outcomes on the renal NOS system. The decrease in NOS activity with OVX was likely independent of BP given that we and others have reported that OVX does not alter BP in female SHRs.…”

“…In contrast, OVX of Sprague‐Dawley rats at 4 weeks, 8 Dahl salt‐sensitive rats (on 0.1% NaCl) at 3 months 17 or Fischer‐344 rats at 3 to 4 months 31 does not alter cortical or medullary total NOS expression when studied 6 weeks to 6 months post‐OVX. Based on the dependence on the NOS system to limit increases in BP in female SHRs, 37,50 we speculate that they have a greater sensitivity to estrogen‐mediated loss of NOS. Indeed, female SHRs have much greater NOS expression than Dahl salt‐sensitive rats; as a result, it is not surprising that the effect of OVX is more pronounced in SHRs.…”

Sex- and age-related differences in the chronic pressure-natriuresis relationship: role of the angiotensin type 2 receptor

“…Furthermore, it is well established that the AT 2 R exerts its actions through a pathway mediated by nitric oxide (NO) (7). Given that NO opposes the renal actions of ANG II, it is plausible that greater activation of the renal AT 2 R in adult females contributes to the functional role of NO in female kidneys as well as slowing the progression of age-dependent NO deficiency and renal dysfunction (3,4). Consistent with this hypothesis, the salt sensitivity of arterial pressure increased with age in male, but not female, mice.…”

The Importance of Biological Sex and Estrogen in Rodent Models of Cardiovascular Health and Disease

“…100 In addition, OVX female DSS rats fed a high salt diet developed hypertension in a manner that was not significantly different from males. 107 However, when dietary sodium was decreased to normal levels, blood pressure in the male and intact female DSS decreased, whereas in the OVX female DSS animals, it remained unchanged, suggesting that removing the female sex hormones predisposes the DSS female rats to develop hypertension, independent of sodium intake.…”

“…However, supplementing OVX females with testosterone increased blood pressure by 10 percent, suggesting that androgens may mediate the observed sex difference between SHRs, 96 and that female sex hormones are not protective for hypertension in the female SHR. 100, 101 Interestingly, sex differences are also influenced by the RAS. When male and female SHR, both intact and gonadectomized, were treated with an angiotensin converting enzyme (ACE) inhibitor, sex differences were abrogated as reduced blood pressure was most significant in males and OVX females supplemented with testosterone after treatment.…”