Sex Differences In Control Of Blood Pressure Research Articles

Sex differences in TLR4 expression in SHR do not contribute to sex differences in blood pressure or the renal T cell profile.

Hypertension is a primary risk factor for the development of cardiovascular disease. Mechanisms controlling blood pressure (BP) in men and women are still being investigated; however, there is increasing evidence supporting a role for the innate immune system. Specifically, Toll-like receptors (TLRs), and TLR4 in particular, have been implicated in the development of hypertension in male spontaneously hypertensive rats (SHR). Despite established sex differences in BP control and inflammatory markers in hypertensive males and females, little is known regarding the role of TLR4 in hypertension in females. Our hypotheses were that male SHR have greater TLR4 expression compared with females, and that sex differences in TLR4 contribute to sex differences in BP and the T cell profile. To test these hypotheses, initial studies measured renal TLR4 protein expression in 13-wk-old male and female SHR. Additional SHR were implanted with telemetry devices and randomized to treatment with either IgG or TLR4 neutralizing antibodies. Untreated control male SHR have greater TLR4 protein expression in the kidney compared with females. However, treatment with TLR4 neutralizing antibody for 2 wk did not significantly alter BP in either male or female SHR. Interestingly, neutralization of TLR4 increased renal CD3+ T cells in female SHR, with no alteration in CD4+ T cells or CD8+ T cells in either sex. Taken together, our data indicate that although male SHR have greater renal TLR4 expression than females, TLR4 does not contribute to the higher BP and more proinflammatory renal T cell profile in males versus females.

Acetazolamide Administration Restores the Blood Pressure Lowering Effect of Tempol in Female SHR

The mechanisms responsible for the sex differences in blood pressure (BP) in humans are not clear. Over the past several years, we have studied the spontaneously hypertensive rat (SHR) as a model of sex differences in BP control. Oxidative stress (OS) plays a major role in BP regulation in preclinical studies. There is a sex difference in the BP responses to pro‐oxidants and antioxidants in the SHR. In contrast to males, BP in female SHR does not decrease in response to Tempol or Apocynin. Acetazolamide (Aceta) inhibits proximal tubular sodium reabsorption, increasing sodium delivery to the distal tubule which increases distal tubule OS. We tested the hypothesis that an increase in sodium delivery in the distal tubule will restore the BP lowering effects of Tempol in female SHR.Materials and MethodsFemale SHR, aged twenty weeks, were implanted with radiotelemetry transmitters and following a two week recovery period, baseline mean arterial pressure (MAP) was measured 24 hrs per day. All rats were then given Aceta (100 mg/kg/day sc) for 14 days (n=14). After this period, a group of rats were randomized to receive Tempol (1mmol/L) in drinking water for an additional two weeks (Aceta + Tempol) (n=7/grp) and BP was compared to controls who received Aceta only (n=7/grp). MAP was measured continuously throughout the treatment periods.ResultsAt baseline, MAP was similar in both groups of female SHR (144 ± 1 vs. 145 ± 1 mmHg). Aceta administration for two weeks caused a 10 mmHg reduction in MAP, which was similar in both group of rats (132 ± 1 vs. 131 ± 1 mmHg, p=0.43). Tempol administration significantly lowered MAP in presence of Aceta (138 ± 1vs. 122 ± 1 mmHg, p<0.0001). Body weight was similar between Aceta and Aceta + Tempol groups (200.3 ± 2.0g vs. 192.2 ± 4.0 g).In conclusion, our data suggest that there are sex differences in proximal sodium reabsorption that may impact OS in SHR. By increasing sodium delivery to the distal nephron with acetazolamide, the BP lowering effect of Tempol is restored in female SHR. These data suggest that different mechanisms may control oxidative stress and blood pressure in male and female SHR.Support or Funding InformationThis project was funded by NIH R01 HL135089, P20 GM12334, & PO1HL51971This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Sex Differences in Hypertension: Where We Have Been and Where We Are Going.

While it has been known since the 1940s that men have greater increases in blood pressure (BP) compared with women, there have been intense efforts more recently to increase awareness that women are also at risk for developing hypertension and that cardiovascular diseases (CVDs) are the leading causes of death among both men and women in the United States. With the release of the 2017 Hypertension Clinical Guidelines, 46% of adults in the United States are now classified as hypertensive, and hypertension is the primary modifiable risk factor for the development of CVD. This increase in the prevalence of hypertension is reflected in an increase in prevalence among both men and women across all demographics, although there were greater increases in the prevalence of hypertension among men compared with women. As a result, the well-established gender difference in the prevalence of hypertension is even more pronounced and now extends into the sixth decade of life. The goals of this review are to (i) review the historical clinical trial data and hypertension guidelines from the perspective of both genders and then (ii) review the role of the renin-angiotensin system and T-cell activation in contributing to sex differences in BP control.

Sex differences in blood pressure control in SHR: lack of a role for EETs.

The mechanisms responsible for the gender difference in blood pressure (BP) in humans are not clear. Over the past several years we have studied the spontaneously hypertensive rat (SHR) as a model of sex differences in BP control. In the present study, we tested the hypothesis that renal vascular and microsomal epoxyeicosatrienoic acid (EET) levels are higher in females than males, and increasing vascular EETs by blocking epoxide hydrolase with AUDA will reduce BP more in males than females. Renal vascular and microsomal EETs were higher in female SHR than males. Mean arterial pressure (MAP by telemetry) was higher in males than females during the baseline period of 6 days, and although the epoxide hydrolase inhibitor, AUDA, given for 10 days increased renal microvascular EETs in both groups, AUDA did not affect MAP in either group. These data suggest that EETs do not contribute to the sex differences in hypertension in young SHR.

Abstract 254: Chronic Ang II Hypertension Differentially Impacts the Renal T Cell Profile in Males and Females

T cells contribute to angiotensin (Ang) II hypertension in male animal models yet less is known in females. We previously showed that hypertensive female rats have more immuno-suppressive T regulatory cells (Tregs) and males have more pro-inflammatory Th17 cells in their kidneys. This study tested the hypothesis that Ang II results in greater expression of renal Tregs in females and Th17 cells in males. 12 wk old male and female Sprague Dawley rats (SD) were treated with Ang II (200 ng/kg/min) or vehicle for 2 wks; blood pressure (BP) was measured via tail cuff and renal T cell profiles were measured via flow cytometry. Ang II infusion increased BP in both sexes (mmHg: males: 130±2 to 152±2; females: 123±1 to 146±1; p<0.05). Females had lower CD3 + T cell counts at baseline vs. males (p<0.0001). Ang II significantly increased CD3 + T cells in both sexes (p<0.0001). Baseline CD4 + T cell counts were comparable between male and female SD. Ang II infusion increased CD4 + T cells in both sexes (p<0.0001), however, expression remained lower in females (p=0.04). Females had greater expression of Tregs (p<0.0001) at baseline. Ang II infusion increased Treg expression in females (p=0.004), with no effect in males. Males expressed more baseline Th17 cells than females (p<0.001). Though Ang II increased levels in both sexes (p<0.001), females maintained significantly reduced Th17 cell expression vs. males (p<0.001). Therefore, Ang II resulted in female SD having greater renal expression of Tregs and males having greater expression of Th17 cells. In conclusion, sex differences in the T cell profile may contribute to observed sex differences in BP control.

Differential carotid baroreflex control of arterial blood pressure in young women and men at rest and during dynamic exercise

Arterial baroreceptors play a pivotal role in the rapid reflex adjustments that accompany acute cardiovascular stressors. Previous studies have demonstrated that the arterial blood pressure (BP) response of young women to cardiovascular stressors, such as exercise, was reduced compared to men. However, whether alterations in arterial baroreflex function contribute to sex differences in BP control remains unclear. To address this, 5s pulses of neck suction (NS, ‐60 Torr) and neck pressure (NP, +40 Torr) were applied to load and unload the carotid baroreflex (CBR), respectively at rest and during steady‐state cycling at 50% heart rate reserve in nine young women (22±1 yr) and nine men (22±1 yr). At rest, mean BP responses to NS were significantly greater in women (Δ‐16±1 women vs. Δ‐11±2 men mmHg; P=0.03), whereas responses to NP were similar between groups. Interestingly, exercise eliminated the group differences in mean BP responses to NS (Δ‐11±2 women vs. Δ‐11±2 men mmHg; P=0.98) however; responses to NP were significantly greater in women during exercise. These preliminary findings suggest that sex differences in CBR control of BP exist at rest and during exercise. In comparison to men, young women appear to be better able to defend against hypertensive challenges at rest, whereas during exercise women exhibit augmented CBR‐mediated BP responses to hypotension.Supported by R01HL093167.