Pressure-natriuresis refers to the relationship between sodium excretion and mean arterial pressure, when increased arterial pressure which elicits an increase in sodium excretion and a decreased in extracellular fluid (ECF) volume. It therefore results in a decreased venous return, cardiac output, and finally reduces BP (Fig. 1A).2 Ang II induces elevated BP due to vasoconstriction, as well as an increase of sodium absorption in kidney tubules, rather than decreasing glomerular filtration rate (GFR). Ang II can increase GFR by contraction of the efferent arteriole, since the pressure difference between the afferent and efferent arterioles increases, creating greater filtration pressure. This function has an important role in preventing a decreased GFR during volume depletion.7 However, long-term hypertension and prolonged Ang II production shifts natriuresis right in the relationship curve and results in a reduction in renal excretory function (Fig. 1B). This is because higher intrarenal Ang II can upregulate ion transporters activity as well as the transporter expression such as the Na/H-exchanger in the proximal tubule and Na/Cl^--cotransporter in the distal convoluted tubule.8,9 A decreased renal sodium excretion or rightward shift of this curve can lead to an elevated BP and the development of hypertension by ECF expansion.10 It has been suggested that sex hormones may regulatethe pressure-natriuresis function, according to a reports, the pressure-natriuresis was blunting in male spontaneously hypertensive rat (SHR), testosterone treated, and ovariectomized female rats. In contrast, castration of male SHRs restores the bunted pressure-natriuresis relationship.11

Previous studies have shown that gender differences in the pressure-natriuresis relationship and in RAAS are caused by functional difference between male and female sex hormones. A study demonstrated that plasma renin activity (PRA) is positively modulated by androgens and antagonized by estrogens via an increase in NO generation.12 Therefore, prorenin and PRA levels are greater in men than in women. James et al.13 reported that PRA was 27% higher in men than in women in all age groups. In some female cases, elevated PRA levels were associated with diabetics (21.2 mU/L vs 13.5 mU/L) under conditions without estrogen replacement therapy (13.2 mU/L vs 10.9 mU/L).14 Experimental data show that the level of serum testosterone yielded a linear correlation with PRA in Sprague-Dawley rats.2 These results suggest that better BP control using an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) can be achieved in male than female. Reckelhoff et al.15 demonstrated that Enalapril decreased BP by 65% in male SHRs which was greater than in female rats (40%). Nonetheless, gender differences in the efficacy of ACE inhibitor and ARB have rarely been demonstrated in clinical studies. Although meta-analysis from Rabi et al.16 found a small but better response in men than women, this gender difference in effect was much smaller than the benefit from treatment with these agents in women. The different expression of subtype of Ang II receptor (AT)-Ang II type 1 receptor (AT1R) and Ang II type 2 receptor (AT2R) between two sexes seems to play a partial role in gender differences on the effect of ACE inhibitors or ARB. Because AT1R is the predominant AT receptor in both men and women, most ARB agents used clinically, including losartan, are AT1R antagonists. However, Ang II also activate AT2R and the function of AT2R is counter-regulation of BP and sodium absorption in the proximal tubule.17 Activation of the AT1 receptor increases BP as well as sodium absorption, whereas activation of AT2 receptor reduces BP and Na absorption in the proximal tubule.18 It has been reported that AT2R expression is higher in female than male rats.19 Hilliard et al.20 demonstrated that AT2R blockades the blunted pressure-natriuresis relationship and resulted in a rightward shift of the curve in both males and females; this effect is likely due to increased Na⁺ absorption in proximal tubules by AT2 blocker as we demonstrated previously.17

NO down-regulate the expression of AT1R and antagonize Ang II production.12 As mentioned earlier, estrogen exert stimulatory effects on both endothelial NO synthase (eNOS) activity and NO generation.12 Whole-body production of NO in healthy premenopausal women (mean 2111 nmoL of urinary 15 N nitrate excretion) was greater than in healthy young men (mean 1682 nmoL).21 As female hormones have beneficial effects in preventing development of hypertension and cardiovascular disease, a reduction of GFR according to advancing age is also delayed and attenuated in women (0.8 mL/min/1.73 m² per estimated GFR) compared to men (1.4 mL/min/1.73 m² per estimated GFR).22 Furthermore, the pro gression of acute renal injury and chronic renal disease is slower in women than men.12,23 These findings are related to gender differences of ET activity. ET-1 is well known as not only the most potent long-lasting vasoconstrictor known to date but also a potent pro-inflammatory agent.24,25 It was found that the ET-1 levels are higher in men (mean 5.9 pg/mL) than in age-matched women (mean 4.1 pg/mL) and lower in pregnant women in age-matched compared to non-pregnant controls.26 The crosstalk between ET, Ang II, NO and oxygen free radicals has been investigated intensively. Elevated level of ET-1 increased renal vascular resistance by 37% and reduced sodium excretion by 36% consistent with its vasoconstriction and sodium retention effect in human.27 Two ET receptors have been cloned, ET_A and ET_B, the ET_A receptor, which preferentially binds ET-1 and the ET_B receptor, which equally binds ET-1 and ET-3.28 ET_B receptor engender vasodilatation and natriuresis via NO production on endothelial and tubular cells.29,30 Therefore, ET_B receptors provide a protective mechanism against elevated BP. Females have increased ET_B function and perhaps reduced ET_A effects, and it has a role as one of physiologic mechanisms of reduced BP in women.

Because female sex hormones affect renal sodium excretion as well as BP control, spontaneous free sodium intake appears to be greater in females than in males in many mammals.31 This difference may originate in the need to preserve sodium losses during pregnancy.31 Loss of female sex hormones affect the pressure-natriuresis relationship curve, (it shifted to the right), which indicates how one may become salt sensitive after menopause.32 Kawasaki et al.33 have first used the terms salt-sensitivity and salt-resistant. They classified the subjects who showed an increase BP greater than 10 mmHg at the end of a high-salt diet rather than a normal-salt diet as'salt-sensitivity'.33 In contrast, the term of'salt-resistant' was used in subjects who showed an increase in BP < 5 mmHg.33,34 The renal hemodynamic response is different in salt-sensitive and resistant subjects (Fig. 2). Salt loading during the luteal phase in premenopausal women (progesterone and secondary estrogen surge) resulted in renal vasodilatation and reduced filtration faction, which is the ratio of the GFR to the renal plasma flow (RPF), with no change in GFR.35 In contrast, salt-sensitive postmenopausal women showed reduced GFR and an increase in the filtration fraction.31 Endogenous estrogen may modulate this mechanism by increasing NO bioavailability and decreasing the AT1/AT2 receptor ratio.3

Clinical studies have shown that the prevalence of salt sensitivity increases with age and is higher in hypertensive women than normotensive women. The mean age of the normotensive sodium-sensitive group (35.3 years) was older than the resistant group (26.9 years) and the hypertensive sodium-sensitive group (43.8 years) was older than resistant group (35.5 years).32 In the same study, higher salt sensitivity was identified in more hypertensives (> 50%) than normotensives (25%).32 Tominaga et al.36 also demonstrated that female sex hormone level in hypertensive postmenopausal women were significantly lower than normotensive age-matched women. Further, salt sensitivity was observed in 66.6% (8/12 subjects) in hypertensive patients and 14.2% (1/7) in normotensive women.

Even though WHO guideline recommend salt consumption of 2 g/day, salt consumption in Korea and many countries is two times greater than the recommended value. The efficacy of a low-salt diet on decreased BP in salt-sensitive women depends on the amount of salt restriction. In recent meta-analyses on the effect of lower sodium intake on BP, when sodium intake was < 2 g/day, SBP and DBP were reduced by 3.47 mmHg and 1.81 mmHg.37 This effect has also been demonstrated in children (0.84 mmHg and 0.87 mmHg respectively) and there were no adverse effects on blood lipids, catecholamine levels or renal function. However, caution should be applied in that low salt diets as non-pharmacologic therapy of hypertension are difficult to maintain over the long term.38 Of note, because women become salt sensitive after menopause, the use of diuretics in hypertensive women is strongly encouraged.39

Although endogenous estrogen has beneficial effects on sodium and BP regulation via NO production and RAAS, conflicting results have been reported in many clinical trials of HRT in postmenopausal women. Oral administration of estrogen has produced a neutral effect or a small increase in BP. In this placebo controlled trial of HRT, the estrogen plus progestin increased SBP (average < 2 mmHg), but not DBP.39,40 In contrast, transdermal estrogen replacement was associated with a 4.2 mmHg reduction of mean nighttime SBP after 6 months.41 The mechanisms for the different effects between the oral and transdermal route have not yet been elucidated.39 A novel progesterone with an anti-aldosterone effect, Dropirenone 2 mg and 3 mg in combination with Estradiol reduced SBP by 6.1 mmHg and 4.7 mmHg, respectively.42