A new piece in the hypertension puzzle: central blood pressure regulation by sex steroids.

after the disappointing results from the Women's Health Initiative and the Heart and Estrogen/Progestin Replacement Study I and II in which hormone replacement therapy failed to protect postmenopausal women against primary (1) or secondary (2) cardiovascular events, respectively, two points were very clear: 1) more clinical and basic research is needed to understand why hormone replacement therapy was thought to be cardioprotective for many years; and 2) what is the complex role and by what mechanisms do sex steroids, estrogen and androgens, play in modulating cardiovascular-renal disease? In the study by Xue and colleagues (8) published in the American Journal of Physiology-Heart and Circulatory Physiology, the authors provide evidence for a new player in the study of how sex steroids impact hypertension and the role they play in the modulation of the sympathetic nervous system to impact blood pressure regulation in response to angiotensin II (ANG II) infusion. In previous studies, Xue and colleagues (6) reported that ANG II infusion caused a greater increase in blood pressure in male mice and in ovariectomized (OVX) female mice than in intact females. They went on to show that estrogen receptors mediated the attenuation of the pressor response to ANG II in females (7). In the present study, they go a step further and address whether central nervous system nitric oxide (NO) plays a role in estrogen-mediated attenuation of the blood pressure response to ANG II in female mice. Using state of the art techniques, the authors found that a centrally infused non-isotype-specific blocker of NO synthase (NOS), NG-nitro-l-arginine methyl ester (l-NAME), and a more selective blocker of neuronal NOS (nNOS), N5-(1-imino-3-butenyl)-l-ornithine (l-VNIO), ablated the protective effect on blood pressure in response to ANG II that was found in females. However, in contrast to intact female mice, neither NOS blocker caused a further increase in blood pressure in response to ANG II in OVX females. These data suggest that the attenuated pressor response to ANG II in intact female mice is mediated via central NO, presumably because of estradiol, although estradiol repletion studies were not performed. To show that estradiol is likely involved in the central upregulation of NOS, Xue and colleagues (8) go on to show that nNOS expression is upregulated in the subfornical organ and the paraventricular nucleus in female mice compared with males and that ANG II infusion further increases nNOS expression but only in intact females, not OVX females or males. In further support of a central mechanism, ganglionic blockade with hexamethonium resulted in a greater drop in blood pressure in male rats than females given ANG II, but the blockade of nNOS enhanced the reduction in blood pressure with hexamethonium in females but not males. The reduction in blood pressure with ganglionic blockade in OVX females treated with ANG II was similar to the reduction found in females treated with ANG II and l-VNIO and in males. Taken together, these data support a role for estradiol-mediated stimulation of nNOS to produce central NO in response to ANG II that attenuates sympathetic activity and blunts the systemic increase in blood pressure in female mice compared with males and OVX females. Interestingly, l-NAME had no effect on the depressor response to ganglionic blockade in intact males given ANG II, but castration attenuated both the ANG II pressor response and blunted the response to ganglionic blockade. l-NAME also failed to affect the depressor response to ganglionic blockade in ANG II-infused castrated males. Since ANG II failed to increase the expression of nNOS in male mice, the data suggest that the pressor response to ANG II in males is mediated via androgens and that NO has little role in modulating the response. Thus the mechanisms by which estrogen and testosterone centrally regulate blood pressure seem to be different in females versus males. The effect of sex steroids on blood pressure may be species specific. While the present study and others show that male mice have a greater pressor response to chronic ANG II infusion than females, the pressor response to ANG II in female rats is greater than in males (5). There have been no studies to our knowledge in humans in which the response to chronic ANG II infusion was studied in men and women, nor has the role of the sympathetic nervous system in the ANG II response in men and women been studied. However, Miller and colleagues (3) have evaluated the response to chronic blockade of the endogenous renin-angiotensin system in several studies. These investigators found that women exhibited an inhibition of the pressor response to acute ANG II infusion at lower doses of chronic ANG II type 1 receptor antagonism with irbesartan than did men. In addition, they found that an acute infusion of ANG II caused similar reductions in renal blood flow in men and women, but the glomerular filtration rate was only maintained in men, suggesting that glomerular capillary pressure may be increased more in men than in women with acute ANG II infusion (4). Thus further studies are needed to evaluate the sex differences in the chronic response to ANG II in humans and the role of the sympathetic nervous system in estradiol modulation of renin-angiotensin system in humans. In any case, the work of Xue and colleagues (8) provides provocative new data regarding the role that NO may play in modulating the sympathetic nervous system in intact females in response to chronic ANG II infusion. The central actions of ANG II and NO, or lack thereof with age, may be the answer to some of the questions that have arisen after the Women's Health Initiative and the Heart and Estrogen/Progestin Replacement Study since it is well known that the NO system is blunted with aging. One could speculate then that with aging in women and reductions in estradiol, there is a decrease in NO that leads to sympathetic activation and would increase the pressor action of ANG II. Whether exogenous estrogen via hormone replacement therapy can upregulate central NOS, as endogenous estradiol does, and thereby increase the level of NO reducing sympathetic activation in postmenopausal women is unclear. Two things are clear: sex steroids modulate blood pressure, and the mechanisms by which they do are complex and require more study.