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 usually unclear. 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), em N /em G-nitro-l-arginine methyl ester (l-NAME), and a more selective blocker of neuronal NOS (nNOS), em N /em 5-(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 usually 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 usually 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 Rabbit Polyclonal to SCAMP1 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 Peptide5 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 usually mediated via Peptide5 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 as well as 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 Peptide5 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.