.-It has been suggested that estrogen modulates baroreflex regulation of autonomic function. The present study evaluated the effects of estrogen on baroreflex regulation of heart rate in response to changes in blood pressure with phenylephrine (PE), ANG II, and sodium nitroprusside (SNP) in a conscious mouse model. Males and ovariectomized females with (OvxEϩ) and without (OvxEϪ) estradiol replacement chronically implanted with arterial and venous catheters were used in these studies. The slope of the baroreflex bradycardic responses to PE was significantly facilitated in OvxEϩ females (Ϫ7.65 Ϯ 1.37) compared with OvxEϪ females (Ϫ4.5 Ϯ 0.4). Likewise, the slope of the baroreflex bradycardic responses to ANG II was significantly facilitated in OvxEϩ females (Ϫ7.97 Ϯ 1.06) compared with OvxEϪ females (Ϫ4.8 Ϯ 1.6). Reflex tachycardic responses to SNP were comparable in all the groups. Finally, in male mice, the slope of ANG II-induced baroreflex bradycardia (Ϫ5.17 Ϯ 0.95) was significantly less than that induced by PE (Ϫ8.50 Ϯ 0.92), but this ANG II-mediated attenuation of reflex bradycardia was not observed in the female mice. These data support the hypothesis that estrogen facilitates baroreflex function in female mice and suggest that ANG II-mediated acute blunting of baroreflex regulation of heart rate may be sex dependent. gender differences; autonomic regulation; cardiac baroreflexes EPIDEMIOLOGICAL STUDIES have shown that cardiovascular diseases such as hypertension and coronary heart disease are less common in premenopausal women compared with age-matched men (16,18,23,50). This innate protection in women against cardiovascular disease disappears with reproductive senescence or with removal of endogenous ovarian steroids (4,45,49).It is thought that estrogen may affect cardiovascular function at numerous levels including the vasculature, heart, and brain (36, 46). A potential mechanism by which estrogen provides cardioprotection in women is by acting at central cardiovascular regulatory centers to modulate autonomic regulation of the cardiovascular system. Hormone replacement therapy appears to have favorable effects on the cardiovascular autonomic regulation in postmenopausal women by improving baroreflex sensitivity and overall heart rate (HR) variability (19). Similar observations have also been made in male and ovariectomized female rats where estrogen replacement appears to improve baroreflex sensitivity via central mechanisms (32,43). However, to date, there have been no studies about the role of estrogen or gender in baroreflex control of HR in mice.ANG II is a potent circulatory peptide implicated in pathogenesis of hypertension. In addition to its peripheral vasoconstrictor effects, this peptide has been known to modulate reflex regulation of HR and sympathetic activity through circumventricular organs such as the area postrema (13, 37). In rabbits, dogs, and rats, acute increases in circulating ANG II blunt baroreflex regulation of HR (1,31,38,39). It is interesting to know if centrally mediated e...