Sex has an important influence on blood pressure (BP) regulation. There is increasing evidence that sex hormones interfere with the renin-angiotensin system. Thus the purpose of this study was to determine whether there are sex differences in the development of ANG II-induced hypertension in conscious male and female mice. We used telemetry implants to measure aortic BP and heart rate (HR) in conscious, freely moving animals. ANG II (800 ng.kg(-1).min(-1)) was delivered via an osmotic pump implanted subcutaneously. Our results showed baseline BP in male and female mice to be similar. Chronic systemic infusion of ANG II induced a greater increase in BP in male (35.1 +/- 5.7 mmHg) than in female mice (7.2 +/- 2.0 mmHg). Gonadectomy attenuated ANG II-induced hypertension in male mice (15.2 +/- 2.4 mmHg) and augmented it in female mice (23.1 +/- 1.0 mmHg). Baseline HR was significantly higher in females relative to males (630.1 +/- 7.9 vs. 544.8 +/- 16.2 beats/min). In females, ANG II infusion significantly decreased HR. However, the increase in BP with ANG II did not result in the expected decrease in HR in either intact male or gonadectomized mice. Moreover, the slope of the baroreflex bradycardia to phenylephrine was blunted in males (-5.6 +/- 0.3 to -2.9 +/- 0.5) but not in females (-6.5 +/- 0.5 to -5.6 +/- 0.3) during infusion of ANG II, suggesting that, in male mice, infusion of ANG II results in a resetting of the baroreflex control of HR. Ganglionic blockade resulted in greater reduction in BP on day 7 after ANG II infusion in males compared with females (-61.0 +/- 8.9 vs. -36.6 +/- 6.6 mmHg), suggesting an increased contribution of sympathetic nerve activity in arterial BP maintenance in male mice. Together, these data indicate that there are sex differences in the development of chronic ANG II-induced hypertension in conscious mice and that females may be protected from the increases in BP induced by ANG II.

It has been shown that the female sex hormones have a protective role in the development of angiotensin II (ANG II)-induced hypertension. The present study tested the hypotheses that 1) the estrogen receptor-alpha (ERalpha) is involved in the protective effects of estrogen against ANG II-induced hypertension and 2) central ERs are involved. Blood pressure (BP) was measured in female mice with the use of telemetry implants. ANG II (800 ng.kg(-1).min(-1)) was administered subcutaneously via an osmotic pump. Baseline BP in the intact, ovariectomized (OVX) wild-type (WT) and ERalpha knockout (ERalphaKO) mice was similar; however, the increase in BP induced by ANG II was greater in OVX WT (23.0 +/- 1.0 mmHg) and ERalphaKO mice (23.8 +/- 2.5 mmHg) than in intact WT mice (10.1 +/- 4.5 mmHg). In OVX WT mice, central infusion of 17beta-estradiol (E(2); 30 microg.kg(-1).day(-1)) attenuated the pressor effect of ANG II (7.0 +/- 0.4 mmHg), and this protective effect of E(2) was prevented by coadministration of ICI-182,780 (ICI; 1.5 microg.kg(-1).day(-1), 18.8 +/- 1.5 mmHg), a nonselective ER antagonist. Furthermore, central, but not peripheral, infusions of ICI augmented the pressor effects of ANG II in intact WT mice (17.8 +/- 4.2 mmHg). In contrast, the pressor effect of ANG II was unchanged in either central E(2)-treated OVX ERalphaKO mice (19.0 +/- 1.1 mmHg) or central ICI-treated intact ERalphaKO mice (19.6 +/- 1.6 mmHg). Lastly, ganglionic blockade on day 7 after ANG II infusions resulted in a greater reduction in BP in OVX WT, central ER antagonist-treated intact WT, central E(2) + ICI-treated OVX WT, ERalphaKO, and central E(2)- or ICI-treated ERalphaKO mice compared with that in intact WT mice given just ANG II. Together, these data indicate that ERalpha, especially central expression of the ER, mediates the protective effects of estrogen against ANG II-induced hypertension.

.-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...

Incidence of essential hypertension has been reported to be significantly higher in the population afflicted with non-insulin dependent diabetes mellitus (NIDDM). The present studies were under taken in the insulin resistant, Zucker obese rats to evaluate various factors that could lead to the development of high blood pressure. Direct blood pressure measurements in the conscious obese rats indicated that they were not consistently hypertensive although the blood pressures of the obese rats tended to be higher than that of the control lean rats. However, after Inactin anesthesia blood pressures of the obese rats were significantly elevated which can be related to an increase in sympathetic tone since autonomic ganglionic blockade eliminated the differences between the pressures of the two groups. Under anesthesia, cardiac output per 100 gm body weight was significantly lower indicating inadequate tissue perfusion in the obese rats. In a separate series of studies carried out in conscious rats, reflexly mediated alterations in the heart rate to intravenous phenylephrine and sodium nitroprusside were significantly blunted in the obese rats. These observations which include enhanced central sympathetic discharge, inadequate systemic hemodynamics and attenuation of baroreceptor compensation collectively suggest that the insulin resistant obese rats are in a pre-hypertensive state and could develop sustained hypertension if they are exposed to other risk factors.

It is well established that the area postrema, as a circumventricular organ, is susceptible to modulation by circulating hormones and peptides. Furthermore, activation of the area postrema has been shown to modulate central neurons involved in the regulation of cardiovascular function and blood pressure. In particular, the vasoactive peptide angiotensin II (ANG II) has been shown to inhibit baroreflex regulation of heart rate and increase sympathetic outflow and blood pressure via activation of area postrema neurons. Estrogen is thought to protect against hypertension in both humans and animal models and has been shown in a number of systems to alter the effects of ANG II. The purpose of the present study was to determine the effects of estrogen on ANG II activation of area postrema neurons. In this study, the effects of ANG II and KCl on fura 2-measured cytosolic Ca2+ concentration ([Ca2+]i) responses in cultured area postrema neurons in the presence and absence of 12-h exposure to 100 nM 17 beta-estradiol (E2) were evaluated. In neurons incubated in control vehicle media, 50 nM ANG II increased [Ca2+]i by 92 +/- 12%. In neurons preincubated with 100 nM E2, ANG II increased [Ca2+]i by only 68 +/- 11%, for a total inhibition of the ANG II-evoked response of 24%. Coapplication of the estrogen receptor antagonist ICI-182,780 did not inhibit the effects of E2. In the same cells in which the effects of E2 on ANG II-evoked responses were tested, the effects of incubation in E on the depolarization-induced increased [Ca2+2]i due to 60 mM KCl were also tested. Incubation of the cells with 100 nM E increased the KCl-evoked [Ca2+2]i response, and this response was blocked by ICI-182,780. These results suggest that in the area postrema, estrogen may utilize multiple pathways to modulate neural activity and responses to ANG II.