Acute ethanol lowers blood pressure (BP) and cardiac output in proestrus and after chronic estrogen (E2) replacement in ovariectomized (OVX) female rats. However, whether rapid nongenomic effects of estrogen mediate these hemodynamic effects of ethanol remains unanswered. To test this hypothesis, we investigated the effect of ethanol (0.5 or 1.5 g/kg iv) on left ventricular (LV) function and oxidative markers in OVX rats pretreated 30 min earlier with 1 μg/kg E2 (OVXE2) or vehicle (OVX) and in proestrus sham-operated (SO) rats. In SO rats, ethanol caused significant and dose-related reductions in BP, rate of rise in LV pressure (LV dP/dtmax), and LV developed pressure (LVDP). These effects of ethanol disappeared in OVX rats and were restored in OVXE2 rats, suggesting rapid estrogen receptor signaling mediates the detrimental effects of ethanol on LV function. Ex vivo studies revealed that the estrogen-dependent myocardial dysfunction caused by ethanol was coupled with higher LV 1) generation of reactive oxygen species (ROS), 2) expression of malondialdehyde and 4-hydroxynonenal protein adducts, 3) phosphorylation of protein kinase B (Akt) and extracellular signal-regulated kinases (ERK1/2), and 4) catalase activity. ERK1/2 inhibition by PD-98059 (1 mg/kg iv) abrogated the myocardial dysfunction, hypotension, and the elevation in myocardial ROS generation caused by ethanol. We conclude that rapid estrogen receptor signaling is implicated in cellular events that lead to the generation of aldehyde protein adducts and Akt/ERK1/2 phosphorylation, which ultimately mediate the estrogen-dependent LV oxidative stress and dysfunction caused by ethanol in female rats.

Reported clinical and experimental findings have shown that baroreflex control of heart rate is attenuated in women compared with men. This study investigated whether the sexual dimorphism in baroreflex function relates to the ability of the male hormone testosterone to facilitate baroreflex responsiveness. Relative contributions of the vagal and sympathetic autonomic components to testosterone modulation of baroreflex function were also investigated. Baroreflex curves relating changes in heart rate to increases or decreases in blood pressure evoked by phenylephrine and sodium nitroprusside, respectively, were constructed in sham-operated rats and castrated rats with and without testosterone replacement. Slope of the curves was taken as an index of baroreflex sensitivity (BRS PE and BRS NP ). Castration (for 10 days) significantly reduced plasma testosterone levels and attenuated reflex bradycardia, as indicated by significantly smaller BRS PE in castrated rats compared with values in sham-operated rats (-0.85 +/- 0.07 vs. -1.51 +/- 0.10 beats/min per mm Hg). Testosterone replacement in castrated rats restored plasma testosterone and BRS PE to levels similar to those of sham-operated rats. Muscarinic blockade by atropine caused 55% reduction in BRS PE in sham-operated rats, an effect that was significantly (p < 0.05) attenuated in castrated rats and restored to intact levels after testosterone supplementation. beta-Adrenergic blockade by propranolol caused slight and insignificant decreases in BRS PE. Castration and testosterone supplementation had no effect on BRS NP, ruling out a modulatory effect of testosterone on reflex tachycardia. These data provide the first experimental evidence of a favorable role for testosterone in baroreceptor control of reflex bradycardia. Further, baroreflex modulation by testosterone appears to be autonomically mediated and involves an enhancement of cardiomotor vagal activity.

We have recently shown that estrogen enhances baroreceptor control of reflex bradycardia in conscious rats. The present study replicated this finding in pentobarbital sodium-anesthetized rats, and the study was extended to investigate whether this effect of estrogen is centrally or peripherally mediated. Hemodynamic responses to electrical stimulation of the central end of the aortic depressor or the vagal efferent nerve were evaluated in pentobarbital sodium-anesthetized sham-operated (SO), ovariectomized (OVX), and OVX estradiol-treated Sprague-Dawley rats. Phenylephrine (1–16 μg/kg iv) elicited dose-dependent pressor and bradycardic responses. Regression analysis of the baroreflex curves, relating changes in mean arterial pressure and heart rate, revealed a significantly smaller baroreflex sensitivity in OVX compared with SO anesthetized rats (−0.54 ± 0.05 and −0.91 ± 0.12 beats ⋅ min−1 ⋅ mmHg−1, respectively; P < 0.05). Treatment of OVX rats with 17β-estradiol (E2, 50 μg ⋅ kg−1 ⋅ day−1for 2 days subcutaneously) significantly enhanced baroreflex sensitivity to a level similar to that of SO rats ( P < 0.05). The enhancing effect of E2 on the baroreflex-mediated bradycardia, observed in conscious and anesthetized rats, seems to be selective because the baroreflex-mediated tachycardic responses measured in a separate group of conscious rats were not altered by ovariectomy or E2 administration. Electrical stimulation of the aortic nerve elicited frequency-dependent depressor and bradycardic responses that were significantly smaller in OVX compared with SO values ( P < 0.05). Treatment of OVX rats with E2 restored the hemodynamic responses to aortic stimulation to near SO levels. On the other hand, hemodynamic responses to vagal stimulation were not affected by OVX or treatment with E2. These findings suggest that enhancement of reflex bradycardia by estrogen is centrally mediated and involves interaction with central projections of the aortic nerve.

This study determined the chronic hemodynamic effects of ethanol in telemetered freely moving female Sprague-Dawley rats. The role of ovarian hormones and sympathetic activity in the modulation of ethanol responses was also investigated. Changes in blood pressure (BP), heart rate (HR), and plasma estrogen and norepinephrine (NE, as index of sympathetic activity) were evaluated in pair-fed sham-operated (SO) and ovariectomized (OVX) rats receiving liquid diet with or without ethanol (5%, w/v) for 12 weeks. OVX caused a significant increase (about 40 g) in body weight, compared with the sham operation, which was apparent after two weeks and remained so for the duration of the study. The body weight showed gradual and similar increases in both ethanol and control groups. Ethanol feeding had no effect on the plasma estrogen level in SO or OVX rats. Daily ethanol intake was significantly (P < 0.05) less in OVX compared with SO rats whereas the blood ethanol concentration were similar in the two groups except for a significantly (P < 0.05) higher level in OVX rats at weeks 8, 10, and 11. Ethanol feeding caused significant (P < 0.05) decreases in BP in SO rats that started at week land reached maximal response (approximately 10 mmHg) at week 6 and remained at that level till the end of week 12. In OVX rats, ethanol had no effect on BPduring the first 5 weeks of the study. A slight but significant reduction in BP (about 5 mmHg) by ethanol in OVX rats started to appear at week 6 and remained for the following 5 weeks. The reduced hypotensive effect of ethanol in OVX rats was associated with an increase in the sympathetic activity as indicated by the significant (P < 0.05) increases in plasma NE levels. This sympathoexcitatory effect of ethanol was not demonstrated in SO rats. The HR was not affected by ethanol in the two groups of rats except for significant (P < 0.05) increases at weeks 1 through 3 in SO rats. The present findings suggest that the ovarian hormones modulate, at least partly, the hemodynamic and neurohumoral effects of chronic ethanol feeding in female rats. Ethanol lowers BP in female rats and this effect was delayed and diminished in OVX rats due possibly to the associated increase in sympathetic activity.

We have recently shown that intragastric (i.g.) ethanol lowers blood pressure (BP) in conscious female rats via a reduction in cardiac output (CO). However, the mechanisms implicated in these hemodynamic effects of ethanol are not known. Therefore, we tested the hypothesis that ethanol-evoked endotoxemia mediates the reduction in CO via enhanced myocardial inducible nitric-oxide synthase (iNOS) expression. Immunoblot (myocardial iNOS), biochemical (plasma endotoxin and nitrite/ nitrate), and integrative [BP, heart rate, CO, stroke volume (SV), and total peripheral resistance (TPR)] studies were conducted in conscious female rats that received i.g. ethanol (1 g/kg) in the absence or presence of 1400W (N-(3-[aminomethyl]benzyl) acetamidine) or ampicillin to selectively inhibit iNOS and to eliminate endogenous endotoxin, respectively. Ethanol-evoked hypotension coincided with reductions in CO and SV and increases in: 1) TPR, 2) plasma endotoxin and nitrite/nitrate, and 3) myocardial iNOS expression. These effects of ethanol were virtually abolished in rats pretreated with ampicillin (200 mg/kg/ day for 2 days by gavage) or with 1400W (5 mg/kg i.p.) except for the increase in plasma endotoxin, which persisted in 1400W-pretreated rats. These findings yield insight into the mechanistic role of endotoxin-myocardial iNOS signaling in the cardiodepressant action of ethanol, which accounts for its hypotensive effect in conscious female rats.Ethanol elicits hypotension in female, but not in age-matched male, rats (El-Mas and Abdel-Rahman, 1999a). Furthermore, the hypotensive effect of ethanol is estrogen-dependent (El-Mas and Abdel-Rahman, 1999b). It is imperative also to note that moderate ethanol consumption is associated with lower BP in young but not in old women (Klatsky, 1990), which highlights the clinical relevance of the reported experimental findings. The precise mechanism by which ethanol elicits hypotension in female rats is not known. It is noteworthy that there are similarities between the cardiovascular effects of ethanol and estrogen, which include inhibition of calcium influx (Turlapaty et al., 1979;Zhang et al., 1994), enhancement of NOS activity (Weiner et al., 1994;Wang and Abdel-Rahman, 2005;Zhang et al., 2005), and reduction of ␣-adrenergic receptor responsiveness (Abdel-Rahman et al., 1985;Sudhir et al., 1997). Indeed, the NOS-derived NO seems to be the major mediator of the estrogen-dependent hypotensive effect of ethanol because NO is directly or indirectly linked to vasodilation and reduces cardiac contractility (Yeh et al., 2005). It is possible, therefore, that ethanol may interact synergistically with estrogen to produce vascular and/or cardiac changes that might lead to hypotension.Built on the premise that ethanol enhances iNOS signaling (Durante et al., 1995), we demonstrated in a recent study the ability of ethanol to increase vascular (aortic) iNOS expression in female rats (El-Mas et al., 2006). Such a response could not be mechanistically linked to the hypotensive effect of ethan...