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. β-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 E₂on 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 E₂administration. 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 E₂restored 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.

Previous studies have shown that the immunosuppressant drug cyclosporine A attenuates arterial baroreceptor function. This study investigated whether the modulatory effect of cyclosporine on baroreceptor function involves inhibition of the baroreflex-facilitatory effect of testosterone. The role of cardiac autonomic control in cyclosporine-testosterone baroreflex interaction was also investigated. Baroreflex curves relating bradycardic responses to increments in blood pressure evoked by phenylephrine were constructed in conscious, sham-operated, castrated rats and in testosterone-replaced castrated (CAS + T) rats in the absence and presence of cyclosporine. The slopes of the curves were taken as an index of the baroreflex sensitivity (BRS). Short-term (11–13 days) cyclosporine treatment or castration reduced plasma testosterone levels and caused similar attenuation of the reflex bradycardia, as indicated by the significantly smaller BRS compared with sham-operated values (−0.97 ± 0.07, −0.86 ± 0.06, and −1.47 ± 0.10 beats/min/mm Hg, respectively). The notion that androgens facilitate baroreflexes is further confirmed by the observation that testosterone replacement of castrated rats restored plasma testosterone and BRS to sham-operated levels. Cyclosporine had no effect on BRS in castrated rats but caused a significant reduction in CAS + T rats. Muscarinic blockade by atropine caused approximately 60% reduction in the BRS in sham-operated rats, an effect that was significantly and similarly diminished by castration, cyclosporine, or their combination. β-Adrenergic blockade by propranolol caused no significant changes in BRS. These findings suggest that cyclosporine attenuates baroreflex responsiveness via, at least partly, inhibition of the testosterone-induced facilitation of cardiomotor vagal control.

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.