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Dalton Cardiovascular Research Center, Department of Biomedical Sciences and the National Center for Gender Physiology, University of Missouri-Columbia, Columbia, Missouri
Submitted 22 September 2004 ; accepted in final form 22 December 2004
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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cardiovascular disease; sex hormones
Sex differences in the development of hypertension have been suggested to be due to protection of the female by estrogen and/or exacerbation in the male by androgen. In normotensive female rats, ovariectomy increases baseline blood pressure (BP) and treatment with estrogen attenuates this increase (30). In Dahl S rats, castration has been shown to not affect the development of hypertension in males; however, ovariectomy in females results in an accelerated development of hypertension to a level similar to that seen in males (15, 32, 46, 60). These studies suggest that female sex hormones protect normotensive and Dahl S rats against the increases in BP. In contrast, in SHRs, BP was reduced in males by castration but was not increased in females by ovariectomy (10, 51–53), suggesting that the sexually dimorphic pattern of hypertension in the SHR is androgen dependent rather than estrogen dependent. In the DOC-salt hypertensive model, it is likely that both male and female sex hormones are involved in the development of hypertension, since gonadectomy attenuated hypertension in male rats and exacerbated it in females (14). These studies suggest that, although both male and female sex hormones play an important role in the development of hypertension, different sex hormones may be involved in the different models of hypertension.
ANG II is an important factor in many forms of both clinical and experimental hypertension. In addition to its peripheral vasoconstrictor effects, this peptide has been known to increase sympathetic nerve activity (11, 56) and modulate reflex regulation of heart rate (HR) through circumventricular organs such as the area postrema (4, 59, 67). There is increasing evidence that ANG II actions in the central nervous system may largely differ by sex. Doursout et al. (16) reported that the BP and dipsogenic responses to centrally administrated ANG II in conscious dogs were substantially augmented in males relative to females. A recent study from our laboratory (48) has shown that, in male mice, the slope of ANG II-induced baroreflex bradycardia is significantly less than that induced by phenylephrine (PE), but this ANG II-mediated attenuation of reflex bradycardia is not observed in the female mice, suggesting that the ANG II-mediated acute blunting of baroreflex regulation of HR may be sex dependent. However, studies demonstrating the sex differences in sympathetic activity and baroreflex control of HR during chronic infusion of ANG II, which may contribute to sex differences in the development of ANG II-induced hypertension, remain uncertain.
In previous studies, sex differences in BP regulation have often been demonstrated with tail-cuff measurements of BP or short-term in-dwelling arterial catheters. In recent years, telemetry probes developed for mice have permitted recordings of hemodynamics for relatively long periods of time in conscious, freely moving animals without stress of heating, handling, or tethering (5–7). This new technique was used in the present study to determine whether there were sex differences in the development of chronic ANG II-induced hypertension in conscious, freely moving mice. Furthermore, we tested the hypotheses that sex hormones and differences in sympathetic outflow and baroreflex control of HR may contribute to the sex differences in the development of ANG II-induced hypertension.
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METHODS |
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Male and female mice of C57/BL6J strain were obtained from a breeding colony maintained in the animal care facility at University of Missouri. The mice were 12–16 wk old and had an average weight of 21–27 g. Mice were housed in standard polypropylene cages placed in a temperature- and humidity-controlled facility. The mice were maintained in a 12:12-h light-dark cycle (6:00 AM to 6:00 PM) and were fed normal (0.25%) NaCl mouse chow with water available ad libitum. All procedures were approved by the University of Missouri Animal Care and Use Committee.
Surgical Procedures
Gonadectomy. Ten days before implantation of the BP transmitters, bilateral gonadectomies were performed in female and male mice anesthetized with a mixture of ketamine and xylazine (100 mg/kg and 10 mg/kg). In the females, a single 1- to 2-cm dorsal midline incision was made in the skin and underlying muscles. The ovaries were isolated, tied-off with sterile suture, and removed, and the incisions were closed. In the males, a single incision was made in the skin covering the scrotum. The testicles were exteriorized, tied off, and removed, and incisions were sutured.
Telemetry probe implantation.
Implantable mouse BP transmitters (TA11PA-C20, Data Sciences International, St. Paul, MN) were used to directly measure arterial pressure in individual animals. These devices are thought to provide the most sensitive and accurate method available at present to monitor BP in conscious, freely moving mice (5, 43, 66). The mice were anesthetized with a ketamine-xylazine mixture. The carotid artery of the mouse was accessed with a ventral midline incision. The left carotid artery was isolated with fine-tipped vessel dilation forceps. Two occlusion sutures were placed beneath the artery. The elevated artery was punctured with a catheter introducer, and the telemetry catheter was inserted into the vessel. The catheter tip was advanced into the thoracic aorta so that 
3 mm of the thin-walled tip section could reside in the aorta. The sutures were tied and secured with tissue adhesive. Through the same ventral incision a subcutaneous tunnel was formed across the right pectoral area and was enlarged to form a pocket along the right flank. The body of the transmitter was slipped into the pocket and secured with tissue adhesive. The ventral incision was then closed with suture.
Chronic catheterization. After baseline BP and HR recordings were made, the mice were again anesthetized with the ketamine-xylazine mixture and surgically instrumented with intravenous catheters for administration of drugs. A catheter made of microrenethane tubing (MRE25, 0.64 mm OD, 0.30 mm ID; Braintree Scientific, Boston, MA) was inserted into the left femoral vein. The catheter was then tunneled subcutaneously, exteriorized, and placed at the back of the neck. Catheters were flushed daily with dilute sterile heparinized saline (25 U/ml) to maintain patency and resealed.
Osmotic pump implantation. The mice were anesthetized with inhalational isoflurane to allow the implantation of osmotic pumps. Osmotic pumps (model 1002, Alzet) containing ANG II (Sigma Chemical) at a concentration sufficient to allow an infusion rate of 800 ng·kg–1·min–1 were implanted subcutaneously on the left side of the back.
Experimental Protocol
Measurement of BP and HR. All mice were allowed 10 days of recovery from transmitter implantation surgery before any measurements were made (Fig. 1). This time interval is necessary for the mice to regain their circadian BP and HR rhythm (5). Thereafter, BP, HR, and activity responses were telemetrically recorded and stored with the Dataquest ART data acquisition system (Data Sciences International). The baseline measures were averaged over a period of 5 days before the implantation of the pump; the infusion data were collected over a period of 7 days after pump implant.
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Evaluation of response of BP to autonomic blockade. BP levels in male and female mice were also measured in the presence of the ganglionic blocker hexamethonium (10 mg/kg iv). On the day of experiment, the mice were allowed to stabilize for at least 60 min, after which BP was recorded 20 min before hexamethonium infusion and for 20 min after the treatment (Fig. 1). The ganglionic blockade was repeated three times in each animal, during baseline, on day 1, and on day 7, during infusion of ANG II.
Data Analysis
Mean arterial pressure (MAP), HR, and locomotor activity data collected for 5 and 7 consecutive days before and during ANG II pump implant, respectively, were plotted as mean values. All data are expressed as means ± SE. Statistical analyses of the effects of sex or gonadectomy on BP before and after ANG II infusion were performed with two-way ANOVA for repeated measures (Sigma Stat version 2.06). Post hoc analysis was performed with Fisher's least significant difference multiple comparison test where appropriate. One-way ANOVA was used for comparing changes in BP. Statistical significance was accepted at P < 0.05.
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RESULTS |
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Baseline BP and HR in Conscious Mice
Baseline values for BP were comparable in all groups, which included intact males (n = 7, 99.4 ± 1.3 mmHg), castrated males (n = 6, 98.1 ± 2.0 mmHg), intact females (n = 7, 102.4 ± 1.1 mmHg), and ovariectomized females (n = 6, 99.3 ± 1.0 mmHg). However, at comparable levels of activity (4.0 ± 0.6 vs. 4.1 ± 0.3 counts/min), baseline HR was significantly higher in intact female mice (630.1 ± 7.9 beats/min, P < 0.05). There were no differences in HR among intact males (544.8 ± 16.2 beats/min), castrated males (575.0 ± 10.5 beats/min), and ovariectomized females (577.3 ± 27.7 beats/min).
Effects of ANG II on BP and HR in Intact Male and Female Mice
Figure 2A shows MAP in male and female mice over the 12-day period. ANG II osmotic pumps were implanted on day 5. During infusion of ANG II, BP increased significantly in both male and female mice. However, the increase in BP was greater in males than in females (35.1 ± 5.7 vs. 7.2 ± 2.0 mmHg, P < 0.05). Figure 2B summarizes the average MAP before and after the implantation of pumps in male and female mice (females, 102.4 ± 1.1 to 114.2 ± 2.5 mmHg; males, 99.4 ± 1.3 to 142.5 ± 3.8 mmHg; P < 0.05).
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Effects of Autonomic Blockade on BP
Figure 3 shows decreases in BP with acute ganglionic blockade in male and female mice. In both groups, the decreases in BP were much smaller on day 1 compared with that on day 7, suggesting that increases in central autonomic outflow contribute to the ANG II-induced increases in BP on day 7. Acute hexamethonium injection produced similar decreases in BP in the male (n = 6) and female (n = 7) mice before infusion of ANG II (–32.6 ± 10.5 vs. –31.3 ± 9.8 mmHg) and on day 1 of ANG II infusion (–18.7 ± 4.7 vs. –14.0 ± 2.8 mmHg). However, on day 7 of ANG II infusion, the males exhibited significantly greater decreases in BP compared with females (–61 ± 8.9 vs. –36.6 ± 6.6 mmHg, P < 0.05).
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Mean HR baroreflex responses to intravenous infusions of PE in male and female mice are shown in Fig. 4. In the male mice (n = 6), the slope values of regression lines relating changes in HR to changes in BP were significantly blunted during infusion of ANG II (–2.9 ± 0.5 beats·min–1·mmHg–1, P < 0.05) compared with the slope values before infusion of ANG II (–5.6 ± 0.3 beats·min–1·mmHg–1) (Fig. 4A). This ANG II-mediated blunting of baroreflex regulation of HR did not occur in females (n = 6, –6.5 ± 0.5 to –5.6 ± 0.3 beats·min–1·mmHg–1) (Fig. 4B). Reflex tachycardic responses to SNP before and during infusion of ANG II were comparable in both males (–1.8 ± 0.4 to –1.7 ± 0.4 beats·min–1·mmHg–1) and females (–1.4 ± 0.3 to –1.3 ± 0.4 beats·min–1·mmHg–1).
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As shown in Fig. 5A, castration of male mice attenuated the development of ANG II-induced hypertension compared with intact males. Increases in MAP induced by ANG II were less in castrated males (15.2 ± 2.4 mmHg, P < 0.05) than in intact males (35.1 ± 5.7 mmHg) (Fig. 5B). Similar to intact males, chronic ANG II infusion did not produce significant changes in HR in castrated males (575.0 ± 10.5 to 584.5 ± 12.8 beats/min).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Previous studies on the effects of chronic ANG II infusion have, for the most part, been performed in male animal models. These include studies in male rats, dogs, and rabbits (32–35). However, differences between males and females in the expression of other types of hypertension have been well documented. In experimental animals, the sexual dimorphism in the manifestation of high BP occurs in both genetic and induced models of hypertension. For example, compared with females, male SHRs (10, 41, 51, 54), Dahl S rats (13, 60), DOC-salt hypertensive rats (14, 47), and New Zealand genetically hypertensive rats (2) have higher BP. In the present study, chronic infusion of ANG II in conscious mice produced significantly greater increases in BP in males than in females, suggesting sex differences are also observed in the development of ANG II-induced hypertension.
The mechanisms underlying the development of hypertension in the chronic ANG II infusion model have been investigated extensively in rabbits and rats (4, 11, 21, 42, 57–59). Acutely, systemic ANG II infusion increases BP by its peripheral vasoconstrictor effect. Chronically, ANG II-induced increases in BP are attributed, in part, to centrally mediated activation of the sympathetic nervous system (11). In the present study, ganglionic blockade on day 1 of ANG II infusion produced a much smaller reduction in BP than on day 7. Consistent with the observations in rats and rabbits, these data suggest that, in mice, the early increase in BP is mainly due to direct vasoconstriction and the hypertension observed during chronic ANG II infusion is due to increases in sympathetic outflow. More importantly, ganglionic blockade on day 7 produced a significantly smaller decrease in BP in females compared with males, suggesting less activation of sympathetic nervous system by ANG II in females. Systemic infusion of ANG II also leads to increases in BP without the large reflex bradycardia that normally accompanies such increases in BP (4, 42, 67). In male mice, despite a significant increase in BP, the HR during ANG II infusion was similar to that under baseline conditions. The female mice on the other hand showed a significant reduction in HR during ANG II infusion, which may be indicative of females being able to buffer the increases in BP better than the males. Similar observations have been reported in premenopausal women and age-matched men. ANG II infusion produced similar increases in BP, but the reflex decreases in HR shown in men were blunted relative to those observed in women (23).
The chronic phase of ANG II-induced hypertension is also associated with a blunting of baroreflex HR and sympathetic responses (25, 29). We have previously shown that ANG II-mediated acute blunting of baroreflex regulation of HR occurs in male mice but not in female mice (48). In the present study, in male mice, reflex bradycardic responses to PE were significantly blunted during chronic ANG II infusion compared with reflex responses under baseline conditions. This blunting of reflex bradycardic responses to PE was not observed in females, lending further support to the observation that the female mice maintain their ability to buffer changes in BP during ANG II infusion. Reflex tachycardic responses to SNP were similar in males and females under baseline condition and were not altered during ANG II infusion. These data in general may suggest that a reduced activation of sympathetic nervous system and/or better buffering of ANG II-mediated increases in BP protects females and accounts for the sex differences in the development of ANG II-dependent hypertension. However, it is important to note that reflex regulation of HR involves both sympathetic and parasympathetic tone to the heart, and any sex differences observed may also reflect differences in parasympathetic regulation (17). Direct measurement of sympathetic nerve activity may offer further insight (40); however, at present, these studies are not technically feasible in conscious mice.
Under baseline conditions, male and female mice had similar responses to ganglionic blockade and baroreflex responses to PE and SNP. Literature on sex differences in reflex regulation of HR and sympathetic activity has been equivocal, with several groups reporting a greater baroreflex gain in females (9) and others reporting reduced baroreflex sensitivity (1, 33) or absence of any differences (12). Hinojosa-Laborde et al. (31) have suggested that the differences between males and females as a group are masked when the stage of estrous cycle in females is not taken into consideration. These authors have reported a higher baroreflex gain in proestrous female rats and a lower baroreflex gain in diestrous female rats compared with males, suggesting an important role for circulating estrogen levels on baroreflex function (31, 44).
Finally, the present study addressed the contribution of sex hormones to the observed sex differences in ANG II-dependent hypertension. Removal of ovaries, the main source of circulating estrogen in the females, appears to facilitate the development of ANG II-dependent hypertension. This is not unexpected, as considerable evidence has shown that estrogen modulates the renin-angiotensin system, including expression of AT1 receptors in the brain and kidney and at the level of the vasculature (22, 36, 45). In ovariectomized rats, estrogen replacement decreases AT1 receptor expression and binding affinity at several central sites, including the subfornical organ, a circumventricular organ (36). Previous studies from our laboratory (39, 49) have shown that, in rats, estrogen opposes ANG II-mediated increases in neuronal activity and intracellular calcium in area postrema, another circumventricular organ known to mediate many of the central effects of circulating ANG II. In female mice, estrogen facilitates reflex bradycardic responses to PE and ANG II (26). Estrogen in general is also known to facilitate baroreflex functions in humans and rats (34, 61–63). Saleh et al. (61–63) showed that central administration of estrogen decreases sympathetic activity and increases parasympathetic activity to the heart. It is possible that, in the present study, the actions of ANG II are unopposed by estrogen in the ovariectomized females, thus leading to a greater expression of hypertension.
Castration attenuated the development of ANG II hypertension in male mice in the present study. Unlike estrogen, which is in general considered beneficial for cardiovascular health, the male sex hormone testosterone is thought to facilitate the development of hypertension by facilitating the effects of renin-angiotensin system (22, 53, 54). In male SHR, plasma renin activity (PRA) has been shown to be much higher than that in females. Castration decreases PRA in male rats. Testosterone treatment also causes increases in PRA in ovariectomized female rats (19, 35). Compared with female sex hormones, reports on the interaction of the male sex hormones with sympathetic nervous system and baroreflex control of HR are sparse and controversial (20). Although testosterone facilitates development of hypertension, testosterone has also been shown to facilitate reflex bradycardia in male rats by enhancing cardiac vagal activity (20). In the present study, despite the attenuation of ANG II-induced hypertension in the castrated mice, ANG II-mediated blunting of reflex bradycardic responses was not affected. The underlying mechanism is not clear, but testosterone may differentially modulate BP and cardiac baroreflexes.
The molecular and cellular mechanisms underlying the sex differences in ANG II-induced hypertension are unknown. A growing body of evidence has shown that increases in circulating ANG II stimulates oxidative stress that participates in the central effects of ANG II on BP (8, 24, 55, 68). Central and peripheral studies with estrogen and testosterone have suggested that many of the cardiovascularly related effects of sex hormones may be related to their role in development of oxidative stress and their regulatory effect on the generation of reactive oxygen species and nitric oxide (3, 26, 30). For example, in endothelium, estrogen has recently been shown to inhibit ANG II-induced increases in expression of NAD(P)H and nitric oxide synthase (27). In vascular smooth muscle cells, estrogen decreases ANG II-induced free radical production (65). In contrast, androgen stimulates superoxide production either directly or via the effect of ANG II on NAD(P)H oxidases (55). It is reasonable to hypothesize that differences in modulation of reactive oxygen species generation by estrogen and androgen could contribute to the sex differences in effects of ANG II on BP.
In summary, this study demonstrated that there are sex difference in the development of ANG II-induced hypertension in conscious mice and that the sex hormones play an important role in modulating the pathogenesis of ANG II-induced hypertension. Furthermore, the different sympathetic nervous system responses to infusion of ANG II as well as different baroreflex function changes during infusion of ANG II between males and females may contribute, at least in part, to these sex differences.
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GRANTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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-Estradiol prevents oxidative stress and decreases blood pressure in ovariectomized rats. Am J Physiol Regul Integr Comp Physiol 279: R1599–R1605, 2000.
-Estradiol modulation of area postrema potassium currents. J Neurophysiol 84: 1385–1391, 2000.
-Estradiol inhibits angiotensin II activation of area postrema neurons. Am J Physiol Heart Circ Physiol 285: H1515–H1520, 2003.
-estradiol in male rats. Brain Res 867: 200–209, 2000.
-estradiol on parasympathetic tone in male rats. Am J Physiol Regul Integr Comp Physiol 276: R474–R481, 1999.
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HR) to increases in MAP (
Significant differences in slope values between before and during infusion of ANG II.
