Gender-related differences in the baroreceptor reflex control of heart

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difference in baroreflex control of HR exists, the males and females who participated in the study were matched for age and baseline blood pressure. No other ...
Gender-related differences in the baroreceptor of heart rate in normotensive humans

reflex control

A. R. A. ABDEL-RAHMAN, R. H. MERRILL, AND W. R. WOOLES Departments of Pharmacology and Medicine, East Carolina University School of Medicine, Greenville, North Carolina 27858 Abdel-Rahman, A. R. A., R. H. Merrill, and W. R. Wooles. Gender-related differences in the baroreceptor reflex control of heart rate in normotensive humans. J. Appl. Physiol. 77(Z): 606-613,1994.-The present study investigates the baroreceptor reflex control of heart rate (HR) of normotensive male and female human volunteers under two conditions: bolus- and infusion-evoked elevations of blood pressure by intravenous administration of phenylephrine. Average age and blood pressure were similar in both sexes, but females had a significantly lower heart period (HP; higher HR). A major difference existed between the two sexes when the blood pressure was elevated by the bolus method. Females had a significantly (50%) smaller baroreflex sensitivity (regression coefficient), which inferred a gender-related difference in baroreceptor reflex control of HR. However, because a positive correlation existed between basal HP and baroreflex sensitivity, it was important to investigate whether this difference was related to the significantly lower basal HP in females. This possibility was ruled out because a similar difference still existed when the data were collected from another group of females who had basal HP values similar to those of males. This gender-related difference in baroreceptor reflex control of HR seems to depend on the pattern by which the pressor stimulus is evoked. The baroreceptor HP response to a slowly developing pressor response that was maintained at a steady-state level was very similar in both sexes. Because the HP response to abrupt (bolus-evoked) pressor stimuli mainly reflects the activity of the vagal component, our findings suggest that the cardiac vagal component seems to play a substantially smaller role in the baroreflex-mediated bradycardia in females. baroreflex sensitivity; male; female; method; basal heart rate

bolus

method;

infusion

BARORECEPTOR REFLEX CONTROL of heart rate (HR) has been used in many clinical and experimental studies as an index of arterial baroreceptor function. Although its behavior does not always reflect a similar change in baroreceptor reflex control of vascular resistance or sympathetic neural activity (14, 29), its application in clinical studies revealed consistent impairment of baroreflexes in human hypertension (12, 18) and clearly demonstrated the effect of age on this important blood pressure regulator under normo- and hypertensive states (18). In general, baroreflex sensitivity is measured by relating the change in heart period (HP; interbeat interval) to a unit change in blood pressure after evoked changes in the latter either by physiological (e.g., the Valsalva maneuver) or pharmacological (injection of vasoactive agents) methods. Because of its original use as a quantitative method for assessing baroreflex sensitivity by Smyth et al. (23), the technique was used in different laboratories in its original form or after modifications of the method of injecting the vasoactive agents (bolus vs. THE

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infusion) and/or the method of calculating baroreflex sensitivity. Even when comparable techniques for measuring baroreflex activity were used, data obtained from different laboratories did not always agree, most likely because of the differences in age, baseline blood pressure and HR, or method of administration of vasoactive agents, bolus vs. infusion (9,24). However, it has been consistently shown that baroreflex sensitivity is reduced in hypertensive subjects and in older subjects even in the absence of higher blood pressure. An interesting finding was reported by Korner et al. (18), who showed that the degree of reduction was much greater when the bolus method was used compared with the infusion method. These authors suggested that, because of the differences in the time constants of neural changes in vagal and sympathetic supply to the heart after activation of baroreceptors, the bolus method should demonstrate better the function of the vagal component. Another important factor that may influence the direct comparison of data obtained from different laboratories is the male-to-female ratio of the subjects employed. Most of the reported studies do not comment on this issue (e.g., Refs. 10,12,18) or at best report the number of males and females employed (21) but still pool the data obtained from both sexes. In fact, none of the reported studies considered the possibility that males and females may have different baroreflex sensitivity. In a previous study (2), we investigated the acute effects of ethanol on baroreceptor reflex control of HR of normotensive volunteers. Because the effect of ethanol was similar in both sexes, the data were pooled. However, because a potential gender-related difference in baroreflex control has not been seriously considered, we decided to compare the data obtained from males and females in the control (preethanol) period. To our surprise, the data clearly demonstrated a 50% lower baroreflexmediated bradycardia when baroreflex sensitivity was measured by the bolus but not by the infusion method. However, we were not able to unequivocally rule out the possible involvement of a significantly lower HP (higher HR) of females as the cause of this difference in baroreflex sensitivities between the sexes. To answer this question, we felt that it was important to include a second group of females whose baseline HR was similar to that of male subjects. METHODS A total of 36 experiments were conducted on 24 subjects who gave their consent to participate in the two phases of the study after an overnight fast. Each subject had a normal physical examination. None had a history of hypertension or heart dis-

1994 the American

Physiological

Society

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ease. Two groups of randomly selected males (n = 8) and females (F’; n = 8) participated in phase I of the study in which baroreflex sensitivity was measured by the bolus method. In phase II (the infusion method), 13 subjects (7 males, 6 females) participated, 1‘2 of whom were among the 16 who participated in phase I in the previous study (2). All individuals were randomly selected except for the remaining group (F2), which was comprised of seven females who were selected to meet a preset criterion of having a basal HR averaging 60 beats/min for reasons indicated below. Except for two, all volunteers were professional students. They were asked to empty their bladder before starting the experiment. The protocol of the study was approved by the University Policy and Review Committee on Human Research. Because the goal of this study was to determine whether a gender-related difference in baroreflex control of HR exists, the males and females who participated in the study were matched for age and baseline blood pressure. No other selection criteria were imposed except that 1) all participants had to have normal physical examination, 2) those who had a history of hypertension or cardiac disease were excluded, and 3) a preset criterion was imposed for the selection of the participants in F2. In this group, a baseline HR of -60 beats/min was required to determine whether baseline HR contributed to the difference in baroreflex sensitivity between males and F1. Physical fitness was not matched for in the study because the type of physical fitness paradigm and its duration are variables that needed to be considered (21,22). Nonetheless, during the interview, one or two individuals in each group indicated that they performed some sort of exercise, e.g., swimming, jogging, and other exercises. No elaboration on the extent or the duration of the physical fitness was made. The average ages of male and female subjects were similar in both parts of the study (see Table 1). All experiments were carried out in a quiet room in the morning, and subjects rested quietly in the supine position throughout the study. Blood pressure was measured intra-arterially via a catheter inserted in the ipsilateral brachial artery after local anesthesia with 2% procaine under sterile conditions. The catheter was connected with a rigid polyethylene tube to a Statham P23 pressure transducer for recording phasic and mean arterial pressure (MAP) on a Grass polygraph (model 7D). HR was electronically computed from the blood pressure pulse by a Grass tachograph and was simultaneously displayed on another channel of the polygraph. An indwelling needle was inserted into the contralateral antecubital vein for bolus injections or infusion of the pressor agent phenylephrine (Ph). After the cannulations were completed, a 30-min time period was allowed for blood pressure and HR to stabilize. Each study took place in the same observation room after the subjects were introduced to the investigators. Two phases comprised the study of gender-related differences in arterial baroreflexes by means of the vasopressor drug technique. In the first phase bolus injection and in the second phase infusion-evoked elevations in blood pressure were utilized to trigger the baroreceptor HR response as described by Smyth et al. (23) and Korner et al. (18). The influence of respiratory variations on arterial baroreceptor reflex responses (8) was minimized by utilizing data points collected only during expiration for baroreflex sensitivity measurements (24). Ph (Neo-Synephrine, Winthrop Laboratories) was used as the pressor agent and was prepared in 0.9% NaCl so that the required dose could be injected as a bolus in 0.5 ml and flushed in with 2 ml of sterile 0.9% NaCl. An equal volume of saline had no effect on blood pressure and HR. To measure baroreflex sensitivity by the bolus method, bolus doses of 25, 50, 75, and 100 pg of Ph were injected at lo-min intervals. It typically took 30-45 s for blood pressure to rise to peak levels, which was then accompanied by a reflex fall in HR. The rate of MAP elevation

IN BAROREFLEXES

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was similar in all subjects. These responses were over in 2 min, and both variables returned to baseline (preinjection) levels; however, at least a lo-min period was allowed before the subsequent injection, and no injection was made until blood pressure and HR returned to baseline levels. When duplicate experiments (bolus and infusion) were performed on the same individual, a 2- to 3-mo period was allowed between the two phases of the study. Ph was cumulatively infused through the venous line at 25,42,82,110, and 160 pg/min by use of an infusion pump. Ph was prepared in sterile saline at a concentration of 100 pg/ml. The lowest infusion rate was 0.25 ml/min, the highest rate was 1.6 ml/min, and the highest total volume given was 21 ml. Each infusion was maintained for 5 min, and it typically took l-2 min after the infusion was started for blood pressure and HR to reach a plateau, which then remained at that level for the rest of the 5-min period. After the cumulative infusion regimen was completed or when the target rise in blood pressure (25-30 mmHg) was reached, the Ph infusion was stopped and blood pressure and HR were allowed to recover to preinfusion levels. This usually occurred within 5-10 min. The peak expiratory MAP and HP attained during the last 1 min of each infusion dose were used to measure the baroreflex sensitivity as mentioned below. Arterial pressure and interbeat interval (HP, ms) were measured continuously on the chart. During the few seconds before and after Ph injection, the chart speed was increased to 25 mm/s until the peak arterial pressure was reached. The interbeat intervals were then regressed against MAP measured at the respective preceding beat on a beat-to-beat basis. The slope of the linear portion of the relationship for each individual was taken as baroreflex sensitivity. Furthermore, MAP was determined during a single cardiac cycle that showed the peak elevation, and HP was measured during the subsequent cycle. Baroreflex sensitivity was also calculated from the HP/MAP ratio to determine whether it was influenced by the doses of Ph used. The relationship between baroreflex sensitivity values and baseline HP or MAP was evaluated by linear regression analysis. Protocols Effect of gender and method of measurement on baroreceptor HR response. In males and F’, the baroreceptor HR response was measured by the bolus method. The effect of gender on the HR response was investigated by comparing the data obtained from males and females in either phase of the study. The effect of the method of measurement was investigated by comparing the data obtained from each sex in the two phases of the study. Effect of baseline HP on the baroreceptor HR response. In males and F’, the latter had a significantly smaller baroreceptor HR response as determined by the bolus method, which was associated with a significantly lower baseline HP (higher HR). Because a positive correlation existed between baroreflex sensitivity and basal HP, we measured baroreflex sensitivity by the bolus method in another group of females (n = 7) whose baseline HP was similar to that of the male subjects. This was performed to determine whether the smaller baroreflex sensitivity in F1 was gender related or due to the lower HP. Data Analysis All data are presented as means t SE except when otherwise stated. The relationship between changes in MAP and changes in HP was assessed by regression analysis for each subject. The regression coefficient (slope of the regression line) was taken as an index of baroreflex sensitivity. The differences in slopes among sexes and between the two methods of assessing baroreflex sensitivity were determined by a nonpaired t test. P < 0.05 was considered significant.

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1. Baseline data obtained from male and female subjects Bolus

4%

IN

Yr

Weight, kg MAP, mmHg HP, ms BS, mg/mmHg n

Infusion

Method

Method

Female’

Female2

Males

Females

Males

25.4k2.3 53.9-t1.7* 100.6k12.5 776.3k217” 21.7k10.5” 8

28.6k5.3 57.5*11.4* 89.1k9.3 1003.9+114 23.5k14.8” 7

24.1k1.4 77.Ok9.3 97.8k4.8 1012+121 46.1t-16 8

26.2k3.9 55.3-t4.17* 85.3k8.1 862.0+159 17.227.1 6

27.3k6.6 78.428.8 91.Ok6.1 1013.7+267 16.4k9.5 7

Values are means + SD; n, no. of subjects. MAP, mean arterial randomly selected except for those in female2, who met preset criterion * Significantly different compared with values from males, P < 0.05.

pressure; of having

RESULTS

Baseline Data Table 1 shows the pertinent baseline data for each group of subjects in the two phases of the study. Age and basal MAP were similar in male and female subjects. Compared with males, basal HP was significantly (P < 0.05) lower in F1 but was comparable in F2.

HP, heart period; BS, baroreflex sensitivity. All subjects were basal HP value comparable to that of males (see text for details).

when increments in MAP were evoked by the infusion method. Figure 3 shows very similar baroreflex curves of the same slope and maximum HP response to the preset maximum increase in MAP of 25-30 mmHg in the two sexes. The actual baroreflex slopes are shown in Table 1.

n

q

Females’

*

17

Males

T

Baroreceptor Reflex Control of HR Effect of gender. Figure 1 shows the baseline values of MAP and HR that preceded each bolus Ph injection in males and the two groups of females. Also shown are the baroreflex sensitivity values calculated from the HP/ MAP ratio in response to the four bolus doses of Ph administered (25,50,75, and 100 yg). Baroreflex sensitivity values measured by bolus injections of these four dosesof Ph in a particular group were similar, but males exhibited significantly (P < 0.05) greater values compared with females. The average values of baroreflex sensitivity are presented in Table 1 for the three groups. F’ had significantly (P < 0.05) lower baroreflex sensitivity values compared with males of similar age and basal MAP. The lower baroreflex sensitivity obtained in females was evident in the presence (comparing F1 to males) and absence (comparing F2 to males) of any significant difference in baseline HP. Thus, the data suggest that the difference was gender related and was not influenced by the difference in baseline HP that existed between F1 and males. Further analysis revealed another interesting difference in the HP response of females to baroreceptor activation. Baroreflex curves were constructed by relating reflex increments in HP to Ph-evoked increments in MAP. Figure 2 shows that in addition to a significantly reduced baroreflex slope, the HP response of both groups of females reached a maximum of 250 ms when MAP was elevated by -12 mmHg. This is in marked contrast to the HP response of males, which was approximately twofold that of females (500 ms) and apparently did not reach maximum levels. Thus, the HP range and the baroreflex slope of females were significantly lower than those of males of similar age and baseline arterial pressure and HR. In marked contrast to the gender-related differences in baroreflex slopes and HP ranges when the bolus method was utilized, there was no difference between the male and female subjects in baroreflex slope or in HP range

Females

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100 s x E g a. a 2

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FIG. 1. Baseline mean arterial pressure (MAP) and heart rate (HR) of male and female subjects that immediately preceded administration of 4 doses of phenylephrine (Ph; 25, 50, 75, and 100 pg iv) at lo-min intervals. Top: baroreflex sensitivity (BS) values calculated as change in heart period (HP; reciprocal of HR) over change in MAP after Phevoked increments in MAP. Females’, randomly selected females; females2; females who meet preset criterion of having basal HR averaging 60 beats/min. * Significantly different compared with males. + Significantly different compared with females2.

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Effect of method of measurement. The method by which MAP was elevated, bolus vs. infusion, had a significant effect on the baroreceptor-HP response of males only. The baroreflex curve generated by the infusion method was significantly shifted downward and to the right compared with that generated by the bolus method in males (Fig. 4A). Thus, even though neither curve reached a plateau, the data showed that a similar increment in MAP of 16 mmHg evoked by either method increased HP by 300 and 575 ms when the increase in MAP was evoked by the infusion and the bolus methods, respectively. Regression coefficients (baroreflex slopes) were 17.6 and 36.4 ms/mmHg for the infusion and the bolus methods, respectively. On the other hand, the baroreflex curves generated by the two methods demonstrated a very similar behavior of the HP response in females (Fig. 4.B). Regression coefficients (baroreflex slopes) measured by the bolus and infusion methods were similar in females (Table 1). In males and F1, significant (P < 0.05) positive correlations existed between the baroreceptor HP response and baseline HP when the bolus method was used (Fig. 5A). However, a twofold greater slope of the regression line was evident when the data obtained from males were compared with those of females. The positive correlation was also evident when data obtained from males and F1 were pooled (r = 0.80). In contrast, data obtained from F2 revealed a poor correlation between baroreflex sensitivA

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3. Baroreflex curves relating reflex increments in HP to Phevoked increments in MAP by infusion method in male and female subjects (see Table 1 for baseline values). Values are means + SE; no. of subjects in each group is shown in parentheses. FIG.

ity and baseline HP (r = 0.48, P > 0.05). Furthermore, when the data obtained from F2 were added, baroreflex sensitivity was no longer related to baseline HP (data not shown). Furthermore, there was no correlation between baseline HP and baroreflex sensitivity measured by the infusion method in males and females whether considered separately or in combination (Fig. 5B). DISCUSSION

(8)

24

28

Arterial Pressure (mmHg)

2. Baroreflex curves generated by plotting reflex increments in HP against Ph-evoked increments in MAP by bolus method in male and female normotensive volunteers. Females’ had significantly lower baseline HP compared with very similar value obtained in males and females2 (see Table 1 for values). Data are means + SE; no. of subjects in each group is shown in parentheses. Note that greater baroreflex sensitivity in males was associated with lesser increments in MAP compared with females when rises in MAP were evoked by 4 doses of Ph in both sexes. FIG.

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(8)

0 Females’

0

IN

This study confirms the finding that the infusion method of Ph administration results in significantly smaller baroreflex slopes than the bolus method (24) and suggests a gender-related difference in the baroreflex slopes of age-matched normotensive males and females. This difference between males and F’ seems to be related, at least in part, to the method employed to measure baroreflex slopes, bolus vs. infusion. Interestingly, baroreflex sensitivity measured by the bolus but not the infusion method was directly related to baseline HP. This finding raised the possibility that the lower baseline HP of F1 contributed, at least in part, to the lower baroreflex slope. This possibility was ruled out because F2 also exhibited a lower baroreflex slope. It is interesting to note that when the data obtained from F2 were considered alone or in combination with the data obtained from other subjects, the positive relationship between baseline HP and baroreflex sensitivity was no longer evident. The baroreflex slope of females was substantially (54%) lower than that of males when the bolus method used coincided with significantly lower baseline HP in females (Table 1; Fig. 2). Age and/or baseline blood pressure, which are known to influence baroreflex sensitivity (4,13,18), cannot account for the differences observed here as the age and baseline blood pressures of both sexes were similar.

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A m

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FIG. 4. Effect of sion, of measurement ity on HP response MAP evoked by Ph (B) normotensive means + SE; no. of shown in parentheses.

-

method, bolus vs. infuof baroreflex sensitivto similar increments in in male (A) and female volunteers. Values are subjects in each group is

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(7)

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A Mean Arterial Pressure (mmHg) Furthermore, the finding that there was no difference in baroreflex sensitivity between the two sexes when the infusion method was used suggests that the relatively depressed baroreceptor reflex control of HP in females was almost entirely dependent on the pattern of blood pressure elevation, brief (bolus) vs. sustained (infusion). On the basis of this finding, it is important to comment on the influence of the method of measurement employed on the baroreflex slopes in both sexes. The baroreflex slope measured by the bolus compared with the infusion method was significantly greater in males but not in females. Six of eight males participated in the two phases

of the study, and the age and baseline arterial pressure and HR of the two groups of males were similar (Table 1). It is obvious, therefore, that the threefold greater baroreflex slope measured by the bolus compared with the infusion method may be accounted for by a difference in sensitivity of baroreceptors to the rate of rise in blood pressure (24,27). It is possible that an adaptive response that occurs within the central nervous system (19, 25) influences the magnitude of the HR response to baroreceptor activation by slow vs. fast elevations in blood pressure. It has been suggested that prolonged Phevoked pressor stimuli can result in acute “resetting” of

B 8Or e . . Males CP- Females

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FIG. 5. Relationship between BS values of males, females, or both sexes and baseline HP. BS was measured by bolus (A) and infusion (B) methods. A positive correlation existed between 2 variables with either and both sexes only when ramp method was employed [see correlation (T+)and regression (m) coefficient values at bottom]. n, No. of subjects.

OL 11111111 1000

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r 0.68 0.62 0.80

m 0.11 0.06 0.10

n

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r 0.53 -0.17 0.25

m 0.01 -0.01

n 7

6

0.01

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baroreceptors (6,7,18); hence, a smaller HR response to a given rise in pressure is expected after infusion compared with bolus injection. Another factor that may be involved in this difference is the magnitude of involvement of the cardiopulmonary receptors, the input of which influences the baroreceptor HR response (16) in the overall HR response to baroreceptor activation by the bolus vs. the infusion method. As is discussed later, these factors seem to be influenced by gender. Our data agree with the recent findings of Sullebarger et al. (24), who reported a higher baroreflex slope measured by the bolus compared with the infusion method. A quantitative difference exists, however, between the two findings. In this study, the baroreflex slope measured by the bolus method was threefold that measured by the infusion method vs. twofold in the study of Sullebarger et al. Comparison of the data reveals a substantially higher baroreflex slope measured by the bolus method in our study (46.1 t 5.6 vs. 22.5 t 1.8 ms/mmHg), whereas the baroreflex slopes measured by the infusion method in the two studies were comparable (16.4 t 3.6 vs. 9.9 t 0.7 ms/mmHg). The greater than twofold higher baroreflex slope with the bolus method in our study cannot be accounted for by differences in age or basal blood pressure of the subjects employed in the two studies. Because in previous studies (2, 23) the baroreflex slopes reported represent the average of all values obtained from male and female subjects, it is conceivable that the gender-related difference we report in this study may account for this difference. When the baroreflex slope obtained from all male and female subjects employed in this study was compared with that reported by Sullebarger et al., the difference became smaller (30.4 vs. 22.5 ms/mmHg). The difference, however, between the baroreflex slopes measured by the bolus and infusion methods in our study after pooling the data from males and females was still evident and agrees well with the difference reported by Sullebarger et al. It has to be remembered, however, that this difference between baroreflex slopes measured by the two methods was not present when the data obtained only from females were compared. Our present data do not agree with those reported by Ferguson et al. (9), Coleman (5), and even Abdel-Rahman (1). In these studies, the baroreflex slopes measured by the bolus and infusion methods were comparable. The reasons for disagreement between these findings are not clear but may relate to 1) the use of experimental animals (Sprague-Dawley rats) in Coleman and Abdel-Rahman and the use of anesthesia in Abdel-Rahman, and 2) the use of a single dose of Ph per subject, which varied from subject to subject, in the study by Ferguson et al. vs. multiple doses of Ph per subject in our study and that of Sullebarger et al. (24). Ferguson et al. also employed higher dosesof Ph, the lowest dose in their study (150 pg) being much higher than the largest dose (100 pg) in our study. Although our results show that for a given sex the baroreflex gain was not influenced by any of the doses of Ph employed (Fig. l), it is not clear whether the same applies to higher doses of Ph. The same limitation, i.e., the use of a widely varying single dose from a wide range (0.125-l pg. kg-’ min-l), in the study of Ferguson et al. may also explain a differing baroreflex slope measured by the infusion method from ours and that of others. In l

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our study and that of Sullebarger et al., in which multiple doses of Ph were employed to measure baroreflex slopes by the two methods, the slope was significantly higher with the bolus method. Results of our study show that this was the case whether pooled data from males and females or only from males were compared. In contrast, when data obtained from females by the two methods were compared, there was no difference in the baroreflex slopes. Thus, our data suggest a gender-related difference in baroreceptor reflex control of HR that can be demonstrated only with the bolus method. Taken together, these findings suggest the gender-related difference involves, at least in part, the component that differentially controls the baroreflex response measured by the bolus vs. the infusion method. Baroreflex slowing of HR involves reciprocal changes in vagal and sympathetic activity, stimulation, and inhibition, respectively (5). Studies of the time course changes and relative contribution of the components have shown that an increase in vagal tone occurs rapidly, whereas sympathetic withdrawal occurs more slowly (5, 17). Thus, the HP response evoked by the bolus method would be more indicative of reflex changes in vagal outflow, whereas during sustained infusion-evoked rises in blood pressure, the HP response would reflect more the sympathetic contribution. Korner et al. (18) showed that impairment of the vagal component of the baroreceptor HR response would be most evident during ramp rises in blood pressure evoked by bolus injections of vasopressor agents. On the basis of this observation, our findings that the baroreceptor reflex control of HR of females is significantly lower compared with the values obtained from males of similar age and basal blood pressure may suggest a weaker vagal response in females. In males and F’, a positive correlation was found between baseline HP and the HP response to baroreceptor activation by the bolus method. This finding, which confirms the finding of others (2l), was also evident when the data from either sex were analyzed separately. On the other hand, such a relationship could not be demonstrated when baroreceptors were activated by the steadystate stimulus in the same individuals. Thus, the data suggest that basal HP seems to have a bearing on the baroreceptor HP response measured by the bolus but not by the infusion method. This finding raised the interesting possibility that the significantly smaller baroreflex slope of females measured by the bolus method may be related to a significantly lower basal HP in these individuals. Thus, it was important to investigate this possibility before relating the difference to gender. Therefore, we included another group of females, F2, whose characteristics and basal values were similar to those of F1 except that they had to meet the preset criterion of a basal HP comparable to that of males. That the baroreceptor HP response of F2 (low HR) was similar to that of F’ (high HR) but was substantially lower than that of males who exhibited similar baseline HP provided evidence to suggest that the difference is gender related. It is possible that the level of circulating sex hormones in females might be involved in the difference between

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males and females regarding baroreflex sensitivity measured by the bolus method. If this is the case, then a similar difference should be expected when the infusion method is used. The absence of any difference between males and females in this case argues against such an involvement. Furthermore, Von Eiff et al. (26) demonstrated that, even though endogenous estrogen has a protective mechanism against the stress-evoked rise in systolic pressure in women, this effect was minimal in the age range of 20-30 yr, which is the age range of our female subjects. Only two subjects in our study were oral contraceptive users, and their responses were similar to those of the nonusers. Girdler et al. (11) reported that oral contraceptive users exhibited greater HR responses to stressors and myocardial reactivity tended to be greater in contraceptive users. Conversely, the pressor response to mental stress is reduced in contraceptive users. Finally, although physical fitness was not matched for in this study, it is important to discuss its possible contribution to the differences in baroreflex sensitivities between males and females. This is particularly important when one considers the preset criterion (low baseline HR) that was followed in selecting the members of F2. In a controlled study, Pagani et al. (21) reported that standardized physical training increased baroreflex sensitivity and baseline HP (decreased HR). Physical training, on the other hand, was shown to reduce baroreflex sensitivity in another study (22). A difference in the method of measurement of baroreflex sensitivity, bolus vs. infusion, may explain the discrepancy between these findings. Nonetheless, in the study in which the bolus method was used, as well as in the present study (Fig. 5), baroreflex sensitivity was positively related to baseline HP. This correlation was evident when data obtained from males and F’ were considered separately or in combination but not when data from F2 were considered. Regardless of whether the high baseline HP in this group of females was the result of physical training or other factors, it was not associated, as was the case in males, with enhanced baroreflex sensitivity. The gender-related difference seemsto prevail even when the two sexes are matched for baseline HR. Our data should not be interpreted to mean that there is a generalized gender-related attenuation of baroreflexes in females when rapid rises in blood pressure occur. Reported findings suggest that there is a differential baroreflex control of HR and blood pressure in relatively young hypertensive subjects (12). Experimental data also suggest that baroreflex control of peripheral resistance is preserved in hypertensive animals even though the baroreflex control of HR is impaired (l&20). Data from our laboratory also showed that the baroreceptor reflex control of HR can be attenuated by acute ethanol administration (2, 28) or augmented by glutamate microinjection (29), whereas the baroreceptor reflex control of sympathetic efferent discharge remained unchanged (Z&29). In summary, the difference between the baroreflex cardiac sensitivity of males and females relates, at least in part, to the pattern of blood pressure increase and is independent of basal HP values. Although males and females behave similarly when their blood pressure is elevated slowly to a steady-state level, they differ significantly when abrupt rises in blood pressure occur. The difference

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may infer a relatively weaker vagal response to rapid activation of baroreceptors evoked by the bolus method in females. Our results may complement the recent findings of Girdler et al. (11). These authors have reported that a similar pressor response to stressors among males and females involve different gender-related hemodynamic mechanisms. Greater myocardial reactivity (increased HR and cardiac output) contributes more to the pressor response in females than in males, whereas an enhanced vascular reactivity plays a greater role in the pressor response to stressors in males. Address macology, 27834. Received

for reprint requests: A. R. A. Abdel-Rahman, East Carolina Univ., School of Medicine, 4 May

1993; accepted

in final

form

14 March

Dept. of PharGreenville, NC 1994.

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GENDER

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