(Hypertension. 2000;35:795.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Effects of Menstrual Cycle and Race on Peripheral Vascular 
-Adrenergic Responsiveness
From the Departments of Psychiatry and Behavioral Neurosciences and Obstetrics and Gynecology (R.R.F.) and Internal Medicine (Pulmonary) (R.G.), Wayne State University School of Medicine, Detroit, Mich. Correspondence to Robert R. Freedman, PhD, CS Mott Center, 275 E Hancock, Detroit, MI 48201.
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Abstract |
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Abstract—Gender differences in the incidence of many cardiovascular diseases may be due to the effects of sex hormones. Both
1- and
2-adrenergic receptors produce vasoconstriction in
peripheral blood vessels and have demonstrated gender
effects in previous studies. In addition, race has been shown to
influence the effects of some -adrenergic stimuli. We therefore
sought to determine the effects of the menstrual cycle and race on
peripheral blood flow responses to the
intra-arterial infusion of phenylephrine
(1-agonist) and clonidine (2-agonist).
Ten white and 8 black women were studied during the early luteal phase
and the follicular phase; these phases were verified in each woman
through measurements of plasma estradiol and progesterone. Plasma
norepinephrine was measured with HPLC. During
phenylephrine infusion, there was significantly greater
vasoconstriction in the luteal phase versus the follicular phase
(P<0.05). There were no differences
(P>0.8) between white and black women. During clonidine
infusion, white women showed significantly more vasoconstriction in the
follicular phase than during the luteal phase
(P<0.006). For black women, the responses for both
phases did not differ (P>0.9). Blood pressures were
significantly higher in the black women (diastolic
P<0.005, systolic P<0.05). The
luteal-phase elevation of 1-adrenergic responses may be
due to elevated levels of estradiol, progesterone, or both. The lack of
luteal-phase reduction in 2-adrenergic vasoconstriction
in black women may contribute to their increased pressor responses to
adrenergic stimuli.
Key Words: receptors, adrenergic, alpha • gender • race • blacks • estrogen • norepinephrine • blood flow
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Introduction |
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Although the incidence of many cardiovascular diseases differs in men and women, the mechanisms underlying these differences are not completely understood. Previous research has shown that white women have significantly reduced peripheral vasoconstriction in response to the intra-arterial infusion of
1- and
2-adrenergic agonists (ie,
phenylephrine and clonidine) compared with white
men.1 There were no sex differences in response to
intra-arterial nitroglycerin or digoxin or
to reactive hyperemia in that study. Estrogen and progesterone
act on blood vessels through a variety of genomic and nongenomic
mechanisms.2 Here, we sought to determine whether the
menstrual cycle variation of these sex hormones would affect
peripheral vascular 1- and
2-adrenergic responsiveness.
Some previous studies have shown that blacks have greater vascular
reactivity to -adrenergic stimuli than whites.3 4 Other
work has shown that the menstrual cycle differentially affects
adrenergic receptors5 and cardiovascular
responses6 in black and white women. We therefore included
both black and white women in the present investigation. Each woman
was studied during the follicular phase and the luteal phase, and these
phases were verified on the basis of plasma levels of estradiol and
progesterone. Plasma levels of norepinephrine were also
measured because this is an important mechanism of -adrenergic
receptor regulation.7 8 9
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Methods |
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Subjects
The study included 10 white and 8 black women who were recruited from our university campus. Racial classification was based on self-report. All subjects were judged to be healthy and medication free after providing a history and completing an extensive questionnaire. All were normotensive. All subjects gave written informed consent according to procedures approved by our institutional review board.
Subjects reported regular menstrual cycles, which they logged on calendars for 2 months before the study. The study was conducted at the same time of day during 2 consecutive cycles: once during the follicular phase (days 1 to 6) and once during the luteal phase (days 21 to 27). The order of phases was random.
Procedure
Subjects wore cotton hospital scrub suits and were supine in a
23°C temperature- and humidity-controlled room. An
intravenous catheter was inserted into an antecubital vein
and maintained patent with a slow drip of 0.9% sterile saline
solution. After a wait period of 30 minutes, 10 mL blood was drawn
through a stopcock for subsequent analysis of levels of plasma
estradiol and progesterone (via radioimmunoassay) and
norepinephrine. Samples were immediately
centrifuged and stored at -80°C for subsequent
analysis. Then, a 20-gauge catheter was inserted
percutaneously into the brachial artery of the opposite
arm under local anesthesia and maintained patent with a 0.5
mL/min infusion of 0.9% saline solution (901 pump; Harvard
Apparatus).
Finger blood flow was measured with venous occlusion plethysmography and recorded 3 times per minute on a polygraph.1 Both hands were supported slightly above heart level. Oncometer cups were attached with caulking compound to the tip of the index finger of each hand near the distal interphalangeal joint and connected by plastic tubing to pressure transducers. These were calibrated at the beginning and end of each session through the introduction of known volumes of air with precision pistons attached to the transducers. Venous occlusion was produced with a 2.5-cm-wide pneumatic cuff placed just proximal to each cup. Blood pressure was recorded every 4 minutes with an automatic recorder.
After 30 minutes had elapsed, baseline measurements were recorded for 15 minutes, followed by infusion of the first drug. Phenylephrine hydrochloride (0.125, 0.25, 0.5, 1.0, and 2.0 µg/min) and clonidine hydrochloride (0.2, 0.4, 1.0, 2.0, and 4.0 µg/min) were infused in random order with additional Harvard Apparatus 901 pumps. Each dose was infused for 3 minutes, after 2 minutes was allowed for the drug to take effect. Fifteen minutes intervened between the infusion of each drug, during which time blood flow in the infused hand returned to baseline levels.
Previous research10 has shown that at the doses
administered, phenylephrine and clonidine are highly
selective for 1- and
2-adrenergic receptors, respectively, in the
human finger circulation. Vasoconstriction produced with
intra-arterial phenylephrine in this dose range
was blocked with intra-arterial prazosin but not with
yohimbine. Similarly, intra-arterial clonidine in this dose
range was blocked with intra-arterial yohimbine but not
with prazosin.
Norepinephrine Assay
Alumina extractions were performed on 2 mL thawed plasma to
which 20 µL DHBA standard (0.02 ng/µL, 45 to 50 mg acid-washed
alumina, and 1 mL of 1.5 mol/L Tris/0.05 mol/L EDTA buffer) was
added.11 The sample was vortexed and then rotated at a
moderate speed for 5 minutes and spun at 2500 rpm for 3 minutes. The
supernatant was aspirated, and the alumina was washed 3 times with 1.5
mL distilled water. The final wash was vortexed, spun at 2500 rpm for 1
minute, and then aspirated to dryness. The catechols were eluted with
200 µL of 0.2 mol/L perchloric acid, vortexed for 8 minutes, and then
spun at 2500 rpm for 1 minute. The supernatant was removed, and 100
µL was used for catecholamine analysis.
Electrochemical detection was performed with a BAS LC-4C amperometric
detector equipped with a glassy carbon working electrode and a Beckman
ultrasphere ODS 5-µm column (25 cmx4.6 mm). The applied
potential was 675 mV versus Ag/AgCl with a flow rate of 1.5 mL/min at
ambient temperature. The mobile phase consisted of 70 mmol/L
sodium phosphate, monobasic, 2.75 mmol/L octane sulfonic acid,
0.25 mL EDTA, and 7% acetonitrile. The pH was adjusted to 4.3 with
85% phosphoric acid. All chemicals were reagent grade or better. All
samples were measured at 1.0 nA full-scale sensitivity, with a lower
detection limit of 10 pg. The coefficient of variation was 4%.
Data Analysis
Finger blood flow signals from the polygraph were digitized at
100 Hz with an Analog Devices A/D converter and analyzed with a
computer. The tangent to each postocclusion curve was calculated and
converted to finger blood flow in mL · 100 mL
tissue-1 · min-1.
Blood flow measurements were averaged for the final 5 minutes of each
baseline period and for each drug dose.1
To control for spontaneous fluctuations in blood flow, the method described by Duff12 was used. It has been shown that spontaneous blood flow fluctuations in the 2 hands are approximately equal. To control for these fluctuations, the percentages of change from the preceding baseline period are computed for each drug dose, with corrections for the changes in the infused finger by the corresponding changes in the noninfused finger.
These data were analyzed with 3-way (racexphasexdose) repeated measures ANOVAs; this was performed separately for each drug. Significant interactions were further analyzed with simple effects tests.13 The blood pressure, heart rate, and baseline finger blood flow data were also analyzed with 3-way (racexphasextime) repeated measures ANOVAs. The minimum level of statistical significance for all analyses was P<0.05. All values are given as mean±SEM.
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Results |
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In every woman, the luteal levels of plasma estradiol (86±9 pg/mL) and progesterone (12±2 ng/mL) were higher than the respective levels obtained during the follicular phase (plasma estradiol 33±7 pg/mL, P<0.0002; plasma progesterone 2±0.4 ng/mL, P<0.001). There were no significant main or interaction effects between white and black women in mean levels of estradiol (57±8 versus 63±12 pg/mL) or progesterone (6±2 versus 7±2 ng/mL). There were no significant main or interaction effects between follicular- (195±26 pg/mL) and luteal- (180±18 pg/mL) phase levels of plasma norepinephrine or between the levels of white (187±21 pg/mL) and black (188±25 pg/mL) women. There were no significant differences between white and black women in mean age (31.3±1.7 versus 28.5±1.5 years), height (167.5±1.7 versus 166.4±2.6 cm), or weight (61.5±2.2 versus 69.3±3.2 kg).
Phenylephrine infusion produced significant (P<0.001), dose-related vasoconstriction during both phases (Figure 1). During the luteal phase, the dose-response curve was shifted significantly (P<0.05) in the more-sensitive direction. There were no significant differences between black and white women (all P>0.8). Clonidine infusion produced significant (P<0.05) changes in finger blood flow. In white women, there was significantly (P<0.006) less vasoconstriction during the luteal phase compared with during the follicular phase (Figure 2A). In black women, the data for the 2 phases did not differ significantly (P>0.9) (Figure 2B), nor did they differ from follicular-phase data for the white women (P>0.6).
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Diastolic blood pressure was significantly higher in black than in white women and during both menstrual cycle phases (Table). Systolic blood pressure was significantly higher in black than in white women. There were no significant effects for heart rate or for baseline levels of finger blood flow. There were no significant changes in blood pressure or heart rate during either session.
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Discussion |
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In the present investigation, black and white women had significantly greater
1-adrenergic
vasoconstriction during the luteal phase than during the follicular
phase. This effect cannot be attributed to changes in plasma
norepinephrine levels, which did not vary across the
menstrual cycle, or to elevations in blood pressure, because
diastolic blood pressure was actually lower in the luteal
phase. Because plasma levels of estrogen and progesterone were higher
in every woman during the luteal phase, it is possible that the
elevation of 1 or both hormones sensitizes
1-adrenergic responsiveness during this
phase.
In contrast, white women had significantly increased
2-adrenergic vasoconstriction during the
follicular phase, whereas vasoconstriction did not change with the
menstrual cycle in black women. Again, these results cannot be
explained by changes in blood pressure, which did not vary in the same
pattern, or levels of plasma norepinephrine. Thus, it is
possible that 1- and
2-adrenergic receptors are regulated in
opposite directions during the human menstrual cycle, at least in white
women. This is consistent with the results of some, but not
all, studies in showing increased 1- and
decreased 2-adrenoceptor numbers with
menstrual cycle and pregnancy elevation of estrogen and progesterone
levels.14 15 16 17
We did not find menstrual cycle modulation of
2-adrenergic responsiveness in black women.
This is consistent with the results of Mills et
al,5 who did not find menstrual cycle variation of
platelet 2-receptors in black women. There
is evidence from several studies in humans that
2-adrenoceptors are more prominent than
1-adrenoceptors in human resistance
arteries.18 19 20 If this is true, then the lack of
luteal-phase reduction in 2-adrenergic
vasoconstriction in the black women might contribute to their increased
blood pressures in the present study and the increased pressor
responsiveness found in other investigations.4 However,
these hypotheses must be tested in future work.
The results of the present study do not entirely agree with those
of our previous investigation.1 In that study, we found
significant, dose-related vasoconstriction in response to clonidine and
phenylephrine in men but not in women. If elevated sex
hormone levels reduce 2-adrenergic
responsiveness, our results can be partially explained, because there
were no black women in the previous study. In addition, elevated
sympathetic activation has been shown to reduce
2-adrenergic responsiveness. In another
study,21 we reduced peripheral sympathetic
activation in men through indirect heating and found increased
2-adrenergic responsiveness compared with men
who did not receive indirect heating.1
In the case of phenylephrine, we found increased vasoconstriction during menstrual cycle elevation of sex hormones in the present study. In our previous study,1 women participated without regard to cycle phase, and different women received different drug infusions. If more women who received phenylephrine participated during the follicular phase in that study, the results might be explained.
In summary, in the present study we found elevated
1-adrenergic vasoconstriction in black and
white women during menstrual cycle elevation of estrogen and
progesterone levels. In contrast, 2-adrenergic
responses were elevated only during low hormone levels in white women
but did not vary with the menstrual cycle in black women. Further
research is needed to elucidate the mechanisms underlying these
effects.
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Acknowledgments |
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This work was supported by grant HL-30604 from the National Heart, Lung, and Blood Institute. We thank Janice Rodriguez, BS, for performing the recordings and the norepinephrine assays, Dr Phillip Furspan for his comments on the manuscript, and Jeri Pajor for typing the manuscript.
Received July 28, 1999; first decision August 30, 1999; accepted November 8, 1999.
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