Ethanol-Induced Hypertension Involves
Impairment of Baroreceptors
ABDEL A. ABDEL-RAHMAN AND WALLACE R.
WOOLES
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SUMMARY We studied the effect of 12 weeks of ethanol feeding on arterial blood pressure and
baroreceptor reflex control of heart rate in Sprague-Dawley and Wistar rats. Baroreceptor reflex
sensitivity and pressor responsiveness were evaluated by evoking graded rises in mean arterial
pressure with increasing doses of phenylephrine and angiotensin II. After 12 weeks of ethanol feeding
there was a modest increase in mean arterial pressure with no change in heart rate in both strains.
When angiotensin II or phenylephrine was used as the pressor agent, baroreceptor reflex curves
(relationships between changes in mean arterial pressure and heart rate) of Wistar rats were shifted
upward and had a markedly reduced slope compared with those of control rats, suggesting that
impairment of baroreceptor reflex control of heart rate had occurred. This effect was less evident in
the Sprague-Dawley rats. Ethanol-fed rats had a higher sympathetic activity, since /3-blockade with
propranolol decreased heart rate to a greater degree than that seen in control rats. The pressor
response curve of phenylephrine was shifted to the right in control rats challenged with ethanol (0.5
g/kg), implying the presence of a-blockade. This shift was not present in ethanol-fed rats, showing that
tolerance had developed to this effect of ethanol. These findings show that attenuation of baroreceptor
reflex function is associated with ethanol-induced hypertension but do not establish whether this is a
cause or an effect of the developed hypertension. (Hypertension 10: 67-73, 1987)
• ethanoi • hypertension • baroreceptors • heart rate
phenylephrine • cardiac /3-blockade • sympathetic activity
KEY WORDS
N
was associated with a significant increase in plasma
norepinephrine,7 which suggested the possibility that
sympathetic nervous system activity may have been
enhanced by ethanol feeding.
On the other hand, the baroreceptor reflex control of
heart rate (HR) is known to be depressed in human 8 ' 9
and experimental 10 " hypertension. Impairment of
baroreceptors has been shown to precede the development of hypertension in the Dahl salt-sensitive rat,10' "
which suggests that it may be a primary factor in the
development of hypertension in that model. We have
previously shown that Sprague-Dawley rats maintained on ethanol for 4 weeks did not become hypertensive, even though there was a marked inhibition of
baroreceptor reflex activity.12 Therefore, if baroreceptor impairment is a primary factor in ethanol-induced
hypertension, then a longer period of ethanol feeding
should result in elevated arterial pressure.
In this study we report the effect of 12 weeks of
ethanol feeding on blood pressure, HR, baroreceptor
reflex control of HR, and pressor responsiveness to
phenylephrine (PE) and angiotensin II (ANG II). We
used both Sprague-Dawley and Wistar rats to compare
our results with those of Chan et al. 6 ' 7 and to determine
if the effect of ethanol would be greater in the latter
UMEROUS epidemiological studies have established that there is a positive correlation
between the duration and extent of ethanol
intake and the development of hypertension.1"3 Recent
controlled clinical trials have shown that ethanol acts
as a pressor agent, even in hypertensive patients,4 and
that when ethanol intake ceases blood pressure returns
to predrinking levels. 45 However, whether ethanol is
the causative agent cannot be determined from such
studies. Similarly, the mechanism (or mechanisms) by
which ethanol intake elevates blood pressure is unknown, probably because of the absence of a satisfactory animal model.
Recently, Chan and Sutter and colleagues 6 ' 7 developed a rat model for ethanol-induced hypertension in
which they showed that ethanol intake for 4 to 12
weeks caused a moderate rise in blood pressure. After
12 weeks of ethanol feeding, elevated blood pressure
From the Department of Pharmacology, School of Medicine,
East Carolina University, Greenville, North Carolina.
Address for reprints: Dr. Abdel A. Abdel-Rahman, Department
of Pharmacology, School of Medicine, East Carolina University,
Greenville, NC 27858-4354.
Received September 8, 1986; accepted January 8, 1987.
67
68
HYPERTENSION
strain. We also studied the effect of sequential cardiac
blockade with propranolol and atropine to evaluate the
possibility 1) that a higher sympathetic drive to the
heart might be present but masked by a direct negative
chronotropic effect of ethanol, 2) that the HR responses secondary to the injection of pressor agents
were reflex in origin, and 3) that nonreflex chronotropic changes, if any, were not influenced by ethanol.
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Materials and Methods
Male Sprague-Dawley and Wistar rats (Charles River Breeding Laboratories, Research Triangle Park,
NC, USA) weighing 180 to 220 g initially were randomly allocated to either the ethanol-fed or control
group. The method of ethanol feeding was that described by Chan and Sutter* in which rats received 5%
ethanol (vol/vol) in the drinking water for the first
week, 10% for the next 2 weeks, and 20% from Weeks
4 to 12. The control group was fed tap water ad libitum, and all rats had constant access to Purina Lab
Chow (St. Louis, MO, USA). Daily food and water
consumption were recorded, but animals were not
pair-fed. On this regimen average daily ethanol consumption was 10 to 11 g/kg. Blood pressure was determined by the tail-cuff method at Weeks 0 , 2 , and 6 in
Sprague-Dawley rats and Weeks 0, 2, and 8 in Wistar
rats. Blood pressure was measured by direct arterial
cannulation at Week 12. Blood ethanol concentration
was determined by the method of Bonnichsen and
Lundgren13 from arterial blood samples taken from
anesthetized rats at the time of the experiment. All experiments were conducted between 0730 and 1130 to
minimize the diurnal variation in ethanol metabolism.
Measurement of Baroreceptor Reflex Sensitivity
The details of this technique have been published
elsewhere.12 Baroreceptor reflex sensitivity (BRS) was
assessed as the gain in baroreceptor reflex function
according to the method of Komer et a l . u Graded
increases in arterial pressure were produced by bolus
injections of PE or ANG II. The peak change in mean
arterial pressure (MAP) and the associated reflex bradycardia were used to calculate BRS using the ratio
AHR/AMAP (expressed as beats/min • mm Hg' 1 )Since we had previously found that this ratio was independent of the dose of the pressor agent used,12 the
average values of all AHR/AMAP measurements obtained both before and after administration of saline or
ethanol were used as a measure of BRS.
At Week 12 of ethanol feeding, control and ethanolfed rats of both strains were subdivided into two
groups according to the pressor agent used and the
subsequent treatment. BRS of Wistar rats was assessed
by injection of PE, in doses of 0.25, 0.5, 1, 2, and 4
/xg/kg, and of ANG II, in doses of 2.5, 5, 10, 20, 40,
and 80 ng/kg. Immediately after the assessment of
BRS, Wistar rats (ethanol-fed and their controls) were
challenged by a short-term intravenous dose of ethanol
(0.5 g/kg) to determine if tolerance had developed to
the effect of ethanol. BRS was assessed in Sprague-
VOL 10, No
1, JULY
1987
Dawley rats by the same procedure. However, instead
of receiving a short-term dose of ethanol, SpragueDawley rats were treated with propranolol (1 mg/kg)
and 15 minutes later with atropine (1 mg/kg). These
doses have been reported to produce complete blockade of )3-adrenergic receptors and muscarinic receptors
in rats.15
Each rat in the control or ethanol-fed groups in both
strains served as its own control, and the PE or ANG II
dose-response curves were repeated after the shortterm injection of ethanol in the Wistar rats or after /3adrenergic and muscarinic blockade in the SpragueDawley rats. Either pressor agent was administered at
5-minute intervals as this had previously been found
adequate for HR and blood pressure to return to preinjection baseline values.12 Therefore, all baseline, or
resting, MAP and HR values are presented as the mean
of all determinations of both variables over the control
(pretreatment) period. MAP was calculated as diastolic blood pressure plus one third pulse pressure.
Dose-response curves were constructed by plotting
the peak rise in blood pressure evoked by the different
doses of each of the pressor agents and were obtained
under the following conditions: 1) long-term exposure
to ethanol, and 2) short-term administration of ethanol
to control and ethanol-fed rats. Peak rises in MAP
evoked by either pressor agent together with the corresponding nadir changes in HR were used to construct
AMAP-AHR curves for either pressor agent before and
after the short-term treatments. The slope of the linear
regression line relating decreases in HR to increases in
MAP was taken as a measure of the gain in BRS. 16
Statistical Analyses
Values presented are the means ± SE. Student's t
test was used in the analysis of paired and unpaired
means, with the level of significance chosen at p less
than 0.05. The stimulus response curves were analyzed by the one-way analysis of variance, and a test
for the equality of elevations was used to determine
whether the regression lines were identical.
Results
Both Wistar and Sprague-Dawley rats consumed a
comparable amount of ethanol, 10 to 11 g/kg/day,
which resulted in a similar blood ethanol concentration
on the morning of the experiment (0.53 ± 0.04 in Wistar rats and 0.49 ± 0.05 mg/ml in Sprague-Dawley
rats). Ethanol was not detectable in the blood of
control rats of either strain. The average daily food
intake was markedly reduced in ethanol-fed rats of
both strains, which was manifested as a significantly
(p < 0.001) lower body weight at the end of the experiment. The weight difference was more prominent in
Sprague-Dawley rats (420 ± 1 1 g in Wistar ethanolfed rats vs 487 ± 12 g in the appropriate controls and
433 ± 14 g in Sprague-Dawley ethanol-fed rats vs
547 ± 17 g in the control group). The starting body
weights of the treatment and control groups of either
strain were very similar at Week 0 (Table 1).
ETHANOL-INDUCED HYPERTENSION AND BARORECEVTORS/Abdel-Rahman and Wooles
69
TABLE 1. Measurements Taken at Weeks 0 and 12 on Ethanol-Treated and Control Rats
Variable
Wistar rats
Number
Weight (g)
Systolic blood pressure (mm Hg)
Estimated ethanol consumption (g/kg/day)
Blood ethanol concentration (mg/ml)
WeekO
Control
Week 12
Ethanol-treated
WeekO
Week 12
10
220 ±3.9
117±3.9
0
0
13
487+12
131 ±5.5
0
0
420 ±11*
149±4.8t
10.6
0.53 + 0.04
215 + 2.7
117 + 4.0
0
0
Sprague-Dawley rats
Number
Weight (g)
Systolic blood pressure (mm Hg)
Estimated ethanol consumption (g/kg/day)
Blood ethanol concentration (mg/ml)
11
10
547 ±17
195 ±2.7
187+1.9
433 +14*
132 + 4.7
105 + 2.9
106±2.6
147±4.7t
0
10.4
0
0
0
0.49 ±0.05
0
0
Values are means + SEM except for daily ethanol consumption; these values were estimates and not measurements.
Systolic blood pressure was measured by the tail-cuff method at Week 0 in all rats and by the direct method in anesthetized
rats at Week 12.
*p< 0.001, tp<0.05, compared with Week 12 control values.
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Blood Pressure and Heart Rate
Baseline systolic blood pressure, measured by the
tail-cuff method, was similar in all rats at the beginning of the experiment (Week 0; see Table 1). Over the
12-week experimental period systolic pressure of control rats of both strains increased, but the increase in
systolic pressure produced by ethanol was significantly greater than the control levels in both groups "(Figure
1). Thirteen Wistar rats received ethanol, and three of
these did not show any increase in their blood pressure.
Similarly, 10 Sprague-Dawley rats were fed ethanol,
and three did not manifest any increase in blood pressure. In fact, after blood pressure began to be elevated
three ethanol-fed rats in each strain consistently remained normotensive. The nonresponsive rats of either strain had similar blood ethanol concentrations
and body weight values after 12 weeks of ethanol feeding as compared with those ofresponsiverats. However, the values presented in Figure 1 and Table 1 include
all rats initially placed on the ethanol diet. The 12week values were obtained with the rats under anesthesia and were direct measurements of systolic arterial
pressure made before other physiological measurements. Figure 2 shows that the MAPs of ethanol-fed
Wistar and Sprague-Dawley rats after 12 weeks were
significantly (p < 0.02 andp < 0.001) higher than their
respective control values. However, as also shown in
Figure 2, HR of both strains was not altered by ethanol
feeding.
Baroreceptor Reflex Control of Heart Rate
BRS was attenuated by long-term ethanol feeding
particularly, in Wistar rats (Table 2). When BRS was
evaluated by using PE as a pressor agent there was a
61% inhibition, and when ANG II was the pressor
agent there was a 59% inhibition (see Table 2). As
shown in Figure 3, the linerelatingreflexdecreases in
HR to evoked increments in MAP is shifted upward in
ethanol-fed rats, indicating that for a comparable rise
1M
z Control ( 1 0 )
• Ethanol ( 1 3 )
140
130
110
0
1
4
•
B
10
6
8
10
Sprague-Dawley
•
Ethanol ( 1 1 )
100
BO
0
2
4
12
Time (weeks)
FIGURE 1. Changes in systolic blood pressure over a 12-week
ethanolfeeding period in Wistar rats and Sprague-Dawley rats.
Systolic blood pressure was measured by the tail-cuff method
except at Week 12, where it was measured directly while the rats
were under chloralose anesthesia. Values are means ± SEM,
and the number of rats in each group of both strains is shown in
parentheses. Blood pressure was significantly higher at Week 6
in Sprague-Dawley ethanol-fed rats (p <0.05, indicated by asterisk); at Week 8 in Wistar ethanol-fed rats (p < 0.001, indicated by double asterisks); and at Week 12 (p <0.05, indicated by
asterisk) in both strains as compared with the appropriate
control.
HYPERTENSION
70
140
*
:.5 too
Q Control R»t»
0 Ethanol Rats
(10)
(13)
Wtetar
r-L,
T
(10)
(11)
Sprague-Oawley
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FIGURE 2. £/fec/ of 12 weeks of ethanol feeding on MAP and
HR of Wistar and Sprague-Dawley rats. The values presented
were obtained at Week 12 and show that MAP was significantly
(p<0.05, indicated by asterisk) elevated in ethanol-fed rats of
either strain as compared with the respective controls; HR was
slightly lower in ethanol-fed rats. Values are means ± SEM,
and the number of rats in each group is shown in parentheses.
in blood pressure there was a significantly smaller (p <
0.05) decrease in HR. On the other hand, in SpragueDawley rats no significant change in BRS was observed in ethanol-fed rats (Figure 4; see Table 2).
The effect of a short-term dose of ethanol (0.5 g/kg)
on AMAP-AHR relationship in control and chronically
ethanol-fed Wistar rats, evaluated by the effect of PE
and ANGII, is shown in Figures 5 and 6. There was no
change in this relationship when PE was used as the
pressor agent in either the control or ethanol-fed
groups (see Figure 5). When ANG II was used as the
pressor agent there was a slight upward shift in this line
in Wistar control rats, but no change occurred in ethanol-fed animals challenged with a short-term ethanol
dose (see Figure 6).
TABLE 2.
VOL 10, No
1, JULY
Cardiac Autonomic Blockade
Cardiac autonomic blockade experiments were conducted in chronically ethanol-fed Sprague-Dawley rats
and appropriate controls. As shown in Figure 7A, the
MAP of ethanol-fed rats was approximately 20 mm Hg
higher than the control value. Propranolol produced
the expected drop in MAP; however, this propranololevoked decrease in MAP, even though significant
(p<0.05) in both groups, was much greater in the
ethanol-fed rats (22 vs 11%) and resulted in comparable MAP values in both groups (97 ± 4 vs 94 ± 3.2
mm Hg; see Figure 7A). When atropine was added
after propranolol, blood pressure of the control group
returned to control values whereas the blood pressure
of ethanol-fed rats did not return to predrug levels. As
shown in Figure 7B, baseline HR was comparable in
control and ethanol-fed Sprague-Dawley rats. However, after propranolol administration, the HR decreased
10% in the control group, whereas there was an 18%
decrease in the chronically ethanol-fed group that resulted in significantly (p<0.05) lower HR values in
ethanol-fed rats as compared with their controls
(302 ±9.1 vs 332.9 ± 9 beats/min; see Figure 7B).
Additive parasympathetic blockade by atropine restored HR of the control group to predrug levels, and a
similar but lesser effect was observed in the chronically ethanol-fed group (see Figure 7).
As shown in Figure 4, cardiac autonomic blockade
by propranolol and atropine abolished the cardiacslowing response to evoked increments in MAP produced by both PE and ANG II in control and ethanolfed rats. These data clearly show that the bradycardia
observed before blockade was mainly reflex in origin,
the doses of each of the pressor agents used had negligible nonreflex chronotropic effects, and more importantly, long-term ethanol feeding was without effect on
nonreflex chronotropy.
Pressor Responsiveness
Long-term ethanol-feeding had no effect on pressor
responsiveness in either strain of rats since the PE
Blood Pressure, Heart Kate, and Baroreceptor Reflex Sensitivity Values
Phenylephrine
ANG 11[
Control
Ethanol
Control
Ethanol
Wistar rats
Number
MAP (mm Hg)
HR (beats/min)
AHR/AMAP(beats/min-mm Hg"')
5
119.4±3.0
406.2+10.2
-1.I8±O.I9
6
133.8 + 6.1
370.6± 15.6
-0.46±0.26t
101.8±8.0
362.0±14.7
-1.33±0.31
130.8 + 6.0*
380 9 ± 16.3
-0.54 + 0.151:
Sprague-Dawley rats
Number
MAP (mm Hg)
HR (beats/min)
AHR/AMAP (beats/min-mm Hg" 1 )
6
110.3±2.6
375.0± 16.3
— 1.23 ± 0.12
4
137.8±5.4§
388.3 + 20.9
-1.08±0.35
106.2 ±1.7
369.4±12.0
-1.78±0.29
121.8±1.9||
340.0+16.4
-1.12±0.16
Van able
1987
Baroreceptor reflex sensitivity was obtained by averaging four to five measurements made by evoking MAP rises
by graded doses of the pressor agents. Data are means ± SEM and represent the baseline values for the subgroups that
were subsequently treated with short-term ethanol administration (see Figures 5 and 6) or propranolol and atropine (see
Figure 4).
*p<0.002, t p < 0 . 0 5 , $p<0.05, §p<0.01, | | p < 0 . 0 0 1 , compared with control values.
ETHANOL-INDUCED HYPERTENSION AND BARORECEVTORS/Abdel-Rahman and Wooles
A Mean ArteriaJ Pressure
(mmHg)
0
20
40
80
o
0
-20
-20
^ \
-40
(A)
-60
Jj
-80
"3 -'00
PE
71
A Mean Arterial Pressure
(mmHg)
0
20
40
60
80
-40
-60
\
o Control (5)
\
•ETOH (6)
\J,
-120
-120
(D
I
20
90
80
X,
°
8
-20
-40
-40
-80
-60
-80
-80
-100
-100
-120
<
-20
(B)
ETOH Rati(8)
• Pr«a Poit-ETOH (0.5 fl/KoJ
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-120
FIGURE 3. HR response to evoked increments in MAP by
phenylephrine (PE; A) or ANGII (All; B) in Wistar ethanol-fed
rats and their controls. The upward shift of &HR-&MAP curve
of ethanol-fed rats was significantly different when compared
with the control curve; the baroreceptor reflex sensitivity
(&HR/AMAP) values are presented in Table 2. Values are
means ± SEM, and values in parentheses indicate the number
of rats in each group.
o
A Mean Arterial Pressure
(mmHfl)
20
40
80
80
-20
\A
-40
(A)
-60
-80
-100
° Control Rit» (6) ^ £
"^
I ETOH R«t8 (4)
FIGURE 5. Effect of an acute dose of ethanol (0.5 g/kg i.p.) on
hMAP-bHR relationship in control rats (A) and 12-week ethanol-fed rats (B). The increments in MAP were evoked by phenylephrine. Note that acute ethanol administration had no significant effect on this relationship. Data are means ± SEM, and
the numbers in parentheses indicate the number of rats in each
group.
(Figure 8) and ANG II (data not shown) dose-pressor
response curves were similar in control and chronically
ethanol-fed rats. The short-term administration of ethanol (0.5 g/kg) produced a rightward shift of the PE
pressor-response curve (see Figure 8) but not of the
ANG E-evoked curve (data not shown) in control rats.
In contrast, in chronically ethanol-fed rats this shortterm dose of ethanol was not able to shift the PE doseresponse curve to the right (see Figure 8), indicating
that tolerance to this effect of ethanol had developed.
-120
0
20
40
-20
-40
-60
-80
-100
J Control FUts (8)
I ETOH Bin (e)
i
-120
FIGURE 4. Relationship between changes in HR and MAP in
Sprague-Dawley rats fed with ethanol for 12 weeks and their
controls. The rises in MAP were evoked by phenylephrine (A) or
ANG 11 (B) before (circles) and after (triangles) cardiac autonomic blockade with propranolol and atropine (1 mglkg each).
The HR responses to evoked rises in MAP were virtually abolished after cardiac autonomic blockade in both ethanol-fed rats
and their controls. Values are means ± SEM, and the number
of rats in each group is shown in parentheses.
Discussion
The increase in blood pressure after ethanol feeding
began within 4 to 6 weeks and continued over the
remaining 6 weeks of the study. This finding is in
agreement with that of Chan et al. ,7 who reported that
blood pressure elevation began 4 weeks after ethanol
feeding and continued to increase up to 12 weeks. In
both studies the method of feeding ethanol was the
same. At the end of 12 weeks in our study no correlation (r = — 0.03) was observed between the concentration of blood ethanol and the level of hypertension. In
fact, in either strain, the rats that did not manifest
elevated blood pressure had blood ethanol levels comparable to those that did.
The present study, which establishes that long-term
ethanol feeding produces hypertension associated with
an impairment of baroreceptor reflex control of HR, is
an extension of a previous study,12 in which we showed
that ethanol feeding for 4 weeks produced a significant
72
HYPERTENSION
VOL
10,
No
1,
JULY
1987
A Mean Arterial Pressure
(mmHg)
0
20
40
SO
SO
o Control Rata (8)
• ETOH Fed Hlt« (5)
Control Rata (5)
-120
Control Rata
o Before
After 0.8/kg ETOH
oPre» Poat-ETOH
80
20
*tAY ^
y i ETOH Fed Rata
• Before
* A t ) B f O-S^O ETOH
0 28 0.5 1 2 4
Phenyiephrlne
ETOH Rata (7)
(ug/kg)
»Pr»a Poat-ETOH (0.5 oAfl)
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FIGURE 6. The relationship between changes in HR and MAP
is shown as in Figure 5 except that increments in MAP were
evoked by ANG II. Note that the HR response was slightly
attenuated by short-term ethanol administration in the control
group.
140
B°BaaaJ
P- Propranolol
- A-Atropine
(A)
100
SO
(B)
-p<0.05-
380
i
360
340
320
300
280
B
P P+A
Control
FIGURE 8. Phenylephrine dose-pressor response curve obtained in chronically (12 weeks) ethanol-fed rats and their controls (top panel), in control rats (middle panel), and in ethanolfed rats (lower panel) before and after short-term dose of
ethanol (0.5 glkg). Note that acute ethanol administration shifted the phenylephrine dose-pressor response curve to the right in
the control rats but had no effect in ethanol-fed rats. Also, the
pressor responsiveness was similar in chronically ethanol-fed
rats and their controls. Values are means ± SEM, and the
number of rats is shown in parentheses.
a
P P+A
Ethanot
FIGURE 7. Effect of successive administration of propranolol
(1 mg/kg) and atropine (1 mg/kg) on basal MAP (A) and HR (B)
values of 12-week ethanol-fed rats (n = 10) and their controls
(n = 11). Values are means ± SEM. Asterisk indicates
(p<0.05) significant difference compared with pretreatment
values. Note that the HR value of the ethanol-fed rats was
significantly smaller as compared with the control value after
propranolol administration.
attenuation of BRS even though the animals remained
normotensive. It is tempting to speculate that impairment of baroreceptor reflex control of HR is an important determinant in the development of ethanol-induced hypertension. However, neither our previous12
nor the present study establishes a cause-and-effect
relationship between ethanol-induced impairment of
baroreceptor reflex control of HR and the development
of hypertension; whether or not such a relationship
exists is under investigation.
In their most recent study, Chan et al. 7 suggested
that the responses to long-term ethanol consumption
may vary according to the strain of rat. For that reason
we used both Wistar and Sprague-Dawley rats. Our
findings show that a similar degree of hypertension
was produced by long-term ethanol feeding in both
strains. However, the type of alteration of baroreceptor
reflex control of HR was different in each strain. In
Wistar rats there was a definite impairment of BRS at
the end of 12 weeks of ethanol feeding, whereas in
Sprague-Dawley rats there was resetting of baroreceptors. This conclusion is based on the findings that BRS
was significantly depressed in ethanol-fed Wistar rats
(see Table 2 and Figure 4) as compared with the appropriate control. However, the finding that baseline
MAP was significantly higher in ethanol-fed SpragueDawley rats as compared with their controls, while the
baseline HR values were comparable in both groups
suggests a resetting of baroreceptors in this strain following 12 weeks of ethanol feeding. It is possible that
Wistar rats are more sensitive to the effects of ethanol.
Since ethanol intake was comparable in both strains
and since the degree of elevation of arterial pressure
was comparable, our findings show that the development of ethanol-induced hypertension is independent
of strain. However, the finding that Wistar rats were
ETHANOL-INDUCED HYPERTENSION AND BARORECEPTORS/AMe/-/?a/wna/j and Wooles
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better able to maintain body weight while on a longterm ethanol diet may make this strain more desirable.
Our findings that 12 weeks of ethanol-feeding produced resetting of baroreceptor reflex control of HR in
Sprague-Dawley rats is somewhat different from our
previous finding that 4 weeks of ethanol consumption
produced a significant impairment of BRS in the absence of any change in blood pressure.12 In our previous study, after 4 weeks of ethanol feeding, blood
pressure was not changed but HR was decreased. In
this study, after 12 weeks of ethanol, blood pressure
was elevated while HR was comparable to control values. These differences plus the longer duration of ethanol feeding may explain why ethanol-induced impairment of baroreceptor reflex control of HR was noted
earlier12 and not in this study.
Although our data do not establish a mechanism by
which long-term ethanol consumption produces hypertension, it is reasonable to assume that an attenuated
baroreceptor reflex mechanism would cause an enhanced sympathetic activity. This is supported by the
findings that there is an inverse correlation between
BRS and plasma norepinephrine concentration8 and a
positive correlation between plasma norepinephrine
levels and sympathetic neural activity.17 Our data
showing that /3-blockade produced a greater reduction
in HR in ethanol-fed rats than in controls and the findings of Chan et al. 7 that plasma norepinephrine levels
were increased after 12 weeks of ethanol support the
view that long-term ethanol administration is associated with enhanced sympathetic activity. Whether or not
this increased activity is involved in a cause-and-effect
relationship has not been established.
Cardiac autonomic blockade with propranolol and
atropine completely prevented the decreases in HR
secondary to evoked increments in blood pressure induced by PE or ANG II (see Figure 4). This finding
shows that the bradycardia was reflex in origin and
further shows that neither pressor agent, in the doses
used, had any significant direct chronotropic effect.
These data are consistent with the reports of Coleman15
and Gordon et al. ,10 who obtained similar results with
PE and ANG II. This finding also eliminated the possibility that long-term ethanol feeding might have altered the nonreflex effects of either pressor agent in
any way that could have contributed to the observed
alteration of baroreceptor reflex control of HR.
Another factor that should be considered is the areceptor blocking effect of ethanol. This effect should
prevent or at least delay the development of hypertension. We have previously shown12'18 that short-term
administration of ethanol shifts the dose-response
curve of PE, but not ANG II, to the right, suggesting
an a-receptor blocking effect. After 4 weeks of ethanol
feeding this effect was much less evident than in the
short-term situation,12 suggesting that partial tolerance
had developed to this effect. In the present study we
found that this effect was completely lost after 12
weeks of ethanol feeding, suggesting that complete
tolerance had developed. These data show that the areceptor blocking activity of ethanol is inversely relat-
73
ed to the duration of ethanol treatment and that, when
present, it should have a negative effect on the development of ethanol-induced hypertension.
The results presented here and in our previous
study12 strongly suggest that impairment of arterial
baroreceptors may play a contributory role in the
development of ethanol-induced hypertension. However, these conclusions apply to rats; in humans,
impaired BRS associated with long-term alcohol consumption and elevated blood pressure remains to be
demonstrated.
References
1. Arkwright PD, Beilin LJ, Rouse IL, Armstrong BK, Vandongen R. Effects of alcohol use and other aspects of lifestyle on
blood pressure levels and prevalence of hypertension in working populations. Circulation 1982;66:60-66
2. Klatsky AL, Friedman GD, Siegelaub AB, Gerald MJ. Alcohol consumption and blood pressure: Kaiser-Permanente multiphasic health examination data. N Engl J Med 1977;296:
1194-1200
3. Friedman GD, Klatsky AL, Siegelaub AB. Alcohol, tobacco
and hypertension. Hypertension 1982:4(suppl HI):in-143-III150
4. Potter JF, Beevers F. Pressor effect of alcohol in hypertension.
Lancet 1984;1:119-122
5. Puddey IB, Beilin LJ, Vandongen R, Rouse IL, Rogers P.
Evidence for a direct effect of alcohol consumption on blood
pressure in normotensive men: a randomized controlled trial.
Hypertension 1985;7:707-713
6. Chan TCK, Sutter MC. The effects of chronic ethanol consumption on cardiac function in rats. Can J Physiol Pharmacol
1982;60:777-782
7. Chan TCK, Wall RA, Sutter MC. Chronic ethanol consumption, stress, and hypertension. Hypertension 1985;7:519-524
8. Goldstein DS. Arterial baroreflex sensitivity, plasma catecholamines, and pressor responsiveness in essential hypertension.
Circulation 1983;68:234-240
9. Bristow SD, Honour AS, Pickering GW, Sleight P, Smyth HS.
Diminished baroreflex sensitivity in high blood pressure. Circulation 1969;39:48-54
10. Gordon FJ, Matsuguchi H, Mark AL. Abnormal baroreflex
control of heart rate in prehypertensive and hypertensive Dahl
genetically salt-sensitive rats. Hypertension 1981;3(suppl I):I135-1-141
11. Gordon FJ, Mark AL. Impaired baroreflex control of vascular
resistance in prehypertensive Dahl S rats. Am J Physiol
1983;245:H210-H217
12. Abdel-Rahman A-RA, Dar MS, Wooles WR. Effect of chronic
ethanol administration on arterial baroreceptor function and
pressor and depressor responsiveness in rats. J Pharmacol Exp
Ther 1985;232:194-201
13. Bonnichsen RK, Lundgren G. Comparison of the ADH and the
Widmark procedures in forensic chemistry for determining
alcohol. Acta Pharmacol Toxicol (Copenh) 1957; 13:256-266
14. Komer PJ, Shaw J, West MJ, Oliver JR. Central nervous
system control of baroreceptor reflexes in the rabbit. Circ Res
1972;31:639-652
15. Coleman TG. Arterial baroreflex control of heart rate in the
conscious rat. Am J Physiol 1980;238:H515-H520
16. Guo GB, Abboud FM. Angiotensin U attenuates baroreflex
control of heart rate and sympathetic activity. Am J Physiol
1984;246:H80-H89
17. Goldstein DS, McCarty R, Polinsky RJ, Kopin IJ. Relationship between plasma norepinephrine and sympathetic neural
activity. Hypertension 1983;5:552-559
18. Abdel-Rahman A-RA, lams SG, Wooles WR. Pressor effect
for ethanol and absence of its a-blocking activity in the SHR
[Abstract]. Fed Proc 1986;45:195
Ethanol-induced hypertension involves impairment of baroreceptors.
A A Abdel-Rahman and W R Wooles
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Hypertension. 1987;10:67-73
doi: 10.1161/01.HYP.10.1.67
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