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CARDIOVASCULAR
Department of Pharmacology, School of Medicine, East Carolina University, Greenville, North Carolina
Received December 18, 2002; accepted March 14, 2003.
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Abstract |
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 Top Abstract Materials and MethodsResultsDiscussionReferences |
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2-adrenergic
(Timmermans and van Zwieten,
1982
) and imidazoline
(Tibirica et al., 1991)
receptors in the brainstem, resulting in suppression of central sympathetic
outflow. Sympathoinhibition has also been implicated in the clonidine-induced
reductions in blood pressure and heart rate variability as determined by
frequency- and time-domain analyses
(Grichois et al., 1990;
Elghozi et al., 1991;
Janssen et al., 1991;
Tulen et al., 1993). The
reduction in hemodynamic variability by clonidine is important at least in two
clinical settings. First, the long-term reduction in blood pressure
variability by clonidine may contribute to the regression of ventricular and
vascular hypertrophy in hypertensive patients
(Timio et al., 1987;
Strauer, 1988). Second, by
reducing blood pressure and heart rate variability, clonidine promotes
hemodynamic stability in patients undergoing surgery and reduces anesthetic
requirements (Nishikawa et al.,
1991). It is noteworthy that 1) blood pressure and heart rate
variability is an indirect measure of cardiovascular autonomic balance and 2)
oscillation abnormalities in these hemodynamic variables are associated with
life-threatening cardiovascular events such as sudden stroke, ventricular
arrhythmias and myocardial infarction
(Stein et al., 1994).
Regular use of ethanol is associated with inadequate control of blood
pressure in treated hypertensive patients
(Volicer et al., 1978;
Puddey et al., 1987). This
clinically important phenomenon has been demonstrated in experimental animals
in our previous reports, which showed that ethanol, administered acutely or
chronically, counteracts the hypotensive effect of clonidine and related
antihypertensive agents (Abdel-Rahman et
al., 1992; Abdel-Rahman,
1994; El-Mas et al.,
1994b). In contrast, peripherally mediated hypotensive responses
elicited by hydralazine, nitroprusside, or hexamethonium are not influenced by
ethanol (Abdel-Rahman et al.,
1992; El-Mas and Abdel-Rahman,
1999). Central sympathetic tone seems to play a critical role in
the ethanol-clonidine hemodynamic interaction because the counteraction of
clonidine hypotension by ethanol is associated with remarkable increases in
plasma norepinephrine levels (El-Mas et
al., 1994b; El-Mas and
Abdel-Rahman, 1999) and in norepinephrine electrochemical signal
in the rostral ventrolateral medulla (Mao
and Abdel-Rahman, 1998). It is noteworthy, however, that
peripheral hemodynamic effects of ethanol may influence its interaction with
antihypertensive drugs. Moderate doses of ethanol dilate cutaneous blood
vessels partly through a direct action on these vessels
(Turlapaty et al., 1979).
Although ethanol counteraction of clonidine-evoked hypotension has been
documented (Abdel-Rahman, 1994;
El-Mas et al., 1994b), whether
ethanol adversely affects the beneficial actions of clonidine on blood
pressure and heart rate oscillations has not been investigated. This
possibility was investigated in the present study by evaluating the effect of
chronic ethanol feeding on clonidine-evoked acute changes in blood pressure,
heart rate, and their variability in radiotelemetered SHRs. The unique aspects
of the current study are as follows: 1) using radiotelemetry for hemodynamic
measurement, which permits continuous and simultaneous measurements of blood
pressure and heart rate under minimal stressful conditions
(El-Mas and Abdel-Rahman,
2000; Rekik et al.,
2002); 2) studying the effect of two different concentrations of
ethanol [2.5 or 5% (w/v)] on the hemodynamic actions of clonidine to establish
a concentration-effect relationship; and 3) ethanol was given in liquid diet
and the rats (ethanol or control) were pair fed to ensure similar fluid and
nutrient intakes as in our previous studies
(El-Mas and Abdel-Rahman,
2000; Rekik et al.,
2002). The achievement of a similar fluid intake was important
because of its impact on hemodynamics
(Bouby et al., 1990). It is
worth mentioning that the doses of ethanol used in the present study have been
shown in our previous studies (Rekik et
al., 2002) to produce blood ethanol concentrations comparable with
those attained in humans after consumption of moderate to intoxicating amounts
of ethanol (Potter and Beevers,
1984; Abdel-Rahman et al.,
1987).
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Ethanol Feeding. Three groups of SHRs matched for body weight were
used in the present study. Two groups were provided a regular Lieber-DeCarli
liquid diet (Lieber and DeCarli,
1982) containing 2.5 or 5% (w/v) ethanol (18 and 36% of total
caloric intake, respectively; n = 5 each) as described in our
previous studies (El-Mas and Abdel-Rahman,
2000; Rekik et al.,
2002). The third group of rats (controls; n = 4) was pair
fed and received isocaloric amount of dextrin/maltose (89.6 g/l) in place of
ethanol, which allowed similar nutrient intake and fluid consumption to that
of ethanol-fed rats. Fresh diets were prepared every other day and stored in
the refrigerator until dispensed. Rats were maintained on the ethanol or
control diet for 12 weeks.
Telemetry System. The telemetry system (Data Sciences International,
St. Paul, MN) used in this study has been described in our previous studies
(El-Mas and Abdel-Rahman,
2000; Rekik et al.,
2002). The system consists of five major components: 1)
implantable transmitter unit for measurement of blood pressure, 2) radio
receiver to receive telemetered signals, 3) ambient pressure monitor to
measure absolute atmospheric pressure, 4) a consolidation matrix to multiplex
multiple cage signals to the computer, and 5) a PC-based data acquisition
system to process signals. The implanted sensor consisted of a fluid-filled
catheter (0.7 mm in diameter and 15 cm in length; model TA11PA-C40) connected
to a highly stable low-conductance strain-gauge pressure transducer, which
measured the absolute arterial pressure relative to a vacuum, and a radio
frequency transmitter. The tip of the catheter was filled with a viscous gel
that prevented blood reflux and was coated with an antithrombogenic film to
inhibit thrombus formation and maintain patency. The distal 1 cm of the
catheter consisted of a thin-walled thermoplastic membrane, whereas the
remainder of the catheter was composed of a thick-walled low-compliance
urethane. The implants (2.5 cm in length and 1.2 cm in diameter) weighed 9 g
and had a typical battery life of 6 months. Implants were gas sterilized and
provided precalibrated (relative to vacuum) by the manufacturer, and
calibrations were verified to be accurate within 3 mm Hg
(Brockway et al., 1991). A
radio receiver platform (RLA1010; Data Sciences International) connected the
radio signal to digitized input that was sent to a dedicated personal computer
(Compaq Pressario 9548). Arterial pressures were calibrated by using an input
from an ambient-pressure monitor (C11PR; Data Sciences Int.).
Transmitter Implantation. The method described in our previous
studies (El-Mas and Abdel-Rahman,
2000; Rekik et al.,
2002) was adopted. The rats were anesthetized with i.p. injection
of a mixture of ketamine (90 mg/ml; Ketaject) and xylazine (10 mg/ml;
Xyla-ject). The abdomen was opened with a midline incision (4 cm). Another
incision (1.5 cm) was made along the inner thigh to expose the femoral artery.
The abdominal wall was pierced with a large-bore syringe needle (15 gauge)
from the femoral side into the peritoneal cavity. The implant body was placed
in the peritoneal cavity and the catheter (15 cm) was passed caudally through
the syringe needle into the thigh area. A 5-cm portion of the catheter was
inserted into the femoral artery and secured in place with sutures. The
abdominal muscle was closed with nonabsorbable suture incorporating the
implant suture rib with alternating stitches. The skin (abdomen and thigh) was
closed with surgical clips. Each rat received a subcutaneous injection of the
analgesic ketorolac tromethamine (2 mg/kg; Toradol) and an intramuscular
injection of 60,000 U of penicillin G benzathine and penicillin G procaine in
an aqueous suspension (Durapen). Individual rat cages were placed on the top
of the radio receivers, and all data were collected using a computerized data
acquisition system (Dataquest ART; Data Sciences International). The system is
designed to cycle from animal to animal. Transmitter implantation was
performed 9 weeks after ethanol or control diet feeding. Rats were left for
three additional weeks before starting the experiment (i.e., clonidine or
saline administration).
Hemodynamic Effects of Clonidine. This experiment investigated the influence of chronic ethanol feeding on the acute hemodynamic effects of clonidine on blood pressure, heart rate, and their variability in conscious telemetered SHRs. After 12 weeks of ethanol feeding, SHRs received a single i.p. injection of saline (1 ml/kg) and 3 days later, clonidine (30 µg/kg). Blood pressure and heart rate were followed for 7 h after clonidine or saline administration. Waveforms of blood pressure for each rat was sampled at a rate of 500 Hz for 10 s every 10 min. Changes in MAP and heart rate evoked by clonidine from baseline values in pair-fed rats receiving liquid diet with or without ethanol [2.5 or 5% (w/v)] were averaged in 20-min blocks for analysis.
Time-Domain Analyses. Three time-domain parameters were used to
measure hemodynamic variability. The standard deviation of the mean arterial
pressure (SDMAP) was taken as a measure of blood pressure variability. Heart
rate variability was determined by computing the standard deviation of
beat-to-beat intervals (SDRR) and the root mean square of successive
beat-to-beat differences in R-R interval durations (rMSSD)
(Stein et al., 1994;
Sgoifo et al., 1997;
Visser et al., 2002). The RR
intervals were computed from the heart rate values (i.e., the reciprocal of
heart rate in milliseconds) as in our previous study
(Abdel-Rahman et al., 1987).
Our previous studies and others have shown that the time-domain indices of
blood pressure and heart rate variability correlate well with the
frequency-domain measurements (Stein et
al., 1994; Sgoifo et al.,
1997; El-Mas and Abdel-Rahman,
2000). The SDRR is comparable with the total power of the spectrum
of RR variability, which measures the overall autonomic balance of the heart.
The rMSSD is largely validated as a measure of the parasympathetic input to
the heart and, therefore, correlates with the high-frequency power of the
spectrum (Stein et al., 1994;
Sgoifo et al., 1997). Changes
in the short-term variability of MAP and heart rate were calculated by
averaging each 1-h values (i.e., six successive values measured at 10-min
intervals) of SDMAP, SDRR, and rMSSD for a total of 7 h. Baseline values of
different hemodynamic variables were taken as the average of the 3-h period
that preceded clonidine or saline administration.
Measurement of Plasma Ethanol Concentration. A blood sample was
taken from each rat at the end of the study and its ethanol content was
determined by the enzymatic method as in our previous studies (El-Mas and
Abdel-Rahman, 1999,
2000).
Drugs. Clonidine hydrochloride (Sigma-Aldrich, St. Louis, MO), Ketaject (ketamine), Xyla-ject (xylazine) (Phoenix Pharmaceuticals Inc., St Joseph, MI), Toradol (ketorolac tromethamine; Abbott Laboratories, Chicago, IL), Durapen (penicillin G benzathine and penicillin G procaine; Vedco Inc., Overland Park, KS), and ethanol (Midwest Grain Products Co., Weston, MO) were purchased from commercial vendors.
Statistical Analysis. All values are expressed as means ±
S.E.M. Comparisons of the hemodynamic effects of clonidine with the
corresponding baseline or time-course postsaline responses in control and
ethanol-fed SHRs were performed with the repeated measures two-way analysis of
variance followed by a Newman-Keuls post hoc test. This test distinguishes the
within-group responses from the between-group responses. These analyses were
performed by SAS software release 6.04 (SAS Institute Inc., Cary, NC) as in
our previous study (El-Mas and
Abdel-Rahman, 1997). Probability levels less than 0.05 were
considered significant.
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Results |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Effect of Clonidine on Blood Pressure, Heart Rate, and Their Variability. Baseline hemodynamic values in ethanol and control groups before saline administration were similar to the preclonidine values (data not shown). The time-course effects of a single dose of clonidine (30 µg/kg i.p.) or equal volume of saline on blood pressure, heart rate, and their variability in control SHRs are depicted in Tables 2 and 3. Compared with the corresponding baseline value, saline administration had no effect on MAP except for a significant increase observed at 20 min (Table 2). The heart rate was significantly increased in saline-treated rats during the last 3 h of the study (Table 2). Hemodynamic variability (SDMAP, SDRR, and rMSSD) was not affected by saline administration except for a significant increase in SDMAP at 1 h and rMSSD at 6 h (Table 3). Clonidine significantly increased MAP at 20 min that was followed by significant (P < 0.05) reductions in MAP, compared with the corresponding baseline and postsaline values (Table 2). The hypotensive effect of clonidine was observed 40 min after its administration and continued for at least 5 h (Table 2). Compared with the corresponding baseline value, a maximum hypotensive response to clonidine of –35.5 ± 1.2 mm Hg was obtained at 60 min (Table 2). The heart rate was significantly reduced by clonidine during the first 40 min compared with corresponding postsaline values and, like the saline effect, showed significant increases by the end of the study (Table 2). Clonidine elicited significant (P < 0.05) reductions in the MAP variability (SDMAP) that started at 2 h and continued for the following 3 h (Table 3). The time-domain indices of heart rate variability, SDRR and rMSSD, were also reduced by clonidine. These reductions were statistically significant, compared with corresponding baseline and postsaline values, at 1, 2, and 3 h for SDRR and during the first 2 h for rMSSD (Table 3).
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Ethanol-Clonidine Hemodynamic Interaction. Changes evoked by chronic ethanol feeding [2.5 or 5% (w/v), 12 weeks] in the responses of MAP, heart rate, and their variability to clonidine are illustrated in Figs. 1 and 2. Compared with its effect in control rats, the hypotensive effect of clonidine was significantly (P < 0.05) attenuated in ethanol-fed rats in a concentration-related manner (Fig. 1A). The hypotensive action of clonidine in SHRs receiving the lower concentration of ethanol (2.5%) was significantly smaller than corresponding control values during the first1hof clonidine administration (Fig. 1A). On the other hand, the attenuation of clonidine hypotension by the higher concentration of ethanol (5%) was evident for approximately 5 h (Fig. 1A). Similarly, ethanol elicited concentration-dependent attenuation of clonidine-evoked reductions in MAP and heart rate variability indices (SDMAP, SDRR, and rMSSD) (Fig. 2). These effects of ethanol were statistically significant, compared with control values, at 3 and 4 h for SDMAP (Fig. 2A) and at 1 h for SDRR (Fig. 2B) and rMSSD (Fig. 2C). Ethanol feeding (5%) caused significant increases in heart rate only during the first 60-min period of the study (Fig. 1B).
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To eliminate a possible role for the differences in baseline hemodynamic values of control and ethanol-fed rats (Table 1) in the antagonistic ethanol-clonidine interaction, responses to clonidine were expressed as a percentage of baseline (i.e., preclonidine) values and compared in the three groups of rats. The percentage reductions in MAP (Fig. 3A) and its variability index (SDMAP; Fig. 3B) elicited by clonidine were attenuated in ethanol-fed rats in a concentration-dependent manner; the effect of the higher concentration of ethanol (5%) was statistically significant (P < 0.05) compared with control values. Also, the percentage reductions in SDRR and rMSSD evoked by clonidine were virtually abolished by 2.5% ethanol (Fig. 3, C and D) and transformed into significant increases by 5% ethanol (Fig. 3, C and D).
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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;
Abdel-Rahman, 1994). In the
present study, we tested the hypothesis that alteration of autonomic
(sympathovagal) balance contributes to the attenuation of clonidine
hypotension in ethanol-fed rats. This objective was accomplished by
investigating the influence of ethanol feeding on clonidine-evoked changes in
blood pressure, heart rate, and their variability in telemetered SHRs. The
time-domain measurement of blood pressure and heart rate variability was used
in the present study to determine changes in the cardiovascular autonomic
balance. Time-domain indices correlate with frequency-domain measurements and,
therefore, provide a reliable evaluation of cardiovascular autonomic balance
(Stein et al., 1994;
Sgoifo et al., 1997). The
results showed that clonidine produced hypotension that was associated with
significant reductions in the time-domain indices of MAP (SDMAP) and heart
rate (SDRR and rMSSD) variability, which may reflect the clonidine-evoked
inhibition of central sympathetic activity
(Grichois et al., 1990;
Elghozi et al., 1991;
Janssen et al., 1991;
Tulen et al., 1993). Ethanol
feeding, concentration dependently, attenuated the hypotensive effect of
clonidine and the associated reductions in MAP and heart rate variability.
These findings provide evidence that implicates alterations in sympathovagal
balance of the cardiovascular system in the antagonistic ethanol-clonidine
hemodynamic interaction.
The present study showed that clonidine elicited hypotension in control
SHRs and significantly reduced time-domain indices of blood pressure and heart
rate variability (SDMAP, SDRR, and rMSSD). These findings are in agreement
with previous reports that used time- or frequency-domain measurements and
highlight a role for the concomitant reduction in central sympathetic outflow
in mediating clonidine effects (Grichois
et al., 1990; Elghozi et al.,
1991; Janssen et al.,
1991; Tulen et al.,
1993). The brief pressor effect that preceded clonidine
hypotension might be related to the stress associated with the intraperitoneal
injection of the drug because a similar response followed saline
administration. It is generally accepted that the reduction in peripheral
vascular resistance subsequent to sympathoinhibition is the principal
mechanism underlying the hypotensive effect of clonidine
(Mao and Abdel-Rahman, 1998;
El-Mas and Abdel-Rahman,
1999). The reduction caused by clonidine in the variability of
adjacent interbeat intervals (rMSSD), which largely reflects cardiac vagal
activity (Stein et al., 1994;
Sgoifo et al., 1997), may be
secondary to the reduction in sympathetic outflow to maintain the
sympathovagal balance. Similar inhibitory effects of clonidine on the
frequency-domain indices of sympathetic and parasympathetic outflows have been
demonstrated in humans (Tulen et al.,
1993). Several studies have pointed out that heart rate and blood
pressure variabilities are correlated and exhibit feedback and feed-forward
interactions (Di Rienzo et al.,
1991; Saul et al.,
1991; Cerutti et al.,
1994). In addition to sympathoinhibition, two others factors have
been proposed to contribute to the hemodynamic stability produced by
clonidine. First, Grichois et al.
(1990) and Elghozi et al.
(1991) suggested that the
increased arterial baroreflex responsiveness by clonidine might contribute to
the better control of blood pressure and heart rate oscillations. Notably,
baroreflex activity is inversely related to blood pressure variability
(Su et al., 1986). Our own
findings and those of others have shown that partial or complete arterial
baroreceptor denervation results in greater fluctuations in blood pressure
(Krieger, 1964;
El-Mas et al., 1994a). Second,
the sedative effect of clonidine may favor hemodynamic stability. This view
gains support from the observation that clonidine significantly reduces blood
pressure variability only during the dark period when the rats are active
(Janssen et al., 1991).
The primary goal of the present study was to study the influence of chronic
ethanol feeding on clonidine-evoked changes in hemodynamic variability and its
possible involvement in the antagonistic effects of the two drugs on blood
pressure. The time-domain measurement of hemodynamic variability was used, for
the first time, to evaluate the role of the sympathetic activity in the
antagonistic hemodynamic interaction between ethanol and centrally acting
antihypertensive agents. Our previous studies measured norepinephrine levels
in plasma and brainstem to implicate central sympathetic tone in
ethanol-clonidine hemodynamic interaction
(El-Mas et al., 1994b;
Mao and Abdel-Rahman, 1998;
El-Mas and Abdel-Rahman,
1999). The present results showed that the hypotensive effect of
clonidine was significantly attenuated by ethanol in a concentration-dependent
manner. The maximum decrease in blood pressure produced by clonidine in SHRs
receiving 2.5 and 5% ethanol amounted to –23.4 ± 2.8 and
–15.7 ± 1.2 mm Hg, respectively, compared with –35.4
± 1.2 in pair-fed controls. Ethanol also attenuated the parallel
reductions in blood pressure and heart rate variability elicited by clonidine.
Given the positive correlation between clonidine-evoked reduction in
hemodynamic variability and sympathoinhibition
(Grichois et al., 1990;
Elghozi et al., 1991;
Janssen et al., 1991;
Tulen et al., 1993) and the
importance of sympathoexcitation in the ethanol counteraction of centrally
evoked hypotension (El-Mas et al.,
1994b; Mao and Abdel-Rahman,
1998), the attenuation by ethanol of clonidine effects on blood
pressure and heart rate variability supports the involvement of the
sympathetic component in the interaction. Together, these findings demonstrate
that chronic ethanol administration compromises clonidine-induced hemodynamic
stability and sympathoinhibition, which may contribute to the antagonistic
effect of the two drugs on blood pressure.
It may be argued that the reduced effectiveness of clonidine on blood
pressure and hemodynamic variability in ethanol-fed rats might be related to
differences in the baseline values of these parameters in ethanol-fed and
control rats. As shown in Table
1, the baseline blood pressure and its time-domain variability
index (SDMAP) were significantly and concentration dependently reduced by
ethanol. The baseline indices of heart rate variability also exhibited slight
reductions in ethanol-fed rats. The notion that long-term ethanol
administration lowers blood pressure agrees with earlier reports, including
ours (Beilin et al., 1992;
El-Mas and Abdel-Rahman, 2000;
Rekik et al., 2002), and may
be attributed to ethanol-induced myocardial depression
(Kelback et al., 1985),
vasodilation (Turlapaty et al.,
1979), or -adrenergic blockade
(Abdel-Rahman et al., 1985).
Nonetheless, the possibility that the reduced responsiveness to clonidine in
ethanol-fed rats relates to differences in baseline values seems unlikely
because of the following three observations. First, the attenuated hemodynamic
effects of clonidine in ethanol-fed rats were still evident when the responses
were expressed as percentages of baseline values
(Fig. 3). The percentage of
reductions in all measured variables was significantly attenuated in
ethanol-fed rats compared with their control counterparts. In effect,
clonidine increased heart rate variability indices (SDRR and rMSSD) in rats
receiving the higher concentration of ethanol. Second, the hypotensive
response to intracisternally administered clonidine was attenuated in ethanol
chronically fed SHRs whose baseline blood pressure was similar to that of
control SHRs (Abdel-Rahman,
1994), suggesting that differences in baseline blood pressure in
the present study may not account for the attenuated clonidine hypotension in
ethanol-fed rats. Third, the antagonistic ethanol-clonidine hemodynamic
interaction has been demonstrated in arterial barodenervated rats
(El-Mas et al., 1994b;
El-Mas and Abdel-Rahman, 1997)
whose baseline blood pressure was less than that seen in ethanol-fed rats in
the present study. These findings indicate that the ethanol-clonidine
interaction may not be related to baseline hemodynamic differences but rather
to their antagonistic effects on circulatory controlling mechanisms.
Findings of acute studies from our laboratory have shown that the
counteraction by ethanol of the hypotensive and sympathoinhibitory effects of
clonidine is demonstrated only when ethanol is administered during the
hypotensive response, i.e., subsequent to clonidine
(Mao and Abdel-Rahman, 1998;
El-Mas and Abdel-Rahman,
1999), but not when given before clonidine
(El-Mas and Abdel-Rahman,
1997; Mao and Abdel-Rahman,
1998). This led to the suggestion that the preexisting
sympathoinhibitory effect of clonidine acts to unmask the sympathoexcitatory
and hence the pressor effect of ethanol
(El-Mas et al., 1994b,
El-Mas and Abdel-Rahman, 1997;
Mao and Abdel-Rahman, 1998).
These findings may be in contrast with the present observation that long-term
ethanol pretreatment attenuated clonidine hypotension. The reason for the
discrepancies in the effect of acute (no change) and chronic (attenuation)
ethanol pretreatment on the hypotensive effect of clonidine is not clear.
Interestingly, chronic feeding of ethanol in SHRs has been shown to reduce the
density of 2-adrenergic receptors in the nucleus tractus
solitarius (El-Mas and Abdel-Rahman
2001), a possible brainstem target for clonidine hypotension
(Kubo and Misu, 1981).
Biochemical evidence is also available that chronic ethanol reduces
2-receptor sensitivity in the SHR brain
(Szmigielski et al., 1989).
Together, these findings may implicate the reduced binding and functional
activity of central 2-receptors in the attenuated
hypotensive action of clonidine in ethanol-fed rats.
In conclusion, time-domain measurements of hemodynamic variability provide
evidence that implicates the cardiovascular autonomic balance in the
antagonistic ethanol-clonidine hemodynamic interaction. Clonidine reduced
blood pressure as well as blood pressure and heart rate variability in SHRs,
and these effects were attenuated by ethanol in a concentration-dependent
manner. These findings add new insight into the understanding of mechanism
involved in the reduced therapeutic effectiveness of some antihypertensive
medications in regular alcohol users
(Volicer et al., 1978;
Puddey et al., 1987) and
highlight a possible adverse effect for ethanol on clonidine-induced
hemodynamic stability during surgical procedures
(Nishikawa et al., 1991) and
in cardiac and vascular hypertrophy (Timio
et al., 1987; Strauer,
1988).
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Footnotes |
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ABBREVIATIONS: SHR, spontaneously hypertensive rat; MAP, mean arterial pressure; SDMAP, standard deviation of the mean arterial pressure; SDRR, standard deviation of beat-to-beat intervals; rMSSD, root mean square of successive beat-to-beat differences in R-R interval durations.
Address correspondence to: Dr. Abdel A. Abdel-Rahman, Department of Pharmacology, School of Medicine, East Carolina University, Greenville, NC 27858. E-mail: abdelrahmana{at}mail.ecu.edu
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