(Stroke. 1995;26:2097-2102.)
© 1995 American Heart Association, Inc.
Articles |
Acute Effects of Ethanol on Responses of Cerebral Arterioles
From the Department of Physiology and Biophysics, University of Nebraska Medical Center, Omaha.
Correspondence to Dr William G. Mayhan, Department of Physiology, University of Nebraska Medical Center, 600 S 42nd St, Omaha, NE 68198-4575.
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Abstract |
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Background and Purpose Previous studies have suggested that acute exposure of large peripheral arteries to ethanol impairs endothelium-dependent relaxation. The goal of the present study was to determine the acute effects of ethanol exposure on responses of cerebral resistance arterioles in vivo.
Methods We prepared a cranial window in rats to expose the cerebral (pial) microcirculation. We measured the diameter of pial arterioles in vivo in response to agonists that presumably stimulate the synthesis/release of nitric oxide from the endothelium (ADP, acetylcholine, and histamine) or neurons (N-methyl-D-aspartate [NMDA]) before and after topical application of various concentrations of ethanol added to the cerebrospinal fluid (20, 40, 60, 80, and 100 mmol/L). In addition, we examined responses of pial arterioles to nitroglycerin before and 1 hour after topical application of ethanol.
Results Before application of ethanol, ADP, acetylcholine, histamine, NMDA, and nitroglycerin produced dose-related dilatation of pial arterioles. Application of the various concentrations of ethanol did not alter the baseline diameter of pial arterioles. However, application of 80 and 100 mmol/L ethanol inhibited dilatation of pial arterioles in response to agonists that stimulate the synthesis/release of nitric oxide. Dilatation of pial arterioles in response to nitroglycerin was not altered by application of ethanol.
Conclusions The findings of the present study suggest that acute exposure of cerebral arterioles to modest-to-moderate concentrations of ethanol (20 to 60 mmol/L) does not alter responses of cerebral arterioles. In contrast, exposure of cerebral arterioles to higher concentrations of ethanol (80 and 100 mmol/L) can produce specific impairment of dilatation to agonists that stimulate the synthesis/release of nitric oxide from endothelium and neurons.
Key Words: alcohol drinking • microcirculation • nitric oxide • rats
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Endothelium of cerebral microvessels appears to play an important role in the regulation of cerebral vascular tone through the synthesis and release of endothelium-derived relaxing factor (EDRF).1 2 3 4 EDRF has been identified to be nitric oxide (NO) or a closely related compound synthesized from the amino acid L-arginine.5 6 7 Many vasoactive substances stimulate cerebral endothelial cells to release NO or an NO-containing compound, which in turn produces relaxation of vascular muscle by activation of guanylate cyclase.8 9 Previous studies using in vitro methodology have suggested that endothelium-dependent responses of mesenteric arteries10 11 and the aorta12 13 of rats are altered in response to acute exposure to large concentrations of ethanol. Thus, it appears that ethanol exposure may alter the release of NO from the endothelium.
No studies have examined the effects of acute ethanol exposure on responses of resistance arterioles to agonists that stimulate the synthesis/release of NO from the endothelium or from neurons. In addition, no studies have examined the acute effects of ethanol on responses of the cerebral microcirculation to agonists that stimulate the synthesis/release of NO. Thus, the goal of this study was to examine the effects of acute ethanol exposure on responses of cerebral (pial) arterioles to agonists that presumably stimulate the synthesis/release of NO.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Preparation of Animals
This study was approved by the institutional animal care and use committee and is in compliance with the guidelines of the National Institutes of Health for care and handling of animals. We used male Sprague-Dawley rats in these studies (weight, 350 to 400 g). On the day of the experiment, the rats were anesthetized (thiobutabarbital, 100 mg/kg body wt IP), and a tracheotomy was performed. The animals were ventilated mechanically with room air and supplemental oxygen. Skeletal muscle paralysis was obtained with gallamine triethiodide (10 mg/kg IV).
A catheter was placed into a femoral vein for injection of drugs, and a femoral artery was cannulated for measurement of arterial blood pressure.
To visualize the microcirculation of the cerebrum, a craniotomy was prepared over the right parietal cortex.14 The cranial window was suffused with artificial cerebrospinal fluid (2 mL/min) that was bubbled continuously to maintain pH, Pco2, and Po2 constant. The temperature of the suffusate was maintained at 38°C. The cranial window was connected by a three-way valve to an infusion pump, which allowed for infusion of agonists or vehicle into the suffusate. This method, which we have used previously,15 16 17 maintained a constant temperature, pH, Pco2, and Po2 of the suffusate during infusion of drugs. Samples of suffusate, drawn directly from the cranial window, were analyzed before and during infusion of drugs. Arterial blood gases were monitored and were maintained within normal limits throughout the experiment.
Pial arteriolar diameter was measured on-line with the use of a video image shearing device (model 908, Instrumentation for Physiology and Medicine, Inc).
Experimental Protocol
Cerebral vessels were superfused with artificial cerebrospinal
fluid for 30 to 40 minutes before we tested responses of arterioles to
the agonists. Responses of cerebral arterioles were examined during
superfusion of agonists that presumably dilate cerebral arterioles
through the release of NO or an NO-containing compound: ADP (10 and 100
µmol/L), acetylcholine (10 and 100 µmol/L), histamine (1.0 and 10
µmol/L), and NMDA (50 and 100 µmol/L). We also examined responses
of cerebral arterioles to nitroglycerin (1.0 and 10
µmol/L). After initially examining responses of cerebral arterioles
to the agonists, we then suffused the cranial window preparation with
cerebrospinal fluid that contained ethanol (20, 40, 60, 80, or 100
mmol/L). One hour after starting the suffusion of ethanol and
continuing for the duration of the experiment, we again examined
responses of cerebral arterioles to the agonists.
Agonists were mixed in artificial cerebrospinal fluid and then superfused over the cerebral microcirculation. Application of vehicle did not affect vessel diameter, and application of agonists was randomized. In each rat we studied responses of the largest pial arteriole exposed by the craniotomy to application of agonists. The diameter of cerebral arterioles was measured immediately before application of agonists and every minute for 5 minutes during application of agonists. Steady-state responses to agonists were reached within 2 to 3 minutes after application, and the diameter of cerebral arterioles returned to baseline within 3 to 5 minutes after application of agonist was stopped.
Statistical Analysis
A paired t test was used to compare values obtained
before and after application of ethanol to the cerebral
microcirculation. A value of P=.05 was considered
significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Responses After 20 mmol/L Ethanol
Before application of 20 mmol/L ethanol to the cerebral microcirculation, ADP (n=14), acetylcholine (n=12), histamine (n=12), and NMDA (n=14) produced dose-related dilatation of cerebral arterioles (Fig 1
).
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Superfusion of a buffer containing 20 mmol/L ethanol did not
affect the baseline diameter of cerebral arterioles (53±3 µm before
application of 20 mmol/L ethanol versus 54±3 µm [2±1%] after
application of 20 mmol/L ethanol; P>.05). In addition,
superfusion of 20 mmol/L ethanol did not alter responses of cerebral
arterioles to any of the agonists tested (Fig 1
).
Furthermore, application of 20 mmol/L ethanol did not alter responses
of pial arterioles to nitroglycerin (1.0 and 10
µmol/L) (12±1% and 23±3%, respectively, before application of 20
mmol/L ethanol versus 14±1% and 23±1%, respectively, after
application of 20 mmol/L ethanol; P>.05).
Responses After 40 mmol/L Ethanol
Before application of 40 mmol/L ethanol to the cerebral
microcirculation, ADP (n=7), acetylcholine (n=7), histamine (n=7), and
NMDA (n=7) produced dose-related dilatation of cerebral arterioles
(Fig 2).
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Superfusion of a buffer containing 40 mmol/L ethanol did not
affect the baseline diameter of cerebral arterioles (48±1 µm before
application of 40 mmol/L ethanol versus 49±1 µm [2±1%] after
application of 40 mmol/L ethanol; P>.05). In addition,
superfusion of 40 mmol/L ethanol did not alter responses of cerebral
arterioles to any of the agonists tested (Fig 2).
Furthermore, application of 40 mmol/L ethanol did not alter responses
of pial arterioles to nitroglycerin (1.0 and 10
µmol/L) (11±2% and 18±2%, respectively, before application of 40
mmol/L ethanol versus 11±2% and 21±2%, respectively, after
application of 40 mmol/L ethanol; P>.05).
Responses After 60 mmol/L Ethanol
Before application of 60 mmol/L ethanol to the cerebral
microcirculation, ADP (n=5), acetylcholine (n=5), histamine (n=5), and
NMDA (n=5) produced dose-related dilatation of cerebral arterioles
(Fig 3).
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Superfusion of a buffer containing 60 mmol/L ethanol did not
affect the baseline diameter of cerebral arterioles (53±2 µm before
application of 60 mmol/L ethanol versus 54±3 µm [2±3%] after
application of 60 mmol/L ethanol; P>.05). In addition,
superfusion of 60 mmol/L ethanol did not alter responses of cerebral
arterioles to any of the agonists tested (Fig 3).
Furthermore, application of 60 mmol/L ethanol did not alter responses
of pial arterioles to nitroglycerin (1.0 and 10
µmol/L) (15±3% and 21±2%, respectively, before application of 60
mmol/L ethanol versus 10±1% and 19±1%, respectively, after
application of 60 mmol/L ethanol; P>.05).
Responses After 80 mmol/L Ethanol
Before application of 80 mmol/L ethanol to the cerebral
microcirculation, ADP (n=7), acetylcholine (n=7), histamine (n=7), and
NMDA (n=6) produced dose-related dilatation of cerebral arterioles
(Fig 4).
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Superfusion of a buffer containing 80 mmol/L ethanol did not affect the
baseline diameter of cerebral arterioles (47±3 µm before application
of 80 mmol/L ethanol versus 44±2 µm [-4±5%] after
application of 80 mmol/L ethanol; P>.05). Superfusion of 80
mmol/L ethanol did not alter responses of cerebral arterioles to
ADP but significantly impaired dilatation of pial arterioles in
response to acetylcholine, histamine, and the 100 µmol/L
concentration of NMDA (Fig 4). In contrast, application
of 80 mmol/L ethanol did not alter responses of pial arterioles to
nitroglycerin (1.0 and 10 µmol/L) (10±1% and
19±3%, respectively, before application of 80 mmol/L ethanol versus
13±2% and 22±3%, respectively, after application of 80 mmol/L
ethanol; P>.05). Thus, impaired responses of pial
arterioles in response to acetylcholine, histamine, and NMDA after
application of 80 mmol/L ethanol cannot be explained by nonspecific
impairment of vasodilatation.
Responses After 100 mmol/L Ethanol
Before application of 100 mmol/L ethanol to the cerebral
microcirculation, ADP (n=14), acetylcholine (n=7), histamine (n=8), and
NMDA (n=9) produced dose-related dilatation of cerebral arterioles
(Fig 5).
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Superfusion of 100 mmol/L ethanol did not affect the baseline
diameter of cerebral arterioles (54±4 µm before application of 100
mmol/L ethanol versus 53±3 µm [-1.4±1%] after
application of 100 mmol/L ethanol; P>.05). Superfusion of
100 mmol/L ethanol significantly impaired dilatation of pial arterioles
in response to ADP, acetylcholine, histamine, and NMDA (Fig 5). In contrast, application of 100 mmol/L ethanol did
not alter responses of pial arterioles to nitroglycerin
(1.0 and 10 µmol/L) (11±1% and 19±2%, respectively, before
application of 100 mmol/L ethanol versus 11±2% and 22±3%,
respectively, after application of 100 mmol/L ethanol;
P>.05). Thus, impaired responses of pial arterioles in
response to ADP, acetylcholine, histamine, and NMDA after application
of 100 mmol/L ethanol cannot be explained by nonspecific impairment of
vasodilatation.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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There are two major new findings of the present study. First, dilatation of cerebral arterioles in response to agonists that stimulate the synthesis/release of NO from endothelium and neurons is not altered by acute exposure to modest-to-moderate concentrations of ethanol (20, 40, and 60 mmol/L). Second, dilatation of cerebral arterioles in response to agonists that stimulate the synthesis/release of NO from endothelium and neurons is impaired during acute exposure to elevated concentrations of ethanol (80 and 100 mmol/L). This finding cannot be explained by a nonspecific effect of ethanol on arteriolar reactivity since dilatation of pial arterioles in response to nitroglycerin was similar before and after application of 80 and 100 mmol/L ethanol.
Consideration of Methods
We examined reactivity of pial arterioles to ADP, acetylcholine,
histamine, and NMDA before and after application of ethanol.
We18 19 and others20 have shown that ADP and
acetylcholine dilate pial arterioles in rats in vivo by the release of
NO or an NO-containing compound. Application of an NO synthase
inhibitor
(NG-monomethyl-L-arginine;
L-NMMA) impairs dilatation of pial arterioles in response to
ADP18 and acetylcholine.19 20 Recent studies
that examined responses of pial arterioles in rabbits in
vivo21 and brain slices in rats22 have
suggested that NMDA stimulates the release of NO or an NO-containing
compound mainly from neurons. Although no studies have examined the
role of NO or an NO-containing compound in dilatation of pial
arterioles in rats in response to histamine, others have suggested that
histamine dilates cerebral arteries by an
endothelium-dependent mechanism.23 24
We also examined responses of pial arterioles to
nitroglycerin. We have shown previously that dilatation
of pial arterioles in response to nitroglycerin is not
related to the endothelial release of NO or an NO-containing
compound.18 19
Consideration of Previous Studies
Previous studies have examined the acute effects of ethanol on
baseline diameter of large and small peripheral blood
vessels.25 26 27 28 Increasing concentrations of ethanol
(0.001% to 10%) have been shown to produce dose-related
constriction of arterioles in the rat cremaster muscle26
and hamster cheek pouch28 in vivo and contraction of the
aorta25 in vitro. In contrast, another study has shown
that ethanol (0.1% to 100%) produced dose-related dilatation of
arterioles of the rat mesentery.27 The discrepancy between
studies that show that ethanol produces
vasoconstriction25 26 28 and the study that suggests that
ethanol produces vasodilatation27 is not clear but may be
related to vessel size and/or the microvascular bed examined.
Two previous studies have examined the acute effects of ethanol on cerebral blood vessels. Studies by Zhang et al29 suggest that ethanol (8 to 570 mmol/L) produces contraction of large cerebral arteries (basilar and middle cerebral arteries) in dogs, sheep, pigs, and baboons. Although ethanol elicited contraction in cerebral arteries, contraction of cerebral arteries in response to ethanol was variable and appeared to be greatly affected by species and vessel type. In the present study we did not find a significant effect of ethanol on diameter of pial arterioles. The discrepancy between the present study and this previous study29 may be related to differences between in vivo and in vitro methodologies, vessel size, and/or vessel origin.
Another study by Altura et al30 reported that acute exposure to ethanol (10 to 1000 mg/dL) produced dose-related contraction of large canine cerebral arteries and constriction of rat pial arterioles. At the concentrations of ethanol used in the present studies (20 to 100 mmol/L), Altura et al found a 6- to 8-µm change in diameter of pial arterioles. We did not observe a significant constriction of pial arterioles during application of 20 to 100 mmol/L ethanol in the present study. The discrepancy between the present study and that of Altura et al is not clear since the present study and the study of Altura et al examined the effects of ethanol on pial arterioles in rats in vivo. It is possible that the discrepancy between the present study and the study of Altura et al may be related to vascular size and/or method of application of ethanol. We examined pial arterioles that had a baseline diameter of approximately 50 µm, while Altura et al examined responses of pial arterioles of approximately 30 µm in diameter. In addition, we examined responses of pial arterioles during continuous superfusion of ethanol, and the previous study30 examined responses of pial arterioles during a stationary application of ethanol.
Previous studies have examined the effects of acute ethanol exposure on endothelium-dependent and endothelium-independent responses of large peripheral arteries using in vitro methodology.10 11 12 13 Using the isolated perfused rat mesenteric artery preparation, investigators found that infusion of ethanol (1.6 to 7.9 mg/mL) for 60 minutes impaired endothelium-dependent relaxation in response to acetylcholine and ATP.10 In contrast, relaxation in response to an endothelium-independent dilator, papaverine, was not altered by infusion of ethanol.10 In addition, other investigators have shown that acute exposure of the rat aorta to large concentrations of ethanol (100 to 400 mmol/L) produced concentration-dependent inhibition of endothelium-dependent relaxation in response to acetylcholine and ATP but did not alter relaxation in response to sodium nitroprusside.12 13 The results of the present study are in agreement with previous findings.10 11 12 13 We found that responses of cerebral arterioles to agonists that release NO from endothelium and neurons were impaired after acute exposure to high concentrations of ethanol (80 and 100 mmol/L). In contrast, dilatation of cerebral arterioles in response to nitroglycerin was not altered by application of ethanol. Our findings extend previous studies10 11 12 13 by examining the effects of modest-to-moderate concentrations of ethanol (20, 40, and 60 mmol/L) on the cerebral microcirculation. These modest-to-moderate concentrations of ethanol have been shown to produce symptoms in humans ranging from euphoria to coma and strokelike episodes (see Reference 30). Our findings also extend previous studies by suggesting that altered responses during exposure to ethanol are not confined to large arteries but also involve the endothelium and neurons of resistance arterioles and particularly cerebral arterioles.
Mechanism of Altered Endothelium-Dependent
Responses
Although we did not examine the mechanism of impaired
endothelium-dependent responses of cerebral
arterioles during acute ethanol administration, we suggest three
possibilities. First, it is possible that administration of ethanol
alters responses by a direct effect on endothelial
receptors and/or effects on membrane fluidity. Studies have shown that
ethanol fluidizes membranes and thus may prevent receptor coupling and
receptor-mediated membrane processes such as the synthesis and
release of NO.31 32 In support of this concept, it has
been shown that ethanol inhibits acetylcholine-induced
relaxation and increases in cGMP but does not inhibit relaxation or
increases in cGMP during application of sodium nitroprusside or the
calcium ionophore A23187,12 13 a
non–receptor-mediated
endothelium-dependent agonist. Thus, it appears
that ethanol may not affect the formation of NO but may alter receptors
to prevent agonist-induced synthesis/release of NO. Second, it is
possible that ethanol administration stimulates the production
of constrictor substances that modulate relaxation in response to
endothelium-dependent agonists. Previous studies
have shown that ethanol stimulates the synthesis/release of
endothelin-1.33 34 Thus, it is possible that the
production of endothelins during application of ethanol may
alter endothelium-dependent responses of blood
vessels. However, since reactivity of blood vessels to
endothelium-independent agonists is not altered by
application of ethanol, it is not clear how the synthesis/release of
endothelins during application of ethanol would specifically alter
reactivity of vessels to endothelium-dependent
agonists. Third, it is possible that application of ethanol impairs
responses of cerebral arterioles by the production of oxygen
radicals. One study has suggested that ethanol induces the generation
and release of oxygen-derived free radicals,35 and
previous studies have shown that oxygen-derived free radicals can
inhibit endothelium-dependent responses of blood
vessels.36 Thus, it is possible that
ethanol-stimulated release of oxygen radicals may impair cerebral
vasodilatation by a direct effect of oxygen radicals on NO.
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Acknowledgments |
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This study was supported by National Heart, Lung, and Blood Institute grant HL-40781 and a Grant-in-Aid from the American Heart Association–Nebraska Affiliate (93-7792S). The authors would like to thank Glenda Sharpe and Phyllis Anding for their excellent technical assistance.
Received May 1, 1995; revision received July 28, 1995; accepted August 4, 1995.
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