Vol. 275, Issue 3, H861-H867, September 1998
Role of opioids in hypoxic pial artery dilation is stimulus
duration dependent
William M.
Armstead
Departments of Anesthesia and Pharmacology, University of
Pennsylvania and The Children's Hospital of Philadelphia,
Philadelphia, Pennsylvania 19104
 |
ABSTRACT |
Because methionine
enkephalin contributes to and dynorphin opposes dilation during a
10-min hypoxic exposure, opioids modulate pial artery dilation to this
stimulus. However, such modulation may be dependent on the duration of
hypoxia. The present study was designed to characterize the modulation
of hypoxic pial dilation by opioids as a function of stimulus duration
in newborn pigs equipped with a closed cranial window. Hypoxic dilation
was decremented in both moderate and severe groups
(PO2 
35 and 25 mmHg, respectively) during 20-min and 40-min exposure periods compared with
the response during 5 or 10 min of stimulation (24 ± 1, 25 ± 1, 18 ± 1, and 14 ± 1% for 5, 10, 20, and 40 min of moderate hypoxia; means ± SE). Moderate and severe hypoxia had no effect on
cerebral spinal fluid (CSF) methionine enkephalin or dynorphin concentration during a 5-min exposure period. During a 10-min exposure,
however, both opioids were increased in CSF. During 20- and 40-min
exposure periods, CSF dynorphin continued to increase, whereas
methionine enkephalin steadily decreased (962 ± 18, 952 ± 21, 2,821 ± 15, 2,000 ± 81, and 1,726 ± 58 pg/ml methionine enkephalin for control, 5, 10, 20, and 40 min of moderate hypoxia, respectively). The µ-opioid (methionine enkephalin) antagonist 
-funaltrexamine had no influence on dilation during the 5-min exposure, decremented the 10- and 20-min exposures, but had no effect
on 40-min exposure hypoxic dilation. Whereas the 
-opioid (dynorphin)
antagonist norbinaltorphimine similarly had no effect on a
5-min exposure dilation, it, in contrast, potentiated 10-, 20-, and
40-min exposure hypoxic dilations (23 ± 1 vs. 23 ± 1, 24 ± 1 vs. 32 ± 1, 16 ± 1 vs. 24 ± 2, and 13 ± 1 vs. 23 ± 3% for 5, 10, 20, and 40-min hypoxic dilation before and after
norbinaltorphimine). These data show that opioids do not modulate
hypoxic pial dilation during short but do so during longer exposure
periods. Moreover, hypoxic pial dilation is diminished during longer
exposure periods. Decremented hypoxic pial dilation during longer
exposure periods results, at least in part, from decreased release of
methionine enkephalin and accentuated release of dynorphin. These data
suggest that the relative role of opioids in hypoxic pial dilation
changes with the stimulus duration.
newborn; cerebral circulation
| |
INTRODUCTION |
OPIOIDS CONTRIBUTE to the regulation of cerebral
hemodynamics. Opioid receptor binding has been demonstrated on cerebral
microvessels (13). Enkephalin and dynorphin immunoreactivity,
indicative of innervation, has been shown in large cerebral arteries of
the pig and guinea pig, respectively (10, 19). Furthermore, opioids have been detected in cerebrospinal fluid (CSF) (11), and CSF opioid
concentrations are in the vasoactive range under control conditions in the newborn pig (3, 4).
Several mechanisms have been proposed to account for hypoxia-induced
cerebrovasodilation, including adenosine, prostaglandins, and nitric
oxide (NO) (1, 5, 12, 22, 24). Additionally, it has been observed that
hypoxia increases plasma methionine enkephalin in fetal sheep (9) and
plasma -endorphin in human newborns at delivery (8, 21) and in those
infants with hypoxic-ischemic encephalopathy with ongoing
hypoxia (15). In the piglet, hypoxic pial artery dilation is associated
with elevated cortical periarachnoid CSF methionine enkephalin and
dynorphin concentration (1). Because the µ-opioid (methionine
enkephalin) (6) antagonist -funaltrexamine attenuates whereas the
-opioid (dynorphin) (6) antagonist norbinaltorphimine
potentiates hypoxic pial artery dilation, it had been previously
suggested that opioids modulate hypoxic pial artery dilation (1).
The duration of the stimulus period could determine the relative
contributions of different mechanisms to hypoxic pial artery dilation.
Reasons for differences between our data indicating a role for NO in
hypoxic pial dilation and those of Leffler et al. (7), which do not,
are uncertain but could relate to a more prolonged hypoxic exposure in
our study (10 min) compared with that of Leffler et al. (5 min). It is
not inconceivable, therefore, that a more robust hypoxic exposure could
activate mechanisms not recruited during a shorter stimulation period. Whereas opioids have been observed to modulate hypoxic pial dilation during a 10-min exposure period (1, 2), the ability of such opioids to
do so during shorter or longer exposure periods is uncertain.
The present study, therefore, was designed to characterize the
modulation of hypoxic pial artery dilation by opioids as a function of
stimulus duration.
| |
METHODS |
All experiments have been approved by the Institutional Animal Care and
Use Committee. Seventy-two pigs (1-5 days old) of either sex were
used in these experiments. They were first anesthetized with ketamine
hydrochloride-acepromazine (33 mm/kg im). Anesthesia was maintained
with 
-chloralose (30-50 mg/kg initially, supplemented with 5 mg/kg iv). A catheter was inserted into the femoral artery to record
blood pressure and to sample for blood gases and pH. Another catheter
was placed in a femoral vein for injection of drugs. The trachea was
cannulated, and the animals were ventilated with room air. The body
temperature was maintained at 37-38°C with a heating pad.
For insertion of the cranial window, the scalp was removed and an
opening was made in the skull over the parietal cortex. The dura was
cut and retracted over the cut bone edge. The cranial window was placed
in the hole and cemented in place with dental acrylic. The space under
the window was filled with artificial CSF of the following composition
(in mM): 3.0 KCl, 1.5 MgCl2, 1.5 CaCl2, 132 NaCl, 6.6 urea, 3.7 dextrose, and 24.6 NaHCO3 (with pH
7.30-7.36, PCO2 42-49 mmHg,
and PO2 40-50 mmHg).
Pial arterioles were observed with a dissecting microscope, a
television camera mounted on the microscope, and a video monitor. Vascular diameter was measured with a video microscaler.
Protocol.
Animals were divided into nine groups:
1) 5- and 10-min moderate and severe
hypoxia time control (n = 8),
2) 20-min moderate and severe
hypoxia time control (n = 8),
3) 40-min moderate and severe
hypoxia time control (n = 8),
4) 5- and 10-min moderate and severe
hypoxia before and after -funaltrexamine
(n = 8)
5) 20-min moderate and severe
hypoxia before and after -funaltrexamine (n = 8)
6) 40 min moderate and severe
hypoxia before and after -funaltrexamine
(n = 8),
7) 5- and 10-min moderate and severe hypoxia before and after norbinaltorphimine
(n = 8),
8) 20-min moderate and severe
hypoxia before and after norbinaltorphimine (n = 8), and
9) 40-min moderate and severe
hypoxia before and after norbinaltorphimine
(n = 8). Time control experiments were designed so that responses were obtained initially (defined as 1st in
Tables 1 and 2) and then again 30 min later (defined as 2nd in Tables 1
and 2). Severity and durations of hypoxia were randomized within
groups.
Hypoxia (5-, 10-, 20-, and 40-min duration) was produced by decreasing
the inspired oxygen sufficiently to reduce and maintain arterial
PO2
(PaO2) at 35 ± 3 mmHg (for moderate
hypoxia) and at 25 ± 3 mmHg (for severe hypoxia),
while arterial PCO2 (PaCO2) was maintained constant in the
normocapnic range (33 ± 3 mmHg). Changes in pial artery diameter
(small artery 120-160 µm; arteriole 50-70 µm) were
measured every minute during the last 5 min of each hypoxic exposure
period. Two sizes of pial arteries were investigated to determine if
regional vascular differences with respect to the modulation of hypoxic
dilation by opioids could be observed. A sample of blood confirming the
hypoxia was taken 3 min after the hypoxia began. Once the blood
chemistry data confirmed that the desired level of hypoxia had been
achieved, dilator responses were recorded. In longer hypoxic exposure
animals, dilator responses were also recorded during the initial 10 min of exposure to confirm that these animals had responded appropriately to the stimulus. Therefore, differences observed at 20 or 40 min of
hypoxic exposure would not be due to an initially aberrant response.
Responses to hypoxia were separately obtained both before and after
-funaltrexamine (10
8 M)
or norbinaltorphimine (106
M, Research Biochemicals, Natick, MA). For hypoxia experiments in the
presence of -funaltrexamine or norbinaltorphimine, these inhibitors
were topically applied 10 min before induction of hypoxia, and the
subsequent effects of the inhibitor on hypoxia-induced pial artery
dilation were observed for the succeeding variable (5, 10, 20, or 40 min) exposure period. Appropriate aliquots of the vehicle for these
agents (0.9% saline) were added to CSF infused under the window. This
CSF vehicle had no effect on pial artery diameter.
Cortical periarachnoid CSF was collected 10 min after each hypoxic
exposure period and therefore represents the amount of opioid released
after a given stimulus period. Needles incorporated into the side of
the cranial window allowed for the injection of CSF under the window
and the runoff of excess CSF. For sample collection, 300 µl of CSF
were collected from under the cranial window, which has a total volume
of 500 µl, thereby minimizing dilution of the sample. The CSF (300 µl) was collected by slowly infusing artificial CSF into one side of
the window and allowing the CSF under the window to drip freely into a
collection tube on the opposite side.
Opioid analysis.
The CSF samples collected were acidified with 1 N acetic acid to
prevent protein degradation and stored at 
20°C. RIA kits for
methionine enkephalin and dynorphin are commercially available (IncStar, Stillwater, MN; Peninsula Laboratory, Belmont, CA). The RIA
used simultaneous addition of the sample, anti-opioid antibody, and the
125I derivative of the opioid.
After an overnight incubation at 4°C, the free opioid was first
separated from the opioid bound to the antibody by the addition of
saturated ammonium sulfate in the presence of rabbit carrier
-globulin. After centrifugation at 760 g for 10 min, the
supernate was decanted and the pellet was counted using a
gamma scintillation counter. All sample and standards were assayed in
duplicate. Data were calculated as %B/Bo vs. concentration, where
%B/Bo = [(average counts
per minute of sample average counts per minute of nonspecific
binding tube)/Bo] × 100, and Bo = average counts per
minute of total binding tube average counts per minute of
nonspecific binding tube.
Statistical analysis.
All measures were analyzed using ANOVA for repeated measures.
Comparisons were made on the basis of dilation or opioid release as a
function of hypoxic exposure time (e.g., 5-min dilation vs. other
exposures and all exposure durations vs. control for opioid concentration). Additionally, comparisons were made for values in the
presence of an antagonist vs. its absence for each exposure time. If
the values were significant, the Fisher test was performed. An level of P < 0.05 was considered
significant in all statistical tests;
n values then reflect data for one
vessel in each animal. Values are represented as means ± SE of
absolute values or as percent change from control values. Data
presented as percent change were compared by nonparametric means using
the Wilcoxon signed-rank test and Bonferroni correction.
| |
RESULTS |
Role of duration of stimulus in nature of pial artery response to
hypoxia.
Moderate and severe hypoxia (PaO2 35 and 25 mmHg, respectively) elicited reproducible
pial dilation during 5-, 10-, 20-, and 40-min exposure
periods (Tables 1 and
2). Whereas 5 min of hypoxia produced
dilation of magnitude quite similar to that observed during a 10-min
exposure period, the dilation seen during 20 and 40 min was decreased
from that observed during either a 5- or 10-min hypoxic exposure (Fig.
1).
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Fig. 1.
Influence of moderate (A;
n = 8 pigs/group) and severe hypoxia
(B; n = 8 pigs/group) of 5, 10, 20, or 40 min stimulus duration on pial
artery diameter. SA, small artery; A, arteriole.
* P < 0.05 compared
with corresponding response during 5-min exposure.
|
|
Contribution of opioids to hypoxic pial artery dilation as a
function of stimulus duration.
Moderate and severe hypoxia had no effect on cortical periarachnoid CSF
methionine enkephalin or dynorphin concentration during a 5-min
stimulus period (Fig. 2). During a 10-min
stimulation, however, both opioids were increased in CSF. During 20- and 40-min exposure periods, the CSF concentration of dynorphin also
was increased, whereas that of methionine enkephalin decreased (Fig 2).
The µ-opioid (methionine enkephalin) antagonist -funaltrexamine (108 M) had no influence on
dilation during the 5-min exposure, decremented the 10- and 20-min
exposure, but had no effect on 40-min exposure hypoxic dilation (Fig.
3). Whereas the -opioid (dynorphin)
antagonist norbinaltorphimine
(106 M) similarly had no
effect on a 5-min exposure dilation, it, in contrast, potentiated 10-, 20-, and 40-min exposure dilations, respectively (Fig.
4). In fact, norbinaltorphimine
substantially restored dilation during the 40-min exposure back toward
the response observed during a 10-min exposure (Figs. 1 and 4).
-Funaltrexamine had no effect by itself on pial artery diameter (140 ± 5 vs. 139 ± 6 µm, n = 5).
Norbinaltorphimine similarly had no effect on pial diameter.
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Fig. 2.
Influence of moderate and severe hypoxia (5-, 10-, 20-, or 40-min
duration) on cerebral spinal fluid (CSF) methionine enkephalin
(A; n = 8 pigs/group) or CSF dynorphin (B;
n = 8 pigs/group).
* P < 0.05 compared with
corresponding control (C) value.
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Fig. 3.
Influence of -funaltrexamine
(108 M) on pial artery
dilation during 5, 10, 20, or 40 min of moderate
(A) or severe hypoxia
(B)
(n = 8 pigs/group).
* P < 0.05 compared with
corresponding response during 5-min exposure. + P < 0.05 compared with
corresponding control value.
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Fig. 4.
Influence of norbinaltorphimine
(106 M) on pial artery
dilation during 5, 10, 20, or 40 min of moderate
(A) or severe hypoxia
(B)
(n = 8 pigs/group).
* P < 0.05 compared with
corresponding response during 5-min exposure. + P < 0.05 compared with
corresponding control value.
|
|
Blood chemistry and mean arterial blood pressure.
Blood chemistry and mean arterial blood pressure values were obtained
at the beginning and end of all experiments as well as during hypoxia.
Hypoxia decreased PaO2 as expected,
whereas the pH, PaCO2, and mean arterial
blood pressure values were unchanged (Tables
3 and 4).
| |
DISCUSSION |
Results of the present study show that whereas 5 min of hypoxia
produced pial artery dilation of magnitude quite similar to that
observed during a 10-min exposure period, the dilation seen during 20 min was somewhat decreased and that to 40 min substantially decreased
from that observed during either a 5- or 10-min hypoxic exposure. These
results indicate that the duration of the stimulus determines the
nature of the vascular response to hypoxia. As such, these results are
novel and were unanticipated from the original experimental design.
However, it should be noted that, when administered to a whole animal,
a step change in the inspired concentration of oxygen will often
require 10-15 min to produce a stable
PaO2 due to the many systemic
circulatory adjustments hypoxia induces. Thus the measurements at 5 or
10 min of hypoxia may not be steady-state responses, whereas those at
20 and 40 min may have been. This difference in stimulus dynamics could complicate data interpretation.
Additional studies were designed to characterize the contribution of
opioids to hypoxic pial artery dilation as a function of stimulus
duration. These results show that moderate and severe hypoxia had no
effect on cortical periarachnoid CSF methionine enkephalin or dynorphin
concentration during a 5-min stimulus period. Concomitantly, the
µ-opioid (methionine enkephalin) antagonist -funaltrexamine (20)
and the -opioid (dynorphin) antagonist norbinaltorphimine (14) had
no effect on pial dilation during a 5-min hypoxic stimulus. Taken
together, the biochemical data support and corroborate the
pharmacological data and indicate that these two opioids do not
modulate hypoxic pial dilation when the stimulus period is 5 min in
duration. Previously, it had been observed that the synthetic
µ-agonist
[D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin
and methionine enkephalin elicited pial dilation that was blocked by
-funaltrexamine (108 M)
but unchanged by 7-benzylidenenaltrexone, naltrindole, and norbinaltorphimine, i.e., by µ-,
1-,
2-, and -opioid receptor antagonists, respectively (1, 2, 14, 17, 18). Similar cross-selectively pharmacological experiments show that dynorphin pial
dilation was blocked by norbinaltorphimine
(106 M) but unchanged by
the other opioid antagonists (1, 2). Neither -funaltrexamine nor
norbinaltorphimine, however, had any effect on pial artery diameter by
themselves (1). These data indicate that these agents, at the doses
used in this study, are selective probes for characterizing the
contributions of µ- or -opioid receptors to a physiological
response. Additionally, these data suggest that there is little
contribution of these two opioids to baseline pial artery diameter.
In contrast, during a 10-min hypoxic stimulation, both methionine
enkephalin and dynorphin CSF concentrations were increased, consistent
with previous observations (1). Additionally, -funaltrexamine attenuated, whereas norbinaltorphimine potentiated, hypoxic pial artery
dilation. These data indicate that µ-opioid receptors contribute to,
whereas -opioid receptors oppose, hypoxic pial dilation, similarly
to previous observations (1). Taken together, these data also indicate
that the role of opioids in hypoxic pial artery dilation is stimulus
duration dependent.
Two additional hypoxic exposure periods were also investigated to
determine if the nature of the modulation of hypoxic pial dilation by
opioids changed with longer stimulation periods. These data show that
during 20- and 40-min exposure periods, the CSF concentration of
dynorphin continued to increase, whereas that of methionine enkephalin
steadily decreased. -Funaltrexamine attenuated pial artery dilation
during a 20-min hypoxic period but had no effect on the 40-min exposure
hypoxic pial dilation. On the other hand, norbinaltorphimine
potentiated the dilation observed during both 20- and 40-min
hypoxic stimulation periods. These data indicate that µ-opioid
receptor activation contributes to hypoxic pial dilation during a 20- but not a 40-min stimulation period. In contrast, -opioid modulation
of the vascular response became increasingly more important with the
longer duration of the stimulus. Such observations may, in fact, serve
as a partial explanation for the unanticipated results showing that the
duration of the stimulus determines the nature of the vascular response to hypoxia. For example, pharmacological data support and corroborate the biochemical data in this study and suggest that decremented hypoxic
pial dilation during longer exposure periods results, at least in part,
from decreased release of methionine enkephalin and accentuated release
of dynorphin. Additionally, dynorphin is a tone-dependent agent
(dilator during resting tone conditions; constrictor when
cerebrovascular tone decreased) (4). Because hypoxia increases pial
artery diameter, cerebrovascular tone will decrease during this
stimulus. Therefore, it is speculated that reversal of dynorphin from a
dilator to a constrictor during hypoxia could contribute to decremented
dilation during longer stimulation periods, an effect that would only
be accentuated because of elevated CSF dynorphin concentration during
such periods.
The choice of 10 min as the duration of hypoxia in previous studies was
arbitrary. Clinically, episodes of acute hypoxia are variable in
duration and often last longer than 10 min. Recent data from Leffler et
al. (7) in the newborn pig show that NO and activation of ATP-dependent
K+ channels do not contribute to
pial artery dilation during 5 min of hypoxia. Because previous data
from this laboratory show that NO and activation of such
K+ channels contribute to pial
artery dilation during 10 min of hypoxia in the piglet (1, 16, 22),
these studies, together, suggest that the relative importance of other
mechanisms involved in hypoxic pial dilation change as a function of
the duration of the stimulus.
Potential sources of opioids in cortical periarachnoid CSF are neurons,
glia, vascular smooth muscle, and endothelial cells. However, the
source of these substances cannot be determined from the present
experimental design. Whereas the exact mechanism for coupling of
hypoxia to opioid release is uncertain, recent evidence supports roles
for NO, cGMP, cAMP, and pituitary adenylate cyclase-activating polypeptide (22, 23). Additionally, whereas two different sizes of pial
arteries were investigated to determine if segmental differences with
respect to opioid modulation of hypoxic dilation could be observed, no
such difference was readily apparent.
In conclusion, data from the present study show that opioids do not
modulate hypoxic pial artery dilation during short but do so during
longer exposure periods. Moreover, hypoxic pial dilation is diminished
during longer exposure periods. Decremented hypoxic pial dilation
during longer exposure periods results, at least in part, from
decreased release of methionine enkephalin and accentuated release of
dynorphin. These data suggest that the relative role of opioids in
hypoxic pial dilation changes with the stimulus duration.
| |
ACKNOWLEDGEMENTS |
The author thanks Joseph Quinn for technical assistance in the
performance of the experiments.
| |
FOOTNOTES |
This research was supported by grants from the National Institutes of
Health and the American Heart Association (AHA). W. M. Armstead is an
Established Investigator of the AHA.
Address for reprint requests: W. M. Armstead, Dept. of Anesthesia, 34th
& Civic Center Blvd., The Children's Hospital of Philadelphia,
Philadelphia, PA 19104.
Received 11 December 1997; accepted in final form 22 May 1998.
| |
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Am J Physiol Heart Circ Physiol 275(3):H861-H867
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Abstract
Introduction
