Vol. 275, Issue 6, H2072-H2079, December 1998
Vasopressin contributes to dynorphin modulation of hypoxic
cerebrovasodilation
Andrew
Venteicher and
William M.
Armstead
Departments of Anesthesia and Pharmacology, University of
Pennsylvania and The Children's Hospital of Philadelphia,
Philadelphia, Pennsylvania 19104
 |
ABSTRACT |
Because pial artery dilation during a 20- or
40-min hypoxic exposure was less than that observed during a 5- or
10-min exposure, stimulus duration determines the vascular response to
hypoxia. Dynorphin (Dyn) modulates hypoxic pial dilation and
contributes to decremented dilation during longer hypoxic exposures.
This study was designed to determine whether vasopressin (VP)
contributes to Dyn modulation of hypoxic pial dilation in newborn pigs
equipped with a closed cranial window. Moderate (M) and severe (S)
hypoxia (arterial PO2 ~ 35 and 25 mmHg, respectively) had no effect on cerebrospinal fluid VP during a
5-min exposure but increased its concentration during longer exposure
periods. The VP antagonist [
-mercapto-,-cyclopentamethylenepropionyl1,O-Me-Tyr2,Arg8]vasopressin
(MEAVP) had no influence on pial dilation during the 5-min exposure but
potentiated the 20- and 40-min M and S hypoxic exposure dilations: 21 ± 2 vs. 29 ± 3% and 23 ± 2 vs. 33 ± 2% for 20- and
40-min S hypoxic dilation before and after MEAVP. Topical VP during 5 min of hypoxia elicited dilation that was reversed to vasoconstriction
during 20 min of S and 40 min of M and S hypoxia. Similarly, during 5 min of hypoxia, Dyn elicited dilation that was reversed to
vasoconstriction during longer hypoxic periods. MEAVP blunted this
Dyn-induced vasoconstriction. These data show that VP modulates hypoxic
pial dilation in a stimulus duration-dependent manner and that VP
contributes to the reversal of Dyn from a dilator to a constrictor
during prolonged hypoxia. Finally, these data suggest that VP
contributes to Dyn modulation of hypoxic cerebrovasodilation.
newborn; cerebral circulation; opioids
| |
INTRODUCTION |
VASOPRESSIN CONTRIBUTES to the regulation of cerebral
hemodynamics. Previous studies have shown vasopressin to produce
cerebral artery vasoconstriction in the cat, goat, and human (11, 18, 22), dilation in the cat and dog (14), or no effect in the rat (16).
Although there may be species and/or regional vascular differences, a possible explanation for such divergent observations could be that vasopressin's actions are tone dependent. For example, in the piglet, vasopressin elicits dilation during resting tone and
vasoconstriction when cerebrovascular tone is decreased (6).
Several mechanisms have been proposed to account for hypoxia-induced
cerebrovasodilation. These possibilities include opioids, vasopressin,
adenosine, prostaglandins, and nitric oxide (NO) (9, 10, 13, 21). For
example, it was observed that hypoxia increases plasma methionine
enkephalin in fetal sheep (20) and plasma -endorphin in human
newborns at delivery (19, 27) and in infants with hypoxic ischemic
encephalopathy with ongoing hypoxia (24). In the newborn pig, hypoxia
for 10 min was associated with elevated cortical periarachnoid
cerebrospinal fluid (CSF) levels of the opioids methionine enkephalin,
leucine enkephalin, and dynorphin (1, 2), which are µ-, 
-, and
-opioid agonists, respectively. Because µ- and -receptor
antagonists attenuated, whereas a -antagonist potentiated, hypoxic
pial artery dilation, these data indicate that methionine enkephalin
and leucine enkephalin contribute, whereas dynorphin opposes, hypoxic
pial dilation (1, 2). However, recent data indicate that such
modulation of hypoxic dilation by opioids is dependent on the duration
of hypoxia. For example, CSF methionine enkephalin concentration was
unchanged during a 5-min exposure and increased during a 10-min
exposure but decreased during 20- and 40-min hypoxic exposures (4). A
µ-opioid antagonist had no influence on dilation during the 5-min
exposure and decremented the 10- and 20-min exposures but had no effect
on the 40-min exposure to hypoxic dilation. In contrast, CSF dynorphin
concentration was elevated for all except the 5-min hypoxic exposure,
and a -antagonist potentiated 10-, 20-, and 40-min exposure dilation
(4). Interestingly, hypoxic pial dilation was diminished during longer
exposure periods (4). These data, therefore, indicated that such
decremented hypoxic pial dilation during longer exposure periods
resulted from decreased release of methionine enkephalin and
accentuated release of dynorphin. Because dynorphin also is a
tone-dependent agent like vasopressin (6) and hypoxia decreases
cerebral tone, these data suggest that dynorphin reverses from a
dilator to a vasoconstrictor during hypoxia. In the piglet, 10 min of
hypoxia also increased CSF vasopressin, whereas a vasopressin
antagonist attenuated hypoxic pial artery dilation, indicating that
vasopressin contributes to the vascular response during this stimulus
(23). In unrelated studies it had been observed earlier that
vasopressin contributed to the reversal of dynorphin from a dilator to
a constrictor during decreased tone conditions (5, 8). However, the
role of vasopressin in the vascular response during longer hypoxic
exposures is uncertain. Equally uncertain is the ability of vasopressin
to contribute to the dynorphin-induced modulation of hypoxic pial
artery dilation.
Therefore, the present study was designed to determine whether
vasopressin contributes to dynorphin modulation of hypoxic pial artery
dilation by 1) characterizing the
contribution of endogenous vasopressin to hypoxic pial dilation as a
function of exposure duration, 2)
determining the vascular response to exogenous vasopressin during
hypoxia as a function of exposure duration, and
3) determining the contribution of
vasopressin to the vascular response of exogenous dynorphin during
hypoxia as a function of hypoxic exposure duration.
| |
METHODS |
All experiments have been approved by the Institutional Animal Care and
Use Committee. Pigs (1-5 days old) of either gender were
anesthetized with ketamine hydrochloride-acepromazine (33 mg/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 (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 16 groups:
1) 5 and 10 min of moderate and
severe hypoxia time control (n = 5),
2) 20 min of moderate and severe
hypoxia time control (n = 5),
3) 40 min of moderate and severe
hypoxia time control (n = 5),
4) 5 and 10 min of moderate and
severe hypoxia before and after
[-mercapto-,-cyclopentamethylenepropionyl1,O-Me-Tyr2, Arg8]vasopressin
(MEAVP, n = 8),
5) 20 min of moderate and severe hypoxia before and after MEAVP (n = 8), 6) 40 min of moderate and severe
hypoxia before and after MEAVP (n = 8), 7) lysine vasopressin (LVP)
after 5 and 10 min of moderate and severe hypoxia
(n = 8), 8) LVP after 20 min of moderate and
severe hypoxia (n = 8),
9) LVP after 40 min of moderate and
severe hypoxia (n = 8),
10) dynorphin after 5 and 10 min of
moderate and severe hypoxia (n = 8),
11) dynorphin after 20 min of
moderate and severe hypoxia (n = 8), 12) dynorphin after 40 min of
moderate and severe hypoxia (n = 8),
13) dynorphin after 5 and 10 min of
moderate and severe hypoxia in MEAVP-pretreated animals
(n = 8),
14) dynorphin after 20 min of
moderate and severe hypoxia in MEAVP-pretreated animals
(n = 8),
15) dynorphin after 40 min of severe
hypoxia in MEAVP-pretreated animals (n = 8), and 16) LVP and dynorphin time
controls (n = 5). Time control
experiments were designed so that responses were obtained initially
(time 1 in Fig.
1), then again 30 min later (time 2 in Fig. 1). Severity and
duration of hypoxia were randomized within groups.
View larger version (25K):
[in this window]
[in a new window]
|
Fig. 1.
A: influence of moderate hypoxia (5, 10, 20, 40 min) on pial small artery (SA) and arteriole (A) diameter.
B: influence of severe hypoxia (5, 10, 20, 40 min) on pial small artery and arteriole diameter.
Time 1, initial response;
time 2, response at 30 min;
n = 5.
|
|
Hypoxia (5, 10, 20, and 40 min) was produced by decreasing the inspired
O2 sufficiently to reduce and
maintain arterial PO2 (PaO2) at 35 ± 5 and 25 ± 3 mmHg
(moderate and severe hypoxia, respectively) while maintaining constant
arterial PCO2 in the normocapnic
range (33 ± 3 mmHg). Changes in pial artery diameter (120-160
and 50-70 µm for small artery and arteriole, respectively) were
measured every minute during the last 5 min of each hypoxic exposure
period. Two sizes of pial arteries were investigated to determine
whether regional vascular differences with respect to the modulation of
hypoxic dilation by vasopressin 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 animals exposed
to hypoxia for longer periods, 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 obtained before
and after MEAVP (5 µg/kg iv; Sigma Chemical, St. Louis, MO). This
dose of MEAVP has previously been shown to inhibit responses to
topically applied vasopressin (6). For hypoxia experiments in the
presence of MEAVP, this inhibitor was systemically administered 30 min
before induction of hypoxia, and the effects of the inhibitor on
hypoxia-induced pial artery dilation were observed for the succeeding
variable (5-, 10-, 20-, or 40-min exposure period).
Cortical periarachnoid CSF was collected during the last 10 min of each
hypoxic exposure period and therefore represents the amount of
vasopressin 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.
To investigate the effects of hypoxia on responses to vasopressin and
dynorphin, LVP (40, 400, and 4,000 pg/ml; Sigma Chemical) and dynorphin
(10
10,
108, and
106 M; Sigma Chemical) were
topically applied before and during moderate and severe hypoxia (5, 10, 20, and 40 min). The concentrations of vasopressin investigated in this
study were chosen to reflect the concentrations in CSF at rest (40 pg/ml), long hypoxic stimulation (400 pg/ml), or pharmacological (4,000 pg/ml) conditions. For these experiments, these agents were applied
during hypoxia but at the end of the respective time period. Data for
dynorphin and vasopressin responses were calculated by obtaining the
percent change in baseline diameter from that obtained during hypoxia alone for each period of hypoxic exposure. LVP is the form of vasopressin in the pig. Appropriate aliquots of the vehicle for all
agents (0.9% saline) were added to the CSF infused under the window.
This CSF vehicle had no effect on pial artery diameter.
Vasopressin analysis.
CSF samples were immediately frozen and stored at 
20°C. RIA
kits for vasopressin are commercially available (Incstar). The RIA uses
simultaneous addition of sample, rabbit anti-vasopressin antibody, and
the 125I derivative of
vasopressin. The antibody used in this RIA did not cross-react
significantly with oxytocin or vasotocin (<0.5% cross-reactivity).
After an overnight incubation at 4°C, free vasopressin was
separated from vasopressin bound to the antibody by the addition of a
precipitating complex consisting of guinea pig serum precipitated with
goat anti-guinea pig serum and polyethylene glycol. After
centrifugation at 760 g for 20 min,
the supernatant was decanted, and the pellet was counted with a gamma
scintillation counter. All samples and standards were assayed in
duplicate. Data are calculated as
%B/B0 vs.
concentration, where B/B0 is [(average cpm of sample average cpm of nonspecific binding tube)/(average cpm of total
binding tube average cpm of nonspecific binding tube)] × 100.
Statistical analysis.
Pial artery diameter, systemic arterial pressure, and vasopressin
values were analyzed using repeated-measures analysis or t-test where appropriate. If the
F value was significant, Fisher's test was performed on all data analyzed by repeated measures. P < 0.05 was considered significant
in all statistical tests. The n values
reflect data for one vessel in each animal. Values are means ± SE
of absolute values or as percent change from control values. Data
presented as percent change were also compared by nonparametric means
with the Wilcoxon signed rank test.
| |
RESULTS |
Contribution of vasopressin to hypoxic pial artery dilation as a
function of stimulus duration.
Moderate and severe hypoxia (PaO2 ~ 35 and 25 mmHg, respectively) elicited reproducible pial small artery
(120-160 µm) and arteriole (50-70 µm) dilation during 5-, 10-, 20-, and 40-min exposure periods (Fig. 1). Although 5 min of
hypoxia produced dilation of magnitude quite similar to that observed
during a 10-min exposure period (Fig. 1), the dilation seen during 20 and 40 min was decreased from that observed during 5 or 10 min of hypoxic exposure (Fig. 2). Moderate and
severe hypoxia had no effect on cortical periarachnoid CSF vasopressin
concentration during a 5-min stimulus period (Fig.
3). During 10-, 20-, and 40-min exposure
periods, however, vasopressin concentration increased steadily with the
lengthening of the exposure period (Fig. 3). The vasopressin antagonist
MEAVP (5 µg/kg iv) had no influence on dilation during the 5-min
exposure and decremented the 10-min moderate and severe and the 20-min
moderate hypoxic exposure but potentiated the 20-min severe and the
40-min moderate and severe hypoxic exposure dilations (Fig. 2). The
potentiation by MEAVP during 20 min of severe and 40 min of moderate or
severe hypoxia was sufficiently great as to make those responses,
typically diminished because of the effects of longer exposure to
hypoxia, no different from the response observed during shorter (5 or
10 min) exposure (Fig. 2). MEAVP alone had no effect on pial artery
diameter (142 ± 6 vs. 146 ± 7 µm,
n = 8).
View larger version (27K):
[in this window]
[in a new window]
|
Fig. 2.
A: influence of
[-mercapto-,-cyclopentamethylenepropionyl1,O-Me-Tyr2,Arg8]vasopressin
(MEAVP, 5 µg/kg iv) on pial small artery and arteriole dilation
during moderate hypoxia (5, 10, 20, 40 min).
B: influence of MEAVP on pial small
artery and arteriole dilation during severe hypoxia (5, 10, 20, 40 min). n = 8. * P < 0.05 compared with
corresponding response during 5-min exposure;
+ P < 0.05 compared with corresponding control value.
|
|
View larger version (17K):
[in this window]
[in a new window]
|
Fig. 3.
Influence of moderate and severe hypoxia (5, 10, 20, 40 min) on
cerebrospinal fluid vasopressin concentration. C, control;
n = 8. * P < 0.05 compared
with corresponding control value.
|
|
Topical vasopressin elicited reproducible pial small artery and
arteriole dilation (Table 1). Vasopressin
dilation was unchanged during 5- and 10-min hypoxic exposures (Fig.
4). However, vasopressin-induced pial
artery dilation was decremented during a 20-min moderate hypoxic
exposure and reversed to vasoconstriction during a 40-min moderate
hypoxic exposure (Fig. 4, A and
B). Similarly, vasopressin-induced dilation was reversed to vasoconstriction during 20 and 40 min of
severe hypoxia (Fig. 4, C and
D).
View larger version (45K):
[in this window]
[in a new window]
|
Fig. 4.
A: influence of vasopressin (40, 400, 4,000 pg/ml) on pial small artery diameter during moderate hypoxia (0, 5, 10, 20, 40 min). B: influence of
vasopressin on pial arteriole diameter during moderate hypoxia (0, 5, 10, 20, 40 min). C: influence of
vasopressin (40, 400, 4,000 pg/ml) on pial small artery diameter during
severe hypoxia (0, 5, 10, 20, 40 min).
D: influence of vasopressin on pial
arteriole diameter during severe hypoxia (0, 5, 10, 20, 40 min).
n = 8. * P < 0.05 compared with
corresponding response during normoxia (0 min of hypoxia).
|
|
Contribution of vasopressin to dynorphin vascular responses during
hypoxia as a function of duration of hypoxic exposure.
Topical dynorphin (1010,
108, or
106 M) elicited
reproducible pial small artery and arteriole dilation (Table 1).
Dynorphin-induced dilation was unchanged during 5 min of hypoxic
exposure but was reversed to vasoconstriction during 10, 20, and 40 min
of moderate hypoxic exposure (Fig. 5).
Dynorphin dilation during normoxia (0 min of hypoxia in Fig. 5,
C and
D) was potentiated by MEAVP compared
with corresponding normoxic values in the absence of MEAVP (Fig. 5,
A and
B). Although MEAVP had no effect on
dynorphin-induced dilation during 5 min of moderate hypoxia (Fig. 5),
such responses during 5 min of hypoxia were smaller than corresponding
normoxic values because of the aforementioned MEAVP potentiation of
dynorphin dilation during normoxia (Fig. 5,
C and
D). MEAVP modestly accentuated the
reversal of dynorphin from a dilator to a constrictor during 10 min of
moderate hypoxia but blunted such reversal during 20 and 40 min of
moderate hypoxia (Fig. 5, C and
D). MEAVP had similar effects on
dynorphin vascular responses during severe hypoxia (data not shown).
View larger version (38K):
[in this window]
[in a new window]
|
Fig. 5.
A: influence of dynorphin
(1010,
108,
106 M) on pial small artery
diameter during moderate hypoxia (0, 5, 10, 20, 40 min).
B: influence of dynorphin on pial
arteriole diameter during moderate hypoxia (0, 5, 10, 20, 40 min).
C: influence of MEAVP (5 µg/kg iv)
on pial small artery responses to dynorphin
(1010,
108,
106 M) during moderate
hypoxia (0, 5, 10, 20, 40 min). D:
influence of MEAVP on pial arteriole responses to dynorphin during
moderate hypoxia (0, 5, 10, 20, 40 min).
n = 8. * P < 0.05 compared with
corresponding response during normoxia (0 min of hypoxia).
+ P < 0.05 compared with corresponding response in absence of MEAVP (cf.
A and
B).
|
|
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 (35 ± 3, 25 ± 3, and 93 ± 4 mmHg for moderate hypoxia, severe
hypoxia, and normoxia, respectively) whereas the pH, arterial
PCO2, and mean arterial blood
pressure values were unchanged (7.44 ± 0.01, 33 ± 2, and 68 ± 4 mmHg vs. 7.43 ± 0.01, 34 ± 3, and 66 ± 5 mmHg, respectively).
| |
DISCUSSION |
Results of the present study show that although 5 min of hypoxia
produced pial artery dilation of magnitude quite similar to that
observed during 10 min of exposure, the dilation seen during 20 and 40 min was decreased from that observed during 5 or 10 min of hypoxic
exposure. These results indicate that the duration of the stimulus
determines the nature of the vascular response to hypoxia, consistent
with a recent study (4). New data in the present study show that
moderate and severe hypoxia had no effect on cortical periarachnoid CSF
vasopressin concentration during a 5-min stimulus period.
Concomitantly, the vasopressin antagonist MEAVP 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 vasopressin does not contribute to hypoxic pial dilation
when the stimulus period is 5 min.
In contrast, during a 10-min hypoxic stimulation, vasopressin CSF
concentration was increased, consistent with previous observations (23). New data in the present study show that CSF vasopressin concentration continued to increase during 20- and 40-min exposure periods. MEAVP decremented the 10-min moderate and severe and the
20-min moderate hypoxic exposure but potentiated the 20-min severe and
the 40-min moderate and severe hypoxic exposure dilations. Vascular
responses during 20 and 40 min of moderate or severe hypoxia were
typically diminished because of the effects of longer hypoxic exposure.
However, the potentiation by MEAVP made such responses no different
from the response observed during shorter (5- or 10-min) exposures.
Thus vasopressin contributes to 10-min moderate and severe and 20-min
moderate hypoxic pial dilation. The latter data suggested, however,
that vasopressin contributes to decremented hypoxic pial artery
dilation during longer exposure periods. Taken together, these data
indicate that the role of vasopressin in hypoxic pial artery dilation
is stimulus duration dependent. Systemically administered MEAVP had
previously been observed to block vascular responses to topical
vasopressin (6). MEAVP by itself, however, had no effect on pial artery
diameter, indicating that there was little tonic vasopressin
contribution to resting vascular tone.
Because vasopressin is a tone-dependent agent (6), observations that
MEAVP restored decremented hypoxic pial dilation during longer
exposure periods toward values obtained using shorter exposure periods
suggest that vasopressin reversed from a dilator to a vasoconstrictor
during such longer periods. New data in this study, in fact, show this
to be the case. For example, exogenously administered vasopressin-induced dilation was unchanged during 5- and 10-min hypoxic
exposures. However, vasopressin-induced pial artery dilation was
decremented during 20 min of moderate hypoxia. During 20 min of severe
hypoxia and 40 min of moderate or severe hypoxia, vasopressin-induced dilation was reversed to vasoconstriction. These data indicate that the
duration of hypoxia can influence the vascular response to vasopressin.
Similar to vasopressin, the observation that a dynorphin antagonist
partially restored decremented hypoxic pial dilation during long
exposure periods (4) suggested that dynorphin also reversed from a
dilator to a vasoconstrictor during hypoxia. Additional data in the
present study show that dynorphin-induced dilation was unchanged during
a 5-min hypoxic exposure but was reversed to vasoconstriction during
10-, 20-, and 40-min hypoxic exposures. In previous studies,
vasopressin attenuated dynorphin-induced dilation during resting
cerebrovascular tone but contributed to the reversal of dynorphin from
a dilator to a vasoconstrictor during normoxic decreased
cerebrovascular tone conditions (5, 8). At that time, it had been
speculated that dynorphin-induced dilation resulted in a decreased
cerebrovascular tone that reversed the tone-dependent agent vasopressin
from a dilator to a constrictor to oppose dynorphin dilation during
normoxia. Such results were confirmed in the present study. New data in
this study show that although MEAVP had no effect on dynorphin-induced
dilation during the 5-min hypoxic exposure period, it modestly
accentuated the reversal of dynorphin from a dilator to a constrictor
during 10-min moderate and severe hypoxic exposure periods. These data
are consistent with the observations that vasopressin is a vasodilator
during a 5- or 10-min hypoxic exposure, thereby opposing
dynorphin-induced vasoconstriction that occurs during a 10-min hypoxic
exposure. In contrast, MEAVP blunted the reversal of dynorphin from a
dilator to a constrictor during 20- and 40-min hypoxic exposure
periods. These data are consistent with the observation that
vasopressin is a vasoconstrictor during such exposure periods and would
therefore contribute to the reversal of dynorphin from a dilator to a
constrictor. These data then suggest that vasopressin contributes to
dynorphin modulation of hypoxic cerebrovasodilation. Table
2 summarizes the effects of dynorphin and
vasopressin on pial artery diameter as well as the interactions between
these two agents as a function of hypoxic exposure duration. Table 2
shows that although vasopressin has no effect on dynorphin dilation
during 5 min of hypoxia, it opposes dynorphin constriction during 10 min of hypoxic exposure and contributes to such vasoconstriction during
20- and 40-min hypoxic exposures.
View this table:
[in this window]
[in a new window]
|
Table 2.
Influence of dynorphin, vasopressin, and vasopressin-dynorphin
interaction on pial artery diameter as a function of hypoxic
duration
|
|
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 for >10 min. Recent data from Leffler et al.
(17) 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, 25, 28),
these studies together suggest that the relative importance of other
mechanisms involved in hypoxic pial dilation changes as a function of
the duration of the stimulus.
The origin of the vasopressin detected in CSF cannot be determined from
the present experiments. The presence of vasopressin-immunoreactive nerve fibers has been demonstrated in guinea pig pial arteries (12).
Furthermore, it has been reported that vascular tissues obtained from
the aorta, vena cava, renal artery, and mesenteric artery of
Sprague-Dawley and hypophysectomized rats contain immunoreactive stores
of vasopressin (26). These data suggest that vascular stores of
vasopressin could be of nonpituitary origin (26). Although the cellular
site of origin is uncertain, the vasopressin detected in CSF could
therefore be locally derived from pial vessel stores for vasopressin or
from nerves associated with those vessels. Because MEAVP blocked
vasodilation to topical vasopressin (6) and has been reported to be a
V1 antagonist (15), this CSF
vasopressin appears to predominantly interact with the
V1 receptor in the piglet cerebral
circulation. Such vasodilation is dependent on the release of NO (3,
14). Interestingly, the constrictor component for vasopressin during
reduced-tone conditions is also dependent on activation of the same
V1 receptor (6). MEAVP, however,
is specific for antagonism of vasopressinergic receptors in the piglet
cerebral circulation, since it has been previously observed that
responses to norepinephrine, the thromboxane mimic U-46619, and
isoproterenol were unchanged by this antagonist (6).
In conclusion, results of the present study show that vasopressin
modulates hypoxic pial artery dilation in a stimulus duration-dependent manner. These data also show that vasopressin contributes to the reversal of dynorphin from a dilator to a vasoconstrictor during prolonged hypoxia. Finally, these data suggest that vasopressin contributes to dynorphin modulation of hypoxic cerebrovasodilation.
| |
ACKNOWLEDGEMENTS |
The authors thank 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. W. M. Armstead is an
Established Investigator of the American Heart Association.
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests: W. M. Armstead, Dept. of Anesthesia, 34th
& Civic Center Blvd., The Children's Hospital of Philadelphia,
Philadelphia, PA 19104.
Received 15 May 1998; accepted in final form 4 August 1998.
| |
REFERENCES |
1.
Armstead, W. M.
Opioids and nitric oxide contribute to hypoxia-induced pial artery vasodilation in the newborn pig.
Am. J. Physiol.
268 (Heart Circ. Physiol. 37):
H226-H232,
1995[Abstract/Free Full Text].
2.
Armstead, W. M.
The contribution of 1 and 2-opioid receptors to hypoxia-induced pial artery dilation in the newborn pig.
J. Cereb. Blood Flow Metab.
15:
539-546,
1995[Medline].
3.
Armstead, W. M.
Influence of brain injury on vasopressin-induced pial artery vasodilation: role of superoxide anion.
Am. J. Physiol.
270 (Heart Circ. Physiol. 39):
H1272-H1278,
1996[Abstract/Free Full Text].
4.
Armstead, W. M.
Role of opioids in hypoxic pial artery dilation is stimulus duration dependent.
Am. J. Physiol.
275 (Heart Circ. Physiol. 44):
H861-H867,
1998[Abstract/Free Full Text].
5.
Armstead, W. M.,
J. T. Crofton,
L. Share,
R. Mirro,
S. I. Zuckerman,
and
C. W. Leffler.
Influence of opioids on CSF vasopressin concentration in newborn pigs.
Am. J. Physiol.
262 (Heart Circ. Physiol. 31):
H862-H867,
1992[Abstract/Free Full Text].
6.
Armstead, W. M.,
R. Mirro,
D. W. Busija,
and
C. W. Leffler.
Vascular responses to vasopressin are tone-dependent in the cerebral circulation of the newborn pig.
Circ. Res.
64:
136-144,
1989[Abstract/Free Full Text].
7.
Armstead, W. M.,
R. Mirro,
D. W. Busija,
and
C. W. Leffler.
Opioids in cerebrospinal fluid in hypotensive newborn pigs.
Circ. Res.
68:
922-929,
1991[Abstract/Free Full Text].
8.
Armstead, W. M.,
R. Mirro,
S. L. Zuckerman,
and
C. W. Leffler.
Vasopressin modulates cerebrovascular responses to opioids in newborn pigs.
J. Pharmacol. Exp. Ther.
260:
1107-1112,
1992[Abstract/Free Full Text].
9.
Coyle, M. D.,
W. Oh,
and
B. S. Stonestreet.
Effects of indomethacin on brain blood flow and cerebral metabolism in hypoxic newborn piglets.
Am. J. Physiol.
264 (Heart Circ. Physiol. 33):
H141-H149,
1993[Abstract/Free Full Text].
10.
Eisenach, J. C.,
C. Tong,
A. Stump,
and
S. M. Block.
Vasopressin and fetal cerebrovascular regulation.
Am. J. Physiol.
263 (Regulatory Integrative Comp. Physiol. 32):
R376-R381,
1992[Abstract/Free Full Text].
11.
Hanko, J.,
J. E. Hardebo,
and
C. Owman.
Vasomotor effects of some neuropeptides on isolated pial arteries of the cat.
In: Cerebral Microcirculation and Metabolism, edited by J. Cervos-Navarro,
and E. Fritschka. New York: Raven, 1981, p. 157-161.
12.
Itakura, T.,
T. Okuno,
M. Ueno,
K. Nakakita,
K. Nakai,
Y. Naka,
H. Imai,
I. Kamei,
and
N. Komai.
Immunohistochemical demonstration of vasopressin fibers in the cerebral artery.
J. Cereb. Blood Flow Metab.
8:
606-608,
1988[Medline].
13.
Iwamoto, J.,
S. P. Yang,
E. Yoshinaga,
and
J. Krasney.
N
-nitro-L-arginine influences cerebral metabolism in awake sheep.
J. Appl. Physiol.
73:
2233-2240,
1992[Abstract/Free Full Text].
14.
Katusic, Z. A.,
J. T. Shepherd,
and
P. M. Vanhoutte.
Vasopressin causes endothelium-dependent relaxation of the canine basilar artery.
Circ. Res.
55:
575-579,
1984[Abstract/Free Full Text].
15.
Kruszynski, M.,
B. Lammek,
and
M. Manning.
[1-(-Mercapto-,-cyclopentamethylene-propionic acid),2-(O-methyl)tyrosine]arginine vasopressin and [1--mercapto-,-cyclopentamethylene propionic acid]arginine vasopressin, two highly potent antagonists of the vasopressor response to arginine vasopressin.
J. Med. Chem.
23:
364-368,
1980[Medline].
16.
Lassoff, S.,
and
B. M. Altura.
Do pial terminal arterioles respond to local perivascular application of the neurohypophyseal peptide hormones vasopressin and oxytocin?
Brain Res.
196:
266-269,
1980[Medline].
17.
Leffler, C. W.,
J. S. Smith,
J. L. Edrington,
S. L. Zuckerman,
and
H. Parfenova.
Mechanisms of hypoxia-induced cerebrovascular dilation in the newborn pig.
Am. J. Physiol.
272 (Heart Circ. Physiol. 41):
H1323-H1332,
1997[Abstract/Free Full Text].
18.
Lluch, S.,
M. C. Conde,
G. Dieguez,
A. L. Lopez de Pablo,
M. C. Gonzalez,
C. Estrada,
and
B. Gomez.
Evidence for the direct effect of vasopressin on human and goat cerebral arteries.
J. Pharmacol. Exp. Ther.
228:
749-755,
1984[Abstract/Free Full Text].
19.
Martinez, A. M.,
J. J. Padbury,
E. Burnell,
and
S. L. Thio.
Plasma methionine enkephalin levels in the human newborn at birth.
Biol. Neonate
60:
102-103,
1991[Medline].
20.
Martinez, A. M.,
J. F. Padbury,
E. Burnell,
S. L. Thio,
and
J. Humme.
The effects of hypoxia on methionine enkephalin peptide and catecholamine release in fetal sheep.
Pediatr. Res.
27:
52-55,
1990[Medline].
21.
Morii, S.,
A. C. Ngai,
K. R. Ko,
and
H. R. Winn.
Role of adenosine in regulation of cerebral blood flow: effects of theophylline during normoxia and hypoxia.
Am. J. Physiol.
253 (Heart Circ. Physiol. 22):
H165-H175,
1987[Abstract/Free Full Text].
22.
Nakai, M.
Contractile effects of perivascularly applied vasopressin on the pial artery of the cat brain.
J. Physiol. (Lond.)
387:
441-452,
1987[Abstract/Free Full Text].
23.
Rossberg, M. I.,
and
W. M. Armstead.
Relationship between vasopressin and opioids in hypoxia-induced pial artery vasodilation.
Am. J. Physiol.
271 (Heart Circ. Physiol. 40):
H521-H527,
1996[Abstract/Free Full Text].
24.
Sankaran, K.,
K. V. Hindmarsh,
and
V. G. Watson.
Hypoxic-ischemic encephalopathy and plasma -endorphin.
Dev. Pharmacol. Ther.
7:
377-383,
1983.
25.
Shankar, V.,
and
W. M. Armstead.
Opioids contribute to hypoxia-induced pial artery dilation through activation of ATP-sensitive K+ channels.
Am. J. Physiol.
269 (Heart Circ. Physiol. 38):
H997-H1002,
1995[Abstract/Free Full Text].
26.
Simon, J. S.,
B. G. Kasson,
and
M. J. Brody.
Characterization of vasopressin-like peptide in rat and bovine blood vessels.
Am. J. Physiol.
262 (Heart Circ. Physiol. 31):
H799-H805,
1992[Abstract/Free Full Text].
27.
Wardlaw, S. L.,
R. I. Stark,
L. Baxi,
and
A. G. Franz.
Plasma -endorphin and -lipotropin in the human fetus at delivery: correlation with arterial pH and PO2.
J. Clin. Endocrinol. Metab.
49:
888-891,
1979[Abstract].
28.
Wilderman, M. J.,
and
W. M. Armstead.
Relationship between nitric oxide and opioids in hypoxia-induced pial artery vasodilation.
Am. J. Physiol.
270 (Heart Circ. Physiol. 39):
H869-H871,
1996[Abstract/Free Full Text].
Am J Physiol Heart Circ Physiol 275(6):H2072-H2079
0002-9513/98 $5.00
Copyright © 1998 the American Physiological Society
Top
Abstract
Introduction
