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Departments of Anesthesia and Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania 19104
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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This
study characterized the contributions of protein tyrosine kinase (PTK)
and mitogen-activated protein kinase (MAPK) in nociceptin/orphanin FQ
(NOC/oFQ)-induced impairment of hypercapnic pial artery dilation (PAD)
after hypoxia/ischemia (H/I) in piglets equipped with a closed
cranial window. NOC/oFQ (10
10 M cerebrospinal fluid H/I
concentration) impaired hypercapnic PAD (21 ± 2% vs. 13 ± 1%). Coadministration of either of the PTK inhibitors genistein or
tyrphostin A23 or the MAPK inhibitors U-0126 or PD-98059 with NOC/oFQ
(1010 M) partially prevented the inhibition of
hypercapnic PAD compared with that observed in their absence (21 ± 2% vs. 17 ± 1% for genistein). After exposure to H/I, PAD in
response to hypercapnia was impaired, but pretreatment with either
genistein, tyrphostin A23, U-0126, or PD-98059 partially protected such
impairment (17 ± 1% vs. 4 ± 1% vs. 9 ± 1% for sham
control, H/I, and H/I + genistein pretreatment, respectively).
These data show that PTK and MAPK activation contribute to
NOC/oFQ-induced impairment of hypercapnic PAD. These data suggest that
activation of PTK and MAPK is also involved in the mechanism by which
NOC/oFQ impairs hypercapnic PAD after H/I.
newborn; cerebral circulation; opioids; signal transduction; protein tyrosine kinase; mitogen-activated protein kinase; nociceptor/orphanin FQ
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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EPISODES OF INADEQUATE OXYGEN SUPPLY to the brain can result in significant neurological sequelae. Babies are frequently exposed to either combined or sequential hypoxia and ischemia insults during the perinatal period due to problems with delivery or respiratory management postdelivery (29). One contributor to neurological damage is thought to be cerebrovascular dysfunction.
Carbon dioxide is a powerful physiological regulator of the cerebral circulation (11). Previous studies have observed that hypercapnic pial artery dilation was blunted after global cerebral ischemia in the newborn pig (18). While impairment of prostaglandin-associated vascular responses is thought to contribute to such altered hypercapnic dilation postischemia (18, 19, 21, 22), the exact mechanism remains uncertain.
Prostaglandins are thought to be important in the regulation of the neonatal cerebral circulation (15). Prostaglandins are released during hypercapnia and have a permissive role in hypercapnic vasodilation (23). Protein tyrosine kinase (PTK) is an intracellular messenger involved in signal transduction and is released in response to injury (14). Interestingly, PTK is believed to modulate the permissive role of prostaglandins in hypercapnic conditions (27). Additionally, mitogen-activated protein kinase (MAPK) is a substrate for PTK and is thought to contribute to impaired cerebral hemodynamic control in pathological states such as ischemia (14). However, the role of PTK and MAPK activation in impaired hypercapnic dilation observed after cerebral hypoxia/ischemia is uncertain.
During the last 7 years, several groups have isolated and cloned a new
G protein-coupled receptor that showed high homology with opioid
receptors (7, 9, 26). The peptide ligand for this receptor
does not bind to classical opioid receptors (µ, 
, 
) and was
named orphanin FQ by Reinscheid et al. (28) because its
sequence begins with phenylalanine (F) and ends with a glutamine (Q).
The same peptide was called nociceptin by Meunier et al. (25) because it increased the reactivity to pain in
animals in contrast with the analgesic effects of opioid drugs.
However, little is known about the role of nociceptin/orphanin FQ
(NOC/oFQ) in the physiological or pathophysiological control of
cerebral hemodynamics. Recent studies have shown that the cerebrospinal fluid (CSF) concentration of NOC/oFQ is elevated to
~1010 M after hypoxia/ischemia in the piglet
(3). Interestingly, it has also been observed to
contribute to the reduction in cerebral blood flow that occurs after
hypoxia/ischemia (3). More recently, NOC/oFQ has
been observed to contribute to impaired hypercapnic dilation after
hypoxia/ischemia (13). The mechanism whereby NOC/oFQ might contribute to altered hypercapnic dilation postinsult is
unknown. Interestingly, however, NOC/oFQ may activate PTK
(10).
Therefore, this study was designed to characterize the contributions of PTK and MAPK activation in NOC/oFQ-induced impairment of hypercapnic pial artery dilation after cerebral hypoxia/ischemia.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Newborn (1-5 days old) pigs of either sex were used in
these experiments. All protocols were approved by the Institutional Animal Care and Use Committee. Piglets were initially anesthetized with
isoflurane (1-2 MAC). Anesthesia was maintained with
-chloralose (30-50 mg/kg supplemented with 5 mg · kg1 · h1
iv). A catheter was inserted into a femoral artery to monitor blood pressure and to sample for blood gas tensions and pH. Drugs to
maintain anesthesia were administered through a second catheter placed
in a femoral vein. The trachea was cannulated, and the animals were
mechanically ventilated with room air. A heating pad was used to
maintain the animals at 37-39°C (rectal).
A cranial window was placed in the parietal skull of these anesthetized animals. This window consisted of three parts: a stainless steel ring, a circular glass coverslip, and three ports consisting of 17-gauge hypodermic needles attached to three precut holes in the stainless steel ring. For placement, the dura was cut and retracted over the cut bone edge. The cranial window was placed in the opening and cemented in place with dental acrylic. The volume under the window was filled with a solution, similar to CSF, of the following composition (in mM): 3.0 KCl, 1.5 MgC12, 1.5 CaCI2, 132 NaCl, 6.6 urea, 3.7 dextrose, and 24.6 NaHCO3. This artificial CSF was warmed to 37°C and had the following chemistry: pH 7.33, PCO2 46 mmHg, and PO2 43 mmHg, which was similar to that of endogenous CSF. Pial arterial vessels were observed with a dissecting microscope, a television camera mounted on the microscope, and a video output screen. Vascular diameter was measured with a video microscaler. For production of cerebral ischemia, a hollow stainless steel bolt was implanted in a small (2 mm) hole in the skull.
Protocol. Two types of pial arterial vessels, small arteries (resting diameter 120-160 µm) and arterioles (resting diameter 50-70 µm), were examined to determine whether segmental differences in the effects of hypoxia/ischemia could be identified. Pial arterial vessel diameter was determined every minute for a 10-min exposure period after infusion onto the exposed parietal cortex of artificial CSF before drug application and after infusion of artifical CSF containing a drug. Typically, 2-3 ml of CSF were flushed through the window over a 30-s period, and excess CSF was allowed to run off through one of the needle ports.
Techniques for induction of total cerebral ischemia in the piglet have been well documented (18-20). Briefly, total cerebral ischemia was accomplished by infusing artificial CSF into a hollow bolt in the cranium to maintain an intracranial pressure 15 mmHg greater than the numerical mean of systolic and diastolic arterial blood (20). Intracranial pressure was monitored via a sidearm of the cranial window. Blood flow in pial arterioles, viewed with a microscope and video monitor, stopped completely on elevation of intracranial pressure and did not resume until the pressure was lowered (20). To prevent the arterial pressure from rising inordinately (Cushing response), venous blood was withdrawn as necessary to maintain mean arterial pressure no greater than 100 mmHg. As the cerebral ischemic response subsided, the shed blood was returned to the animal. Cerebral ischemia was maintained for 20 min. Hypoxia (PO2 = 34 ± 3 mmHg) was produced for 10 min before ischemia by decreasing the inspired O2 via inhalation of N2, which was immediately followed by the total ischemia protocol as described above after concomitantly restoring ventilation to room air. Seventeen types of experiments were performed (all n = 7): 1) sham control; 2) NOC/oFQ pretreated; 3) NOC/oFQ + genistein (106 M);
4) NOC/oFQ + genistein (105 M);
5) NOC/oFQ + tyrphostin A23 (106 M);
6) NOC/oFQ + U-0126 (106 M);
7) NOC/oFQ + U-0126 (105 M);
8) NOC/oFQ + PD-98059 (105 M);
9) NOC/oFQ + combined genistein (105 M)
and U-0126 (105 M); 10)
hypoxia/ischemia; 11) hypoxia/ischemia
pretreated with genistein (106 M); 12)
hypoxia/ischemia pretreated with genistein (105
M); 13) hypoxia/ischemia pretreated with tyrphostin
A23; 14) hypoxia/ischemia pretreated with U-0126
(106 M); 15) hypoxia/ischemia
pretreated with U-0126 (105 M); 16)
hypoxia/ischemia pretreated with PD-98059; and 17)
hypoxia pretreated with combined genistein (105 M) and
U-0126 (105 M). Thus two structurally different PTK
inhibitors (genistein and tyrphostin A23) and MAPK inhibitors (U-1026
and PD-98059) were used. In sham control animals, responses were
obtained to hypercapnia initially and then again 60 min later. In
NOC/oFQ-pretreated animals, responses were obtained to hypercapnia
before NOC/oFQ was applied. After NOC/oFQ (1010 M) was
applied in these animals, responses to hypercapnia were obtained again
60 min later. Other control experiments involved obtaining responses to
hypercapnia in animals pretreated with each of the inhibitors
alone. Two levels of hypercapnia (low and high) were induced via
inhalation of graded levels of a 10% CO2-21% O2-balance N2 gas mixture to produce
levels of PCO2 of 50-60 mmHg for the low
exposure and 70-80 mmHg for the high exposure. PTK and MAPK
inhibitors were topically applied 30 min before either coadministration with NOC/oFQ or induction of hypoxia/ischemia.
Statistical analysis.
Pial artery diameter and systemic arterial pressure were analyzed for
repeated measures. If the F-value was significant, the data
were then analyzed by Fisher's protected least-significant difference
test. An -level of P < 0.05 was considered
significant in all statistical tests. Values are presented as
means ± SE of absolute values or as percentages of change from
control values.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Role of PTK and MAPK activation in NOC/oFQ-induced impairment of
hypercapnic pail artery dilation.
Two levels of hypercapnia (low and high) elicited reproducible graded
pial small artery (120-160 µm) and arteriole (50-70 µm)
dilation in sham control animals (data not shown). Pretreatment with
NOC/oFQ (1010 M) diminished pial dilation to both levels
of hypercapnia (Fig. 1). On a percentage
basis, NOC/oFQ inhibited low hypercapnic dilation similarly in pial
small arteries and arterioles (35 ± 5% vs 38 ± 4%).
However, the higher level of hypercapnia-induced dilation was inhibited
modestly more in arterioles versus small arteries (50 ± 4% vs.
35 ± 6%). NOC/oFQ (1010 M) by itself had no
significant effect on pial small artery or arteriole diameter.
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6 M) or
tyrphostin A23 (105 M) with NOC/oFQ (1010
M) partially prevented the inhibition of hypercapnic dilation compared
with that observed in its absence (Fig. 1). The data from
coadministration of tyrphostin A23 and NOC/oFQ, on a percentage basis,
reflect a pial small artery and arteriole dilation impairment of
12 ± 3% and 17 ± 5% during the low hypercapnic challenge
and 17 ± 3% and 18 ± 5% inhibition during the high
hypercapnic challenge, respectively. These values are significantly
different from those listed above in the absence of tyrphostin A23.
Coadministration of another PTK inhibitor, genistein (106
M), with NOC/oFQ similarly partially restored decremented hypercapnic dilation compared with NOC/oFQ alone. These data reflect on a percentage basis a pial small artery and arteriole dilation impairment of 14 ± 3% and 15 ± 3% during the low hypercapnic
challenge and 13 ± 4% and 13 ± 4% inhibition during the
high hypercapnic challenge, respectively, during coadministration of
genistein and NOC/oFQ. Administration of a higher concentration of
genistein (105 M) with NOC/oFQ produced no further
restoration of decremented hypercapnic dilation compared with that
observed with genistein (106 M) (data not shown).
In addition, coadministration of either of the MAPK inhibitors U-0126
(106 M) or PD-98059 (105 M) with NOC/oFQ
(1010 M) also partially prevented the inhibition of
hypercapnic dilation compared with that observed in its absence (Fig.
2). The data from coadministration of
U-0126 and NOC/oFQ, on a percentage basis, reflect a pial small artery
and arteriole dilation impairment of 17 ± 6% and 17 ± 4%
during the low hypercapnic challenge and 20 ± 4% and 21 ± 5% inhibition during the high hypercapnic challenge, respectively.
These values are significantly different from those listed above in the
absence of U-0126. Administration of a higher concentration of U-0126
(105 M) with NOC/oFQ produced no further restoration of
decremented hypercapnic dilation compared with that observed with
U-0126 (106 M) (data not shown). Similarly, combined
administration of genistein (105 M) and U-0126
(105 M) did not elicit any further significant
protection. Coadministration of PD-98059 with NOC/oFQ partially
restored decremented hypercapnic dilation compared with NOC/oFQ alone
as well. These data reflect on a percentage basis a pial small artery
and arteriole dilation impairment of 23 ± 6% and 19 ± 6%
during the low hypercapnic challenge and 14 ± 6% and 12 ± 6% inhibition during the high hypercapnic challenge, respectively,
during coadministration of PD9-8059 and NOC/oFQ. The values are
also significantly different from the above listed in the absence of
PD-98059.
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Role of PTK and MAPK activation in impaired hypercapnia-induced
pial artery dilation after hypoxia/ischemia.
After exposure to hypoxia/ischemia, pial arterial dilation in
response to hypercapnia was impaired (Fig.
3). On a percentage basis, these data
reflect a pial small artery and arteriole dilation impairment of
80 ± 3% and 76 ± 5%, respectively, during the low-level hypercapnia, and 77 ± 5 and 76 ± 3% impairment during the
high-level hypercapnia. Pretreatment with either genistein
(106 M) or tyrphostin A23 (105 M) before
insult partially protected impairment of the hypercapnic dilation after
hypoxia/ischemia (Fig. 3). On a percentage basis, these data
reflect a pial small artery and arteriole dilation impairment of
59 ± 5% and 51 ± 4% during low-level hypercapnia and
62 ± 2% and 62 ± 3% inhibition during high-level
hypercapnia for tyrphostin A23-pretreated animals. These data also
reflect a pial small artery and arteriole dilation impairment of
46 ± 2% and 46 ± 8% during low-level hypercapnia and
46 ± 3 and 45 ± 2% inhibition during high-level
hypercapnia for genistein-pretreated animals. Both sets of these
inhibition values are significantly different from the respective
values in the absence of tyrphostin A23 or genistein. Administration of
a higher concentration of genistein (105 M) produced no
further protection of hypercapnic dilation postinsult compared with
that obtained with genistein (106 M) (Fig. 3). On a
percentage basis, these data reflect 49 ± 5% and 52 ± 5%
inhibition during low-level hypercapnia and 44 ± 3% and 45 ± 3% inhibition during high-level hypercapnia, respectively.
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6 M) or
PD-98059 (105 M) before insult also partially protected
impairment of the hypercapnic dilation after hypoxia/ischemia
(Fig. 4). On a percentage basis, these
data reflect a pial small artery and arteriole dilation impairment of
47 ± 6% and 35 ± 5% during low-level hypercapnia and
50 ± 6% and 42 ± 7% inhibition during high-level
hypercapnia for U-0126-pretreated animals. These data also reflect a
pial small artery and arteriole dilation impairment of 44 ± 7%
and 31 ± 5% during low-level hypercapnia and 54 ± 6% and
39 ± 7% inhibition during high-level hypercapnia for
PD-98059-pretreated animals. Both sets of these percent inhibition
values are significantly different from the respective values in the
absence of either U-0126 or PD-98059. Administration of a higher
concentration of U-0126 (105 M) produced no further
protection of hypercapnic dilation postinsult compared with that
obtained with U-0126 (106 M) (Fig. 4). Combined
administration of genistein (105 M) with U-0126
(105 M) also had no further significant protective
effect.
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Influence of PTK and MAPK inhibitors on pial artery diameter and
hypercapnic pial artery dilation.
Topical tyrphostin A23, genistein, U-0126, and PD-98059 all had no
effect on pial artery diameter by themselves (118 ± 6 vs. 120 ± 6 µm and 121 ± 5 vs. 128 ± 6 µm before and
after 106 and 105 M genistein,
respectively). Similarly, all inhibitors had no effect on
hypercapnic pial artery dilation in the absence of NOC/oFQ or
hypoxia/ischemia (Fig. 5).
However, combined genistein (105 M) and U-0126
(105 M) increased diameter (120 ± 5 vs. 147 ± 10 µm). Finally, there were no group differences in baseline diameter
during normocapnia after hypoxia/ischemia.
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Blood chemistry and mean arterial blood pressure. The blood chemistry and mean arterial blood pressure values were collected before and after all experiments and during periods of hypoxia and hypercapnia. Hypoxia decreased PO2 to 34 ± 3 mmHg. Low hypercapnia raised PCO2 to 56 ± 2 mmHg, and high hypercapnia raised PCO2 to 74 ± 3 mmHg. Carbon dioxide levels were kept constant during periods of hypoxia, and oxygen levels were kept constant during periods of hypercapnia. Before and after all experiments, the pH, PCO2, PO2, and mean blood pressure were unchanged.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The results of the present study show that coadministration of
NOC/oFQ, in a concentration observed in cortical periarachnoid CSF
after hypoxia/ischemia (1010M) (3),
with hypercapnia attenuated pial artery vasodilation in response to
this stimulus, consistent with earlier work (13). Because
the concentration of NOC/oFQ had no effect on pial artery diameter by
itself, decremented hypercapnic dilation did not result from
physiological antagonism. These experiments were designed to
biochemically mimic hypoxic/ischemic conditions regarding
NOC/oFQ. These data suggest that such concentrations of this
opioid-like peptide observed after hypoxia/ischemia could have
physiological significance. Another series of experiments was then
designed to determine the mechanism for such NOC/oFQ-induced impairment of hypercapnic dilation. For example, the data in the present study
show that coadministration either of the PTK inhibitors tyrphostin A23
or genistein with NOC/oFQ partially prevented the inhibition of
hypercapnic dilation under such biochemically mimicked injury
conditions. Administration of genistein and administration of
tyrphostin A23 alone had no effect on arterial diameter by itself,
suggesting a lack of physiological antagonism as a potential explanation for such observations. In addition, coadministration of
each of the MAPK inhibitors U-0126 and PD-98059 with NOC/oFQ also
partially prevented the inhibition of hypercapnic dilation. Similarly,
administration of either U-0126 or PD-98059 alone had no effect on
arterial diameter by itself. These data show that PTK and MAPK
activation contributes to NOC/oFQ-induced impairment of hypercapnic
dilation. The use of two structurally distinct PTK and MAPK inhibitors
(8, 12) in the above study design strengthened such
conclusions regarding the role of these two signal transduction
pathways in the modulation of hypercapnic dilation by NOC/oFQ.
Furthermore, the use of two concentrations of genistein and U-0126
(106 and 105 M) helped to establish that
the lower concentration was near maximally efficacious in inhibition of
PTK and MAPK, respectively.
The functional significance of the above-noted interaction of NOC/oFQ with hypercapnia has been investigated previously. The results of these studies show that hypoxia/ischemia blunted hypercapnia-induced pial artery dilation at 1 h of reperfusion (13), similar to previous studies that investigated the effects of ischemia-reperfusion without prior hypoxia on hypercapnic cerebrovasodilation (18). However, new data show that the NOC/oFQ receptor antagonist [F/G]NOC/oFQ(1-13)NH2 partially prevented such diminished hypercapnic dilation postinsult (13). These data suggest the involvement of released NOC/oFQ after hypoxia/ischemia in altered hypercapnic cerebrovasodilation after this insult (13).
Accordingly, the present study was designed to characterize mechanisms
involved in such a NOC/oFQ contribution to hypercapnic dilation
impairment postinsult. The results of these studies show the
pretreatment with genistein or tyrphostin A23 partially protected hypoxic/ischemic impairment of hypercapnic pial artery dilation. Because both genistein and tyrphostin are two structurally distinct inhibitors of PTK, these data suggest that activation of PTK is involved in the mechanism by which hypoxia/ischemia impairs
hypercapnic dilation. Pretreatment with the structurally distinct MAPK
inhibitors U-0126 or PD-98059 also partially protected
hypoxic/ischemic impairment. These data suggest that activation
of MAPK is also involved in the mechanism by which this insult impairs
hypercapnic dilation. Taken together, these data further suggest that
activation of PTK and MAPK is also involved in the mechanism by which
NOC/oFQ impairs hypercapnic dilation after hypoxia/ischemia.
Administration of higher concentrations (105 M) of
genistein and U-0126 had no further protective effect, indicating that
the lower concentration (106 M) was near maximal in
efficacy. However, because either combined or single administration of
such antagonists did not completely restore impaired hypercapnic
dilution posthypoxia/ischemia, these data suggest that other
mechanisms are involved in such impairment. Because MAPK is actually a
family of kinases (ERK, JNK, and p38) and U-0126 and PD-98059 are
thought to be more selective ERK MAPK inhibitors, it is speculated that
either JNK or p38 MAPK activation may also be contributory to such
impairment. Alternatively, PTK and/or MAPK inhibitors may also
have protective effects on neurons during ischemia. Thereby,
they may have indirect effects on neuronal metabolism and function
after reperfusion, which, in turn, would influence reactivity to hypercapnia.
Because the drugs used as probes for PTK and MAPK activation did not have any effect on pial artery diameter in sham control animals, these data indicate that these signal transduction pathways do not significantly contribute to the control of resting cerebrovascular tone. Additionally, such antagonists did not have any effect on hypercapnic dilation in the absence of hypoxia/ischemia or NOC/oFQ, indicating a greater role for such signal transduction pathways in pathological compared with physiological states. Such observations are consistent with the idea that PTK and MAPK are activated with injury, such as ischemia, and thereby contribute to cerebral vasospasm (14). The choice of concentration for the PTK and MAPK inhibitors used in the present study was based on in vitro assay data that demonstrate efficacy and selectivity (8, 12) as well as on in vivo data in the newborn pig (4).
Global cerebral ischemia in a piglet model has been previously observed to result in blunted pial artery dilation to hypercapnia (18). The cerebral vasodilation caused by hypercapnia and hypotension requires active prostaglandin synthesis, whereas dilation to isoproterenol does not (6, 16, 17, 30). After cerebral ischemia, elevated cerebral prostaglandin synthesis during hypercapnia and hypotension does not occur (18, 19). Vasodilation in response to these stimuli is likewise absent, whereas the responses to isoproterenol are unchanged (18, 19, 22). These studies suggest, then, that prostaglandin-associated stimuli are preferentially altered by cerebral ischemia. More recent studies have shown that one prostaglandin, PGI2, subserves a permissive role in hypercapnic pial artery dilation (23), which, in turn, is modulated by PTK (27).
The mechanism for impaired hypercapnic cerebrovasodilation after cerebral ischemia has proven to be more elusive. Oxygen free radicals such as superoxide anion are released after cerebral ischemia (5) and are known to contribute to impaired vascular responsiveness postinsult. However, superoxide anion release does not contribute to impaired hypercapnic cerebrovasodilation after cerebral ischemia in the piglet (24). Inactivation of PGH synthase, like superoxide anion, does not appear to be involved, because conversion of exogenous arachidonic acid to prostanoids on the brain surface is not altered after cerebral ischemia (21). Therefore, ischemia may decrease the release of arachidonic acid in response to the specific induction stimuli. Inasmuch as phospholipase A2 appears to be involved in the increase in prostanoid synthesis caused by hypercapnia in newborn pigs (30), it is possible that ischemia results in phospholipase A2 inactivation. Another possibility that must be considered is that of depletion of arachidonic acid from a specific membrane pool that provides a source for hypercapnia- and hypotension-induced arachidonic acid release. The marked increase in free arachidonic acid induced by ischemia (1, 31) makes such a possibility more attractive. Consistent with this hypothesis, topically applied arachidonic acid restores pial arteriolar dilation to hypercapnia after ischemia (22).
The results of the present study extend the above findings to indicate that a relatively newly described opioid, NOC/oFQ, contributes to impaired hypercapnic cerebrovasodilation after hypoxia/ischemia. Such an interaction is not entirely surprising in that opioids exert prominent effects in the control of the perinatal cerebral circulation, particularly under pathological conditions (2).
In conclusion, the results of the present study show that PTK and MAPK activation contribute to NOC/oFQ-induced impairment of hypercapnic dilation. These data suggest that activation of PTK and MAPK is also involved in the mechanism by which NOC/oFQ impairs hypercapnic dilation after hypoxia/ischemia.
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ACKNOWLEDGEMENTS |
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The authors thank John Ross for excellent technical assistance in the performance of the experiments.
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FOOTNOTES |
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This research was supported by grants from the National Institutes of Health and the American Heart Association, Pennsylvania-Delaware Affiliate.
Address for reprint requests and other correspondence: W. M. Armstead, Dept. of Anesthesia, Univ. of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104 (E-mail: armsteaw{at}uphs.upenn.edu).
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. Section 1734 solely to indicate this fact.
10.1152/ajpheart.00457.2002
Received 29 May 2002; accepted in final form 28 August 2002.
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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