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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
METHODS
RESULTS
DISCUSSION
REFERENCES
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This
study determined whether nociceptin/orphanin FQ (NOC/oFQ) generates
superoxide anion (O2
) in a protein kinase C
(PKC)-dependent manner and whether such production contributes to
hypoxic-ischemic (H-I) impairment of N-methyl-D-aspartate (NMDA)-induced pial artery
dilation in newborn pigs equipped with closed cranial windows.
Superoxide dismutase (SOD)-inhibitable nitroblue tetrazolium (NBT)
reduction was an index of O2 generation. Under
non-H-I conditions, topical NOC/oFQ (1010 M,
concentration present in cerebrospinal fluid after I or H-I) increased
SOD-inhibitable NBT reduction from 1 ± 1 to 20 ± 3 pmol/mm2. PKC inhibitors staurosporine and chelerythrine
(107 M) blunted NBT reduction (1 ± 1 to 7 ± 2 pmol/mm2 for chelerythrine), whereas the NOC/oFQ receptor
antagonist [F/G]NOC/oFQ (1-13)-NH2
(106 M) blocked NBT reduction.
[F/G]NOC/oFQ(1-13)-NH2 and
staurosporine also blunted the NBT reduction observed after I or H-I.
NMDA (108, 106 M)-induced pial artery
dilation was reversed to vasoconstriction after H-I. The NOC/oFQ
antagonist staurosporine and free radical scavengers partially
prevented this impaired dilation (sham: 9 ± 1 and 16 ± 1;
H-I: 
5 and 10 ± 1; H-I staurosporine pretreated: 3 ± 1 and 6 ± 1%). These data show that NOC/oFQ increased
O2 production in a PKC-dependent manner and
contributed to this production after insult and that NOC/oFQ
contributed to impaired NMDA-induced pial artery dilation after H-I,
suggesting, therefore, that PKC-dependent O2
generation by NOC/oFQ links NOC/oFQ release to impaired NMDA dilation
after H-I.
newborn; cerebral circulation; opioids; free radicals; excitatory amino acids; protein kinase C; nociceptin/orphanin FQ; N-methyl-D-aspartate
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
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 hypoxic-ischemic (H-I) insults during the perinatal period. One contributor to neurological damage is thought to be cerebrovascular dysfunction. Global cerebral ischemia results in reductions in pial artery diameter and cerebral blood flow as well as impaired cerebrovascular control during hypotension and hypercapnia in a newborn pig model (19, 21, 22). Less, however, is known about the cerebrovascular consequences of combined H-I.
Glutamate is an important excitatory amino acid transmitter in the
brain. It can bind to any of three different ionotropic receptor
subtypes named after specific synthetic analogs:
N-methyl-D-aspartate (NMDA), kainate, and
-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA).
Activation of NMDA receptors has been observed to elicit
cerebrovascular dilation and may represent one of the mechanisms for
the coupling of local cerebral metabolism to blood flow
(13). Several studies observed that NMDA-induced pial
artery dilation was attenuated after global cerebral
ischemia-reperfusion (I/R) (9, 31). Mechanisms
for such altered dilation to NMDA after such an insult have been less
well characterized.
During the last 5 years, several groups have isolated and
cloned a new G protein-coupled receptor that showed high homology with
opioid receptors (11, 15, 28). The peptide ligand for this
receptor does not bind to classical opioid receptors (µ, 
, 
)
and was named orphanin FQ by Reinscheid et al. (30)
because its sequence begins with phenylalanine (F) and ends with
glutamine (Q). The same peptide was called nociceptin by Meunier et al. (27) because it increased the reactivity to pain in
animals in contrast with the analgesic effects of opioid drugs.
Recently, nociceptin/orphanin FQ (NOC/oFQ) has been observed to elicit
pial artery vasodilation in the newborn pig (1). However,
little is known about the role of 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 after H-I in the piglet (3). Interestingly, it
has also been observed that NOC/oFQ can both inhibit the release of
glutamate from rat cerebrocortical slices and inhibit glutamatergic
transmission in the rat spinal cord as well as have its own signaling
modulated by NMDA (12, 29, 36). Because of the latter
observations, more recent studies were designed to investigate the
interaction between NOC/oFQ and excitatory amino acids in the piglet
cerebral circulation. Results of these studies show that
coadministration of NOC/oFQ, in a concentration similar to that in CSF
after H-I, diminished NMDA and glutamate-induced pial dilation under
non-H-I conditions (4). Additionally, NOC/oFQ antagonist
pretreatment partially restored decremented NMDA and glutamate dilation
after H-I (4). These data then suggest that NOC/oFQ
release contributes to impaired excitatory amino acid-induced
cerebrovasodilation after H-I.
The present study, therefore, was designed to determine a potential
mechanism whereby NOC/oFQ might contribute to H-I-impaired NMDA
cerebrovasodilation. Importantly, NOC/oFQ has been observed to activate
protein kinase C (PKC) (26), and PKC activation has also
been observed to generate superoxide anion (O2)
(2). This study was then designed to determine whether
NOC/oFQ generates O2 in a PKC-dependent manner and
whether such O2 production contributes to H-I
impairment of NMDA-induced pial artery dilation.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Newborn (1-5 days old, 1.3-2.1 kg) 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 minimum alveolar
concentration). 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.
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 CaCl2, 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 is 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 H-I 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 (19, 21, 22). 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 pressure (22). 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 (22). 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. In combined H+I/R animals, hypoxia (PO2 = 35 ± 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. Twenty major types of experiments were performed (all n = 7 animals): 1) generation of O2 with NOC/oFQ, 2) generation of
O2 with NOC/oFQ in the presence of staurosporine,
3) generation of O2 with NOC/oFQ in the
presence of the NOC/oFQ receptor antagonist [F/G]NOC/oFQ(1-13)-NH2, 4)
generation of O2 with NOC/oFQ in the presence of
chelerythrine, 5) generation of O2 with
I/R, 6) generation of O2 with I/R in
staurosporine-pretreated animals, 7) generation of O2 with I/R in
[F/G]NOC/oFQ(1-13)-NH2-pretreated
animals, 8) generation of O2 with H+I/R,
9) generation of O2 with H+I/R in
staurosporine-pretreated animals, 10) generation of
O2 with H+I/R in
[F/G]NOC/oFQ(1-13)-NH2-pretreated
animals, 11) generation of O2 with H+I/R
in chelerythrine-pretreated animals, 12) vascular responses
to agonists in the absence of H+I/R (sham control), 13)
vascular responses to agonists after I/R, 14) vascular
responses to agonists after I/R in staurosporine-pretreated animals,
15) vascular responses to agonists after I/R in
[F/G]NOC/oFQ(1-13)-NH2-pretreated animals, 16) vascular responses after I/R in polyethylene
glycol (PEG) superoxide dismutase (SOD) and catalase (CAT)-pretreated animals, 17) vascular responses after H+I/R, 18)
vascular responses after H+I/R in staurosporine-pretreated animals,
19) vascular responses after H+I/R in
[F/G]NOC/oFQ(1-13)-NH2-pretreated
animals, and 20) vascular responses after H+I/R in
SODCAT-pretreated animals.
In the first three series of experiments designed to investigate
generation of O2, NOC/oFQ
(1010 M, Phoenix) was applied to the cerebral cortex for
20 min in either the absence or the presence of staurosporine
(107 M),
[F/G]NOC/oFQ(1-13)-NH2
(106 M, Phoenix) or chelerythrine (107 M).
In the next three series of experiments, generation of
O2 1 h after I/R or H+I/R was investigated in
the absence and presence of staurosporine,
[F/G]NOC/oFQ(1-13)-NH2, or
chelerythrine. In these experiments, staurosporine,
[F/G]NOC/oFQ(1-13)-NH2, and chelerythrine were administered 20 min before I/R or H+I/R. The NOC/oFQ
antagonist staurosporine or chelerythrine was kept in constant contact
with the cerebral cortex for the duration of the experiment.
In the vascular experiments, responses of arterial vessels to NMDA and
glutamate (108 and 106 M; Sigma) were
obtained before and 1 h after I/R or H+I/R either in the absence
or presence of staurosporine,
[F/G]NOC/oFQ(1-13)-NH2, and SODCAT
(1,000 and 10,000 U/kg of PEGSOD and CAT, respectively).
O2 analysis.
SOD-inhibitable nitroblue tetrazolium (NBT) reduction was determined as
an index of O2 generation, as previously described
(2, 5, 17). Such reduction was determined by placing NBT
(2.4 mM, Sigma) dissolved in artificial CSF under one window and NBT
(2.5 mM) and SOD (Sigma, 60 U/ml) in artificial CSF under the other
window 1 h after I/R or H+I/R.
. The SOD-inhibitable NBT
reduction was determined by the difference in the quantities of
nitroblue formazan precipitated on the brain surface under the two
windows. Although NBT can be reduced by a variety of agents, SOD
provides specificity for the assay. Details of this methodology have
been published previously (2, 5, 18).
Statistical analysis.
Pial arteriolar diameter, systemic arterial pressure, and NBT reduction
values were analyzed using ANOVA for repeated measures or
t-test where appropriate. If the 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 represented
as means ± SE of the absolute values or percent changes from
control values.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Role of PKC activation in NOC/oFQ-induced O2
generation during non-H-I and H-I conditions.
Topical application of NOC/oFQ (1010 M, concentration
present in cortical periarachnoid CSF after I/R or H+I/R) to the
cerebral cortical surface of non-H-I animals increased SOD-inhibitable NBT reduction (Fig. 1A). This
NBT reduction by NOC/oFQ was blunted by staurosporine
(107 M) and blocked by the NOC/oFQ receptor antagonist
[F/G]NOC/oFQ(1-13)-NH2 (106 M) (Fig. 1A). NBT reduction by NOC/oFQ
was similarly blunted by chelerythrine, another PKC inhibitor (1 ± 1 to 20 ± 3 vs. 1 ± 1 to 7 ± 2 pmol
NBT/mm2 for absence and presence of chelerythrine,
respectively). Under H-I conditions, SOD-inhibitable NBT
reduction was increased 1 h after either I/R or H+I/R (Fig.
1B). This enhanced NBT reduction after either insult was
blunted by both staurosporine and
[F/G]NOC/oFQ(1-13)-NH2 (Fig.
1B). NBT reduction after H+I/R was similarly blunted by chelerythrine (1 ± 1 to 15 ± 2 vs. 1 ± 1 to 6 ± 2 pmol NBT/mm2 for the absence and presence of
chelerythrine, respectively).
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Role of NOC/oFQ, PKC activation, and O2
generation in impaired excitatory amino acid-induced pial artery
dilation after I/R and H+I/R.
NMDA and glutamate (both at 108 and 106 M)
elicited reproducible pial small artery (120-160 µm) and
arteriole (50-70 µm) vasodilation in sham control animals (data
not shown). However, NMDA and glutamate-induced vasodilation was
attenuated with 1 h of reperfusion after cerebral ischemia (Figs.
2 and
3). This postinsult diminished
excitatory amino acid dilation was partially prevented by pretreatment
with [F/G]NOC/oFQ(1-13)-NH2,
staurosporine, and the free radical scavenger SODCAT (Figs. 2 and 3).
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Effect of staurosporine, chelerythrine, [F/G]NOC/oFQ(1-13)-NH2, SODCAT, and NOC/oFQ on pial artery diameter. Staurosporine, chelerythrine, [F/G]NOC/oFQ(1-13)-NH2, SODCAT, and NOC/oFQ all had no effect on pial artery diameter.
Blood chemistry. 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 PO2 to 35 ± 3 mmHg, whereas the pH, PCO2, and mean arterial blood pressure values were unchanged. Values for pH, PCO2, PO2, and mean arterial blood pressure were 7.45 ± 0.02, 37 ± 3 mmHg, 92 ± 5 mmHg, and 71 ± 5 mmHg, respectively, at the start of experiments vs. 7.44 ± 0.02, 38 ± 3 mmHg, 91 ± 6 mmHg, and 68 ± 6 mmHg, respectively, at the end of experiments. There were no group differences in either blood pressure or blood chemistry values.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The results of the present study show that, under non-H-I
conditions, topical administration of NOC/oFQ, in a concentration approximately that observed in cortical periarachnoid CSF after I/R or
H+I/R (3), results in increased SOD-inhibitable NBT reduction by the newborn pig brain. These data indicate that
O2 was generated. Because staurosporine and
chelerythrine blunted this elevation in SOD-inhibitable NBT reduction
by NOC/oFQ, these data indicate that PKC activation contributes to
O2 generation by this opioid. Previously,
staurosporine was observed to block the NBT reduction after topical
application of the PKC activator phorbol 12,13-dibutyrate to the
cerebral cortical surface of the piglet, indicating that staurosporine
is an efficacious PKC inhibitor (2). Moreover, the
putative NOC/oFQ antagonist [F/G]NOC/oFQ(1-13)-NH2 (1, 16,
17) blocked NOC/oFQ-induced NBT reduction, indicating that this
opioid generates O2 in a selective manner.
Additionally, staurosporine, chelerythrine, and
[F/G]NOC/oFQ(1-13)-NH2 blunted I/R and
H+I/R-induced elevated SOD-inhibitable NBT reduction. Previously, I/R
was observed to be associated with generation of O2
on the piglet cerebral cortical surface (5). Results of
the present study extend the latter observation to show that H+I/R also
generates O2 to a level modestly greater than that
observed with I/R alone. New data in this study also suggest that
NOC/oFQ contributes to the generation of O2 after H-I
through activation of PKC. Because the concentration of NOC/oFQ
observed in CSF after I/R and H+I/R, 1010 M, did not have
any effect on pial artery diameter, such O2
generation by NOC/oFQ appears independent of vascular contributory effects. These observations extend those previously published, indicating that activation of cyclooxygenase contributes to
O2 generation after I/R (5). It should
be cautioned, however, that concerns related to the accuracy of the NBT
assay have recently been raised (14). For example, many
enzymes can cause the reduction of tetrazolium salts to the
corresponding formazan. Specifically, the reduction of NBT may be
caused by another radical ( · R), which is capable of
reversibly reacting with oxygen to generate O2 as
follows: · R + O2 
x + O2. SOD, by removing O2, displaces
the oxidation to the right and prevents the formation of formazan. This
would then erroneously be interpreted as indicating the occurrence of
SOD-mediated reduction of NBT. For this reason, it has been suggested
that many tetrazolium reductions can be inhibited by SOD even though
O2 is not being produced in the absence of the
tetrazolium (14). However, because the concentrations of
SOD required to inhibit NBT reduction were equally effective when the
reduction was initiated by NOC/oFQ or endothelin-1 (18) as
when the reduction was initiated by xanthine plus xanthine oxidase
(2), an enzymatic system known to generate
O2, it is concluded that the radical being dealt with
is O2.
The cerebrovascular consequences of free radical production are not
fully understood. It has been suggested that O2 could
be involved in irreversible vascular damage, delayed hypoperfusion, and
edema produced by cerebral I/R (32). Topical application of a xanthine/xanthine oxidase-activated oxygen-generating system, severe hypertension, topical application of arachidonic acid, and fluid
percussion brain injury cause morphological, functional, and
biochemical cerebral artery abnormalities, which include reduced responsiveness to vasoconstrictor and vasodilator stimuli (2, 18,
20, 33-35). O2 and species derived from
it, such as hydrogen peroxide and hydroxyl radical, appear to mediate
these abnormalities (13, 18, 35). Intracellular generation
of O2 or other species could alter structure and/or
production of nucleotides, second messengers, receptors, and membranes,
and the movement of O2 out of the cell through anion
channels could result in high concentrations of activated oxygen
species at cell surfaces, including the endothelium. More importantly,
current concepts point toward the significant contribution to damage by
the reaction of O2 with nitric oxide to form the
highly reactive prooxidant peroxynitrite (8, 25). The
latter species, and not O2, is currently thought to
be the more direct mediator of damage. However, because oxygen free
radical scavengers did not attenuate impairment of hypercapnic dilation
after piglet cerebral I/R (23), postischemic loss of
vasodilator responsiveness may not always involve O2
or a subsequent reduced form of oxygen.
Because it had been previously observed that NOC/oFQ interacts with
NMDA and glutamate in studies unrelated to vascular activity (12,
29, 36), additional studies were designed to investigate the
relationship among NOC/oFQ, O2, PKC activation, and
excitatory amino acid-induced vascular activity after I/R and H+I/R.
The results of those studies show that NMDA-induced pial artery
dilation was attenuated after I/R, consistent with previous studies
(9). After H+I/R, however, dilator responses to NMDA and
glutamate were reversed to vasoconstriction. Results of this study
extend those of others (9) in that the present study shows
that glutamate as well as NMDA-induced pial artery dilation is altered
after I/R. Additionally, others did not note a reversal of NMDA-induced
dilation to vasoconstriction after global cerebral ischemia
(9). Such postinsult excitatory amino acid-induced
impaired vasodilation or vasoconstriction was attenuated by
[F/G]NOC/oFQ(1-13)-NH2, indicating
NOC/oFQ involvement in this altered vascular activity. However, both
staurosporine and SODCAT administration prevented the post-H+I/R
excitatory amino acid vasoconstriction, although responses were only
partially restored to control values. Together, these data suggest that
PKC-dependent O2 generation links NOC/oFQ release to
impaired NMDA and glutamate-induced pial artery dilation after H-I.
However, because both staurosporine and SODCAT prevented impairment of
excitatory amino acid dilation to a greater extent than
[F/G]NOC/oFQ(1-13)-NH2 in I/R animals, those data further suggest that other as yet to be determined factors
also contribute to activation of PKC, subsequent O2
generation, and final impairment of excitatory amino acid-induced vasodilation after H+I/R.
The mechanism by which NMDA-induced pial artery dilation is altered
after global cerebral I/R or combined H+I/R is unclear at this time.
Recent work by others suggests a role for oxygen free radicals and
protein synthesis (6, 9, 31). In that proposed scenario,
increased cyclooxygenase synthesis might account for the previously
observed role for oxygen free radicals in I/R-associated cerebrovascular derangement (31). Alternatively, the
observed beneficial action of protein synthase inhibitors might relate to the block of the production of an unidentified regulatory protein that is rapidly overexpressed after ischemia (31).
Interestingly, adenosine, which is released during hypoxia, has been
observed to inhibit NMDA-induced pial artery dilation when
coadministered with this excitatory amino acid (7), very
similarly to that observed with NOC/oFQ. In those studies it was
suggested that adenosine might reduce calcium entry into nerve cells
and activation of nitric oxide synthase by promoting hyperpolarization
or by blocking N- and Q-type channels (7). It was further
suggested that adenosine might reduce presynaptic glutamate release and thus suppress autoamplification of glutamate effects (7).
Equally interesting, then, is the observation that NOC/oFQ can inhibit the release of glutamate from rat cerebrocortical slices and can inhibit glutamatergic transmission in the rat spinal cord (12, 29). NOC/oFQ signaling can also be modulated by NMDA
(36). More distal mechanisms by which NOC/oFQ-induced
O2 generation might alter NMDA-induced pial artery
dilation, as observed in the present study, are currently uncertain.
The experimental design of the present study did not allow for the identification of the cellular site of origin for NOC/oFQ detected in cortical periarachnoid CSF. Potential cellular sites of origin include neurons, glia, vascular smooth muscle, and endothelial cells.
Although glutamate is an excitatory neurotransmitter thought to be a predominant contributor to neurotoxicity associated with H-I (10, 24), little attention has been paid to the functional implications of vascular abnormalities to NMDA and glutamate after such an insult. In the present study, endogenous NOC/oFQ could either function to limit vascular responses to abnormally high glutamate levels after fluid percussion injury or, alternatively, exacerbate them. It is speculated that the latter is more plausible. Recent data show that, at concentrations higher than those studied presently, NOC/oFQ-induced vasodilation is reversed to vasoconstriction after I/R and H+I/R (3). The preadministration of the NOC/oFQ antagonist [F/G]NOC/oFQ(1-13)-NH2 attenuated reductions in cerebral blood flow observed after H-I, thereby acting in a neuroprotective or vasoprotective manner (3). Therefore, it is hypothesized that the abnormal vascular responses to glutamate and NMDA are deleterious and that H-I-accentuated release of NOC/oFQ contributes to impaired cerebral hemodynamics via modulation of vasodilation by excitatory neurotransmitters.
Opioids are important contributors to the regulation of the piglet cerebral circulation (18). Results of the present study extend such studies by characterizing the contribution of the newly described opioid NOC/oFQ to altered cerebrovascular regulation observed after I/R and H+I/R.
In conclusion, the results of the present study show that NOC/oFQ, in
concentrations present in CSF after H-I, increases O2
production in a PKC-dependent manner and contributes to this production
after H-I. These data also show that NOC/oFQ contributes to impaired
NMDA and glutamate-induced pial artery dilation after H-I. These data
suggest, therefore, that PKC-dependent O2 generation
links NOC/oFQ release to impaired NMDA-induced cerebrovasodilation after H-I.
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ACKNOWLEDGEMENTS |
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The author thanks Miriam Kulkarni for 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, the American Heart Association, Pennsylvania-Delaware Affiliate, and the University of Pennsylvania Research Foundation.
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}mail.med.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.
Received 27 April 2000; accepted in final form 25 July 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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1.
Armstead, WM.
Nociceptin/orphanin FQ dilates pial arteries by KATP and Kca channel activation.
Brain Res
835:
315-323,
1999[ISI][Medline].
2.
Armstead, WM.
Superoxide generation links protein kinase C activation to impaired ATP-sensitive K+ channel function after brain injury.
Stroke
30:
153-159,
1999
3.
Armstead, WM.
Relationship between nociceptin/orphanin FQ and cerebral hemodynamics after hypoxia-ischemia in piglets.
Am J Physiol Heart Circ Physiol
278:
H477-H483,
2000
4.
Armstead, WM.
NOC/oFQ contributes to hypoxic/ischemic impairment of N-methyl-D-aspartate-induced cerebral vasodilation.
Brain Res
868:
48-55,
2000[ISI][Medline].
5.
Armstead, WM,
Mirro R,
Busija DW,
and
Leffler CW.
Postischemic generation of superoxide anion by newborn pig brain.
Am J Physiol Heart Circ Physiol
255:
H401-H403,
1988
6.
Bari, F,
Errico RA,
Louis TM,
and
Busija DW.
Differential effects of short-term hypoxia and hypercapnia on N-methyl-D-aspartate-induced cerebral vasodilation in piglets.
Stroke
27:
1634-1640,
1996
7.
Bari, F,
Thore TM,
Louis TM,
and
Busija DW.
Inhibitory effects of hypoxia and adenosine on N-methyl-D-aspartate-induced pial arteriolar dilation in piglets.
Brain Res
780:
237-244,
1998[ISI][Medline].
8.
Beckman, JS.
Peroxynitrite versus hydroxyl radial: the role of nitric oxide in superoxide-dependent cerebral injury.
Ann NY Acad Sci
738:
69-75,
1994[ISI][Medline].
9.
Busija, DW,
Meng W,
Bari F,
McGough RA,
Errico RA,
Tobin T,
and
Louis TM.
Effects of ischemia on cerebrovascular responses to N-methyl-D-aspartate in piglets.
Am J Physiol Heart Circ Physiol
270:
H1225-H1230,
1996
10.
Choi, DW.
Glutamate neurotoxicity: relationship to specific channel types and role in ischemic damage.
Trends Neurosci
11:
456-469,
1998.
11.
Chen Fan, YY,
Liu J,
Mestek A,
Tian M,
Kozak CA,
and
Yu L.
Molecular cloning, tissue distribution and chromosomal localization of a novel member of the opioid receptor gene family.
FEBS Lett
347:
279-283,
1994[ISI][Medline].
12.
Faber, ESL,
Chambers JP,
Evans RH,
and
Henderson G.
Depression of glutamatergic transmission by nociceptin in the neonatal rat hemisected spinal cord preparation in vitro.
Br J Pharmacol
189:
189-190,
1996.
13.
Faraci, FM,
and
Breese KR.
Nitric oxide mediates vasodilation in response to activation to N-methyl-D-aspartate receptors in the brain.
Circ Res
72:
476-480,
1993
14.
Fridovich, I.
Superoxide anion radical (O2), superoxide dismutases, and related matters.
J Biol Chem
272:
18515-18517,
1997
15.
Fukuda, K,
Kato S,
Mori K,
Nishi M,
Takeshima H,
Iwabe N,
Miyata T,
Houtani T,
and
Sugimoto T.
DNA cloning and regional distribution of a novel member of the opioid receptor family.
FEBS Lett
343:
42-46,
1994[ISI][Medline].
16.
Guerrini, R,
Calo G,
Rizzi A,
Bigoni R,
Bianchi C,
Salvadori S,
and
Regoli D.
A new selective antagonist for the nociceptin receptor.
Br J Pharmacol
123:
163-165,
1998[ISI][Medline].
17.
Kapusta, DR,
Chang JJ,
and
Kenigs VA.
Central administration of Phe1 
(CH2-NH) Gly2 Nociceptin(1-13) NH2 and orphanin FQ/nociceptin (OFQ/N) produce similar cardiovascular and renal responses in conscious rats.
J Pharmacol Exp Ther
289:
173-180,
1999
18.
Kasemsri, T,
and
Armstead WM.
Endothelin production links superoxide generation to altered opioid-induced pial artery vasodilation after brain injury in pigs.
Stroke
28:
190-197,
1997
19.
Leffler, CW,
Busija DW,
Armstead WM,
Mirro R,
and
Beasley DG.
Ischemia alters cerebral vascular responses to hypercapnia and acetylcholine in piglets.
Pediatr Res
25:
180-183,
1989[ISI][Medline].
20.
Leffler, CW,
Busija DW,
Armstead WM,
Shanklin DR,
Mirro R,
and
Thelin O.
Activated oxygen and arachidonate effects on newborn cerebral arterioles.
Am J Physiol Heart Circ Physiol
259:
H1230-H1238,
1990
21.
Leffler, CW,
Busija DW,
Beasley DG,
Armstead WM,
and
Mirro R.
Postischemic microvascular cerebral responses to norepinephrine and hypotension in newborn pigs.
Stroke
20:
541-546,
1989
22.
Leffler, CW,
Busija DW,
Mirro R,
Armstead WM,
and
Beasley DG.
Effects of ischemia on brain blood flow and oxygen consumption of newborn pigs.
Am J Physiol Heart Circ Physiol
257:
H1917-H1926,
1989
23.
Leffler, CW,
Thompson C,
Armstead WM,
Mirro R,
Shibata M,
Busija DW,
and
Shanklin DR.
Superoxide scavengers do not prevent ischemia-induced alteration of cerebral vasodilation in piglets.
Pediatr Res
33:
164-170,
1993[ISI][Medline].
24.
Lipton, P.
Ischemic cell death in brain neurons.
Physiol Rev
79:
1432-1568,
1999.
25.
Lipton, SA,
Choi YB,
and
Pan ZH.
A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso compounds.
Nature
364:
626-632,
1993[Medline].
26.
Meunier, JC.
Nociceptin/orphanin FQ and the opioid receptor-like ORL 1 receptor.
Eur J Pharmacol
340:
1-15,
1997[ISI][Medline].
27.
Meunier, JC,
Mollereau C,
Toll L,
Suandeau C,
Moisdan C,
Alvinerie P,
Mazarguil H,
Vassart G,
Parmentier M,
and
Costenin J.
Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor.
Nature
377:
532-535,
1995[Medline].
28.
Mollereau, C,
Parmentier M,
Mailleux P,
Burour JJ,
Moisdan C,
Chalon P,
Caput D,
Vassant G,
and
Meunier JC.
ORL1, a novel member of the opioid receptor family. Cloning, functional expression and localization.
FEBS Lett
3431:
33-38,
1994.
29.
Nicol, B,
Lambert DG,
Rowbotha DJ,
Smart D,
and
McKnight AT.
Nociceptin induced inhibition of K+ evoked glutamate release from rat cerebrocortical slices.
Br J Pharmacol
119:
1081-1083,
1996[ISI][Medline].
30.
Reinscheid, RK,
Nothacker HP,
Bourson A,
Ardati A,
Henningsen RA,
Bunzow JR,
Grady DK,
Langen H,
Monsma FJ,
and
Civelli O.
Orphanin FQ: a neuropeptide that activates an opioid like G protein-coupled receptor.
Science
270:
792-794,
1995
31.
VeltKamp, R,
Domoki F,
Bari F,
Louis TM,
and
Busija DW.
Inhibitors of protein synthesis preserve the N-methyl-D-aspartate-induced cerebral arteriolar dilation after ischemia in piglets.
Stroke
30:
148-152,
1999
32.
Watson, DB,
Bresto R,
Goldberg WJ,
Santiso M,
Yoshida S,
and
Ginsberg MD.
Lipid peroxidation in vivo induced by reversible global ischemia in rat brain.
J Neurochem
41:
268-274,
1984.
33.
Wei, EP,
Christman W,
Kontos HA,
and
Povlishock JT.
Effects of oxygen radicals on cerebral arterioles.
Am J Physiol Heart Circ Physiol
248:
H157-H167,
1985.
34.
Wei, EP,
Dietrich WD,
Povlishock JT,
Navari RM,
and
Kontos HA.
Functional, morphological, and metabolic abnormalities of the cerebral microcirculation after concussive brain injury in cats.
Circ Res
46:
37-47,
1980
35.
Wei, EP,
Kontos HA,
Christman VC,
DeWitt DS,
and
Povlishock JT.
Superoxide generation and reversal of acetylcholine-induced cerebral arteriolar dilation after acute hypertension.
Circ Res
57:
781-787,
1985
36.
Zhao, J,
Zhany Y,
Xin S-M,
Ma L,
and
Pei G.
Attenuation of nociceptin/orphanin FQ-induced signaling by N-methyl-D-aspartate in neuronal cells.
Neuroreport
9:
631-636,
1998[ISI][Medline].
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