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Query: UMLS:C0020440 (
hypercapnia
)
7,939
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
In the newborn, cyclooxygenase (COX)-derived products play an important role in the cerebrovascular dysfunction after ischemia-reperfusion (I/R). We examined effects of I/R on expression of
COX-1
and COX-2 isoforms in large cerebral arteries of anesthetized piglets. The circle of Willis, the basilar, and the middle cerebral arteries were collected from piglets at 0.5-12 h after global ischemia (2.5-10 min, n = 50), hypoxia (n = 3), or
hypercapnia
(n = 2) and from time-control (n = 19) or untreated animals (n = 7). Tissues were analyzed for
COX-1
and COX-2 mRNA and protein using RNase protection assay and immunoblot analysis, respectively. Ischemia increased COX-2 mRNA by 30 min, and maximal levels were reached at 2 h. Hypoxia or
hypercapnia
had minimal effects on COX-2 mRNA. COX-2 protein levels were also consistently elevated by 8 h after I/R. Increases in COX-2 mRNA or protein were not influenced by pretreatment with either indomethacin (5 mg/kg iv, n = 5) or nitro-L-arginine methyl ester (15 mg/kg iv, n = 7).
COX-1
mRNA levels were low in time controls, and ischemic stress had no significant effect on
COX-1
expression. Thus ischemic stress leads to relatively rapid, selective induction of COX-2 in cerebral arteries.
...
PMID:Ischemia-reperfusion rapidly increases COX-2 expression in piglet cerebral arteries. 1048 43
Cyclooxygenase (COX) is a prostanoid-synthesizing enzyme present in 2 isoforms:
COX-1
and COX-2. Although it has long been hypothesized that prostanoids participate in cerebrovascular regulation, the lack of adequate pharmacological tools has led to conflicting results and has not permitted investigators to define the relative contribution of
COX-1
and COX-2. We used the
COX-1
inhibitor SC-560 and
COX-1
-null (
COX-1
(-/-)) mice to investigate whether
COX-1
plays a role in cerebrovascular regulation. Mice were anesthetized (urethane and chloralose) and equipped with a cranial window. Cerebral blood flow (CBF) was measured by laser Doppler flowmetry or by the (14)C-iodoantipyrine technique with quantitative autoradiography. In wild-type mice, SC-560 (25 micromol/L) reduced resting CBF by 21+/-4% and attenuated the CBF increase produced by topical application of bradykinin (-59%) or calcium ionophore A23187 (-49%) and by systemic
hypercapnia
(-58%) (P<0.05 to 0.01). However, SC-560 did not reduce responses to acetylcholine or the increase in somatosensory cortex blood flow produced by vibrissal stimulation. In
COX-1
(-/-) mice, resting CBF assessed by (14)C-iodoantipyrine was reduced (-13% to -20%) in cerebral cortex and other telencephalic regions (P<0.05). The CBF increase produced by bradykinin, A23187, and
hypercapnia
, but not acetylcholine or vibrissal stimulation, were attenuated (P<0.05 to 0.01). The free radical scavenger superoxide dismutase attenuated responses to bradykinin and A23187 in wild-type mice but not in
COX-1
(-/-) mice, suggesting that
COX-1
is the source of the reactive oxygen species known to mediate these responses. The data provide evidence for a critical role of
COX-1
in maintaining resting vascular tone and in selected vasodilator responses of the cerebral microcirculation.
...
PMID:Cyclooxygenase-1 participates in selected vasodilator responses of the cerebral circulation. 1128 94
Cyclooxygenase (COX)-derived prostanoids play an important role in the cerebrovascular control of newborns. In humans and in the widely accepted model of piglets, both the
COX-1
and the COX-2 isoforms are expressed in cerebral arteries. However, the involvement of these isoforms in cerebrovascular control is unknown. Therefore we tested if specific inhibitors of
COX-1
and/or COX-2 would differentially affect pial arteriolar responses to COX-dependent stimuli in piglets. Anesthetized, ventilated piglets (n = 35) were equipped with a closed cranial window, and changes in pial arteriolar diameters (baseline approximately 100 microm) to
hypercapnia
(ventilation with 5-10% CO(2), 21% O(2), balance N(2)), arterial hypotension (40 mm Hg MABP achieved by blood withdrawal), and Ach (Ach, 10-100 microM) were determined via intravital microscopy. Arteriolar responses were repeatedly tested 15 min after IV administration of selective
COX-1
and COX-2 inhibitors SC-560 and NS-398 (1-1 mg/kg), and nonselective inhibitors indomethacin (0.3-1 mg/kg), acetaminophen (30 mg/kg), and ibuprofen (30 mg/kg).
Hypercapnia
resulted in concentration-dependent, reversible, (approximately 20-40%) increases in pial arteriolar diameters that were unaffected by NS-398, SC-560, acetaminophen and ibuprofen. In contrast, 0.3 mg/kg indomethacin significantly reduced, 1 mg/kg virtually abolished the vasodilation. Arterial hypotension elicited (approximately 15-20%) vasodilation that was similarly reduced by NS-398 and indomethacin but was unaltered by SC-560. Ach dose-dependently constricted pial arterioles. This response was similarly attenuated by NS-398, indomethacin, and ibuprofen, but left intact by SC-560. We conclude that the assessed COX-dependent vascular reactions appear to depend largely on COX-2 activity. However,
hypercapnia
-induced vasodilation was found indomethacin-sensitive instead of a COX-dependent response in the piglet.
...
PMID:Selective inhibitors differentially affect cyclooxygenase-dependent pial arteriolar responses in newborn pigs. 1584 34
Cerebral blood flow (CBF) is controlled by arterial blood pressure, arterial CO
2
, arterial O
2
, and brain activity and is largely constant in the awake state. Although small changes in arterial CO
2
are particularly potent to change CBF (1 mmHg variation in arterial CO
2
changes CBF by 3%-4%), the coupling mechanism is incompletely understood. We tested the hypothesis that astrocytic prostaglandin E
2
(PgE
2
) plays a key role for cerebrovascular CO
2
reactivity, and that preserved synthesis of glutathione is essential for the full development of this response. We combined two-photon imaging microscopy in brain slices with
in vivo
work in rats and C57BL/6J mice to examine the hemodynamic responses to CO
2
and somatosensory stimulation before and after inhibition of astrocytic glutathione and PgE
2
synthesis. We demonstrate that
hypercapnia
(increased CO
2
) evokes an increase in astrocyte [Ca
2+
]
i
and stimulates
COX-1
activity. The enzyme downstream of
COX-1
that synthesizes PgE
2
(microsomal prostaglandin E synthase-1) depends critically for its vasodilator activity on the level of glutathione in the brain. We show that, when glutathione levels are reduced, astrocyte calcium-evoked release of PgE
2
is decreased and vasodilation triggered by increased astrocyte [Ca
2+
]
i
in vitro
and by
hypercapnia
in vivo
is inhibited. Astrocyte synthetic pathways, dependent on glutathione, are involved in cerebrovascular reactivity to CO
2
Reductions in glutathione levels in aging, stroke, or schizophrenia could lead to dysfunctional regulation of CBF and subsequent neuronal damage.
SIGNIFICANCE STATEMENT
Neuronal activity leads to the generation of CO
2
, which has previously been shown to evoke cerebral blood flow (CBF) increases via the release of the vasodilator PgE
2
We demonstrate that
hypercapnia
(increased CO
2
) evokes increases in astrocyte calcium signaling, which in turn stimulates
COX-1
activity and generates downstream PgE
2
production. We demonstrate that astrocyte calcium-evoked production of the vasodilator PgE
2
is critically dependent on brain levels of the antioxidant glutathione. These data suggest a novel role for astrocytes in the regulation of CO
2
-evoked CBF responses. Furthermore, these results suggest that depleted glutathione levels, which occur in aging and stroke, will give rise to dysfunctional CBF regulation and may result in subsequent neuronal damage.
...
PMID:A Critical Role for Astrocytes in Hypercapnic Vasodilation in Brain. 2846 12
