Differential Effects of Short-term Hypoxia and Hypercapnia on N-Methyl-d-Aspartate–Induced Cerebral Vasodilatation in Piglets
Background and Purpose Recent studies in piglets show that either asphyxia or global cerebral ischemia, which combines effects of hypoxia and hypercapnia, transiently attenuates N-methyl-d-aspartate (NMDA)–induced pial arteriolar dilation. The purpose of this study was to determine individually the effects of hypoxic hypoxia and normoxic hypercapnia on NMDA-dependent cerebrovascular reactivity. In addition, we examined mechanisms involved in reduced cerebral vascular dilation to NMDA.
Methods In anesthetized piglets, we examined pial arteriolar diameters using a cranial window and intravital microscopy. Arteriolar responses to topically applied NMDA were determined under control conditions and after arterial hypoxia or arterial hypercapnia. In addition, arteriolar responses to NMDA were examined in animals given indomethacin (10 mg/kg IV) or superoxide dismutase (100 U/mL, topical application) before hypoxia.
Results Under control conditions, application of NMDA produced a dose-related dilation of pial arterioles (eg, 9±1% to 10−5, 15±2% to 5×10−5, and 28±5% to 10−4 mol/L NMDA above baseline, respectively, in the hypoxic group; n=6, P<.05). After transient exposure to 15 minutes of hypoxic hypoxia, arteriolar responses to NMDA were reduced at 30 minutes and at 60 minutes (10−4 mol/L NMDA dilated by 12±5% and 18±5%, respectively; n=6, P<.05). Five minutes of hypoxic hypoxia also reduced dilatation to NMDA. Indomethacin or superoxide dismutase preserved arteriolar responses to NMDA after 15 minutes of hypoxia. Pial arteriolar responses to NMDA remained unimpaired during and after hypercapnia.
Conclusions Short-term severe hypoxic hypoxia and reventilation impair the NMDA-induced dilatation of pial arterioles. Respiratory acidosis alone does not modify pial arteriolar reactivity to NMDA. The reduced responsiveness of the cerebral blood vessels to NMDA caused by hypoxia appears to be due to action of oxygen radicals.
Cerebral ischemia and asphyxia are common insults during the perinatal period.1 We have previously reported that 10 minutes of either asphyxia or global cerebral ischemia transiently reduces arteriolar dilatation to NMDA.2 3 However, the factors affecting arteriolar dilation under these conditions are unclear but may involve modification of the NMDA receptor-ion channel complex. The activity of the complex can be modified by various conditions and agents4 5 6 such as acidosis7 and hypoxia,8 which are prominent features of ischemia and asphyxia. Interestingly, we found no studies published on modulation of NMDA-dependent cerebral vasodilatation by arterial hypoxia or hypercapnia alone.
Accordingly, the aims of the present experiments were to determine the separate effects of hypoxic hypoxia and normoxic hypercapnia on NMDA-dependent vascular reactivity. We tested the hypothesis that arterial hypoxia and hypercapnia would attenuate arteriolar dilation to NMDA. In addition, based on previous observations,2 we have tested the hypothesis that indomethacin pretreatment preserves NMDA-induced arteriolar dilation. Furthermore, we directly tested the hypothesis that changes in arteriolar dilation to NMDA were due to actions of oxygen radicals.
Materials and Methods
Newborn (1 to 7 days old) piglets of either sex with body weight of 0.9 to 1.4 kg were used in this study. All procedures were approved by the institution's animal care and use committee. Anesthesia was induced with sodium thiopental (30 mg/kg) followed by intravenous injection of α-chloralose (75 mg/kg). Supplemental doses of α-chloralose were given as needed to maintain a stable level of anesthesia. Animals were intubated by tracheotomy and artificially ventilated with room air. Body temperature was maintained at 37°C to 38°C by a heating pad. Systemic arterial blood pressure was recorded by means of a cannula introduced to the right femoral artery connected to a pressure transducer. The right femoral vein was cannulated for drug administration. The head was fixed in a stereotaxic frame. The scalp was incised, and connective tissue over the parietal bone was removed. A craniectomy for a 19-mm stainless steel/glass cranial window was made in the left parietal bone 10 mm rostral to the coronal suture. The dura was exposed, cut, and reflected over the skull. A cranial window with three needle ports was placed into the hole, sealed by bone wax, and cemented with cynoacrylate ester and dental acrylic. The closed window was filled with aCSF, which was warmed to 37°C and equilibrated with 6% O2 and 6.5 CO2% in N2. The composition of the aCSF was as follows (mmol/L): KCl 2.9, MgCl2 1.4, CaCl2 1.2, NaCl 132, NaHCO3 24.6, urea 6.7, and glucose 3.7. Diameters of pial arterioles were measured with a microscope (Wild M36) equipped with a video camera (Panasonic) and video microscaler (IV-550, For-A Co). After the surgical procedure, the cranial window was gently infused with aCSF several times until a stable baseline was obtained.
There were six experimental groups of animals in this study.
Group 1: Exposure to 15-Minute Hypoxia
In the first group of piglets (n=6), we examined responses of cerebral arterioles to three different doses of NMDA (10−5, 5×10−5, and 10−4 mol/L) applied topically before and 30 and 60 minutes after a 15-minute exposure to hypoxia. Hypoxia was produced by inhalation of a gas mixture of 7.5% O2/92.5% N2. Arterial blood gas and pH levels were measured at the 5th and the 14th minutes of the hypoxic period.
Group 2: Exposure to 5-Minute Hypoxia
To determine how the duration of the hypoxic exposure influences the NMDA-dependent pial arteriolar responsiveness, in a second group of animals (n=5), we recorded the vascular responses before and 30 minutes after 5 minutes of hypoxia.
Group 3: Exposure to Hypoxia With Indomethacin Treatment
Previously, we have shown that indomethacin pretreatment preserves NMDA-induced pial arteriolar dilatation after global cerebral ischemia3 or asphyxia.2 Therefore, in the third group of piglets (n=6), we examined responses to NMDA as in group 1, but animals were treated with indomethacin (10 mg/kg IV) 20 minutes before hypoxia.
Group 4: Exposure to Hypoxia With SOD Treatment
We have shown previously that SOD can scavenge superoxide anions after ischemia or asphyxia.9 10 Therefore, in the fourth group of animals (n=6), we examined responses to NMDA under control conditions as in the first group. After vessel diameters returned to baseline, SOD (100 U/mL) was topically applied three to four times for a 30-minute period and allowed to remain under the window during the 15-minute hypoxic exposure. NMDA responsiveness was tested 30 minutes after the hypoxic period.
Group 5: Exposure to 30-Minute Hypercapnia
In the fifth group of animals (n=7), we investigated whether normoxic hypercapnia and subsequent acidosis influence the responsiveness of the cerebral blood vessels to NMDA. Vascular responses were evaluated under control conditions and 30 and 60 minutes after exposure to 10% CO2 in air for 30 minutes. Blood gas values and pH were measured at 5, 15, and 25 minutes of hypercapnia.
Group 6: Exposure to Hypercapnia With Indomethacin Treatment
In piglets, we have previously shown that 10 mg/kg IV indomethacin blocks prostanoid production to various stimuli and reduces cerebral vasodilator responses to normoxic hypercapnia.11 Therefore, in indomethacin-pretreated animals it was possible to examine the NMDA-induced pial arteriolar responses during persistent respiratory acidosis when changes in diameter were minimal. In this group of piglets (n=6), indomethacin was given 20 minutes before the hypercapnic period, and NMDA responsiveness was tested during and after hypercapnia.
Group 7: Vascular Responses to SNP and Forskolin After Hypoxia
In a separate group of animals (n=4), we examined vascular responses to SNP and forskolin before and after 15 minutes of hypoxia to test whether hypoxia alters responsiveness of pial arterioles to other vasodilator substances.
The drugs used in this study were N-methyl-d-aspartic acid (Sigma), SOD (Sigma), and indomethacin sodium trihydrate (Merck). Appropriate dilutions of NMDA were made with aCSF just before application.
Values are presented as mean±SE. When appropriate, data were analyzed with the paired t test or with repeated measures ANOVA, and Student-Newman-Keuls test was performed. Comparisons between treatment groups were made with ANOVA. A value of P<.05 was considered statistically significant.
Application of NMDA produced a dose-related dilatation of pial arterioles under control conditions (Figs 1 through 4⇓⇓⇓⇓). Baseline mean arterial blood pressure was approximately 60 mm Hg in each group and did not change during application of NMDA.
Effects of Hypoxia on NMDA Responses
Inhalation of 7.5% O2 for 15 minutes resulted in a pial arteriolar dilatation. The vasodilator effect developed in 3 to 4 minutes, with a maximal dilation of 33±4% above baseline. At the end of the hypoxic period arteriolar diameter was 121±11 μm, which was approximately 20% above baseline (Table 1⇓, group 1). Arterial Pco2 did not change, whereas arterial Po2 decreased from 91±5 to 22±1 mm Hg during hypoxia. Change in arterial pH indicates development of a slight metabolic acidosis. Arterial blood pressure was kept at normal levels. After the end of 7.5% oxygen inhalation, arteriolar diameters recovered to baseline levels by 10 minutes. Thirty minutes after the hypoxic period, arteriolar diameter was not statistically different from the original baseline. After 15 minutes of hypoxic hypoxia, arteriolar responses to NMDA were reduced at 30 and 60 minutes as well (Table 1⇓; Figs 1 and 2⇑⇑).
In animals exposed to 5 minutes of hypoxia, the size of the arteriolar dilatation was similar to the first group (Table 1⇑, group 2). Arteriolar diameter was 108±6 μm before and 139±8 μm at the end of the hypoxic period. Five minutes of hypoxic exposure significantly reduced arteriolar dilatation to NMDA. Thirty minutes after the hypoxic period, 10−4 mol/L NMDA dilated pial arterioles by 19±2%, whereas dilation under control circumstances was 30±3% (P<.05, Fig 1⇑).
Comparing the effects of the 15-minute and 5-minute hypoxic exposures, we found that 15-minute hypoxia reduced the vascular responses to NMDA more than 5-minute hypoxia (Fig 1⇑).
In group 3, 20 minutes after administration of indomethacin the diameter of the arterioles was 80±2 μm, 12% less than baseline value (Table 1⇑, group 3). In animals pretreated with indomethacin, hypoxia also resulted in cerebral vasodilatation, and arteriolar diameter was 21±10% above the original baseline at the end of the hypoxic period. In contrast to groups 1 and 2, arteriolar responses to each dose of NMDA 30 or 60 minutes after the hypoxic period were not changed significantly (Table 1⇑, Fig 2⇑).
Topically applied SOD neither altered baseline diameter (102±4 μm under control conditions and 102±5 μm after SOD treatment) nor altered cerebral arteriolar dilation during hypoxia (Table 1⇑, group 4). Mean arterial blood pressure was not influenced by SOD treatment. Thirty minutes after 15 minutes of hypoxic hypoxia, arteriolar responses to NMDA did not differ from responses before hypoxia (Fig 3⇑).
Effects of Hypercapnia on NMDA Responses
During hypercapnia, arterial blood pH decreased from 7.45±0.04 to 7.13±0.03 at the 15th minute of the hypercapnic period. Arterial Pco2 rose from 34±1 to 73±3 mm Hg, but arterial Po2 was unchanged from baseline (Table 2⇓, group 5). Hypercapnia caused dilatation of pial arterioles to a degree close to the response evoked by 10−4 mol/L NMDA (Table 2⇓). The diameter of the arterioles was 125±7 μm, 33% above the baseline at the end of the hypercapnic period. Thirty minutes after the hypercapnic period, arteriolar dilation to NMDA did not differ from the values measured under control conditions (Table 2⇓ and Fig 4⇑).
In the indomethacin-pretreated group (group 6), the hypercapnic response was significantly attenuated compared with the untreated group. However, the vessel diameter increased slightly, by 10% above baseline (115±9 versus 104±4 μm). Arteriolar dilation to NMDA was not different from baseline responses during the hypercapnic period (Table 2⇑, group 6); 10−4 mol/L NMDA dilated pial arterioles by 31±4% during hypercapnia (Fig 4⇑). Although baseline diameters increased slightly by 30 minutes after the hypercapnic period, arteriolar responses to NMDA (either absolute or percent values) were unchanged (Table 2⇑, Fig 4⇑).
Dilatation of cerebral arterioles in response to SNP was not affected by 15 minutes of hypoxia. Baseline diameter of cerebral arterioles was 104±2 μm in this group (n=4). The increase in diameter was 15±% and 29±2% before and 16±2% and 30±4% 30 minutes after hypoxia in response to 10−6 and 10−5 mol/L SNP, respectively.
Forskolin at concentrations of 5×10−8 and 5×10−6 mol/L resulted in vasodilation before hypoxia (9±1% and 29±1%, respectively; n=4). Baseline diameters did not differ before and 60 minutes after hypoxia (104±1 versus 102±1 μm; n=4). Hypoxia had no significant effect on vasodilatation: increases in arteriolar diameter were 8±1% and 31±4% after hypoxia.
We report four important new findings in this study. First, a brief period (5 or 15 minutes) of hypoxic hypoxia is able to impair NMDA-induced dilation of pial arterioles of newborn pigs for at least 30 to 60 minutes. Second, responsiveness of cerebral arterioles to NMDA remains intact during and after 30 minutes of respiratory acidosis. Third, administration of indomethacin before hypoxia preserves the NMDA reactivity of pial arterioles. And fourth, topical application of SOD preserves cerebral arteriolar dilator responses to NMDA. Thus, oxygen radicals appear to play a role in altered arteriolar responses to NMDA after hypoxia.
Glutamate and NMDA affect cerebral blood vessels secondarily by initiating neuronal NO synthesis.12 13 Previous studies by other laboratories14 and by us2 3 have shown that cerebrovascular responsiveness to topical NMDA did not change with repeated drug application. In addition, the magnitude of arteriolar dilatation to NMDA in the present study was similar to changes reported previously.2 3 However, several studies on piglets have shown that cerebrovascular responses to several dilator substances and other dilator stimuli are impaired after asphyxia2 or ischemia.3 15 On the other hand, vasodilation to isoproterenol16 and SNP3 is intact in piglets after global ischemia. Our present data indicate that 15 minutes of severe hypoxia does not alter responsiveness of pial arterioles to NO. Similarly, direct activation of adenylate cyclase by forskolin results in the same vasodilation before and after hypoxia.
Detailed description of structure and function of the NMDA receptor is available in many reviews.4 17 In vitro studies revealed that the receptor activity can be modified by extracellular pH18 and oxygen radicals, as well as by other factors.19 20 21 However, it was previously unclear whether acidosis or oxygen radicals have a major influence on cortical NMDA receptor function in vivo.
Arterial hypoxia and hypercapnia can influence extracellular pH through different mechanisms.22 In the present experiments, inhalation of 10% CO2 resulted in arterial hypercapnia and acidosis by 5 minutes. Arterial pH and CO2 did not change further during the exposure period. Several studies have shown that extracellular brain pH parallels arterial blood pH during arterial hypercapnia.23 Studies on the extracellular pH of the brain during hypoxia reveal that a brief initial transient alkaline shift is followed by acidosis.22 On inhalation of room air after arterial hypercapnia or hypoxia, arterial blood pH returns quickly to baseline levels.23 24
One difficulty with examining the effects of acidosis on arteriolar dilation to NMDA is the change in baseline arteriolar diameter during hypercapnia. Consequently, we took advantage of the ability of indomethacin to suppress arteriolar dilation during hypercapnia.25 Indomethacin does not alter NMDA-induced arteriolar dilation.26 Despite severe acidosis, NMDA-evoked responses remained intact during and after hypercapnia. It is therefore unlikely that extracellular acidosis alone is responsible for changes in NMDA-evoked responses after ischemia or asphyxia.2 3 However, we cannot completely rule out a depressive effect of H+ on NMDA-induced dilatation at greater levels of acidosis.
Our present finding is apparently in contrast to deductions based on studies27 28 in which acidosis reduced the NMDA-activated inward Ca2+ current. In those experiments the acidosis appeared to be more severe than in our model.
In contrast to acidosis, we showed that even a brief period of hypoxic stress and reoxygenation induces a persistent change in NMDA-mediated vascular responses. Reduced oxygen supply affects the metabolism of neuronal and glial tissues and causes a rise in extracellular concentration of various vasodilator metabolites.29 These metabolites include adenosine, lactic acid, prostaglandins, NO, and vasoactive peptides. Accumulation of a variety of vasoactive substances in the cerebrospinal fluid could have immediate or sustained effects on NMDA receptor functions. Changes in the composition of endogenous redox compounds associated with hypoxia/reoxygenation could also interact with the NMDA receptor complex.8 19 20
Information regarding the functional changes of the NMDA receptor itself after hypoxic insults is sparse. Reduced NMDA receptor numbers and [3H]glutamate binding sites have been described immediately or 24 hours after hypoxic exposure in fetal guinea pig cortex8 and neonatal rat brain.30 Conversely, hypoxia enhances ligand binding affinity of the NMDA receptor.8 Thus, based on ligand binding experiments performed ex vivo, it is impossible to predict effects of hypoxia on NMDA-induced pial arteriolar dilation.
Indomethacin administration alone does not affect NMDA-initiated cerebral hemodynamics, suggesting that cyclooxygenase products do not mediate responses to NMDA.11 26 The finding that preadministration of indomethacin restored NMDA-induced pial arteriolar dilation after hypoxia is consistent with our previous results with asphyxia.2 The mechanism of protective action on NMDA-induced arteriolar responsiveness is unclear. Indomethacin blocks prostaglandin synthase31 and prevents free radical production20 32 during conversion of PGG2 to PGH2. Our previous data2 indicate that oxypurinol, an oxygen radical scavenger and xanthine oxidase inhibitor, preserves the NMDA-induced dilation after asphyxia. This adds support to the view that oxygen radicals depress NMDA-induced arteriolar dilation. In addition, the present findings with SOD provide strong evidence that oxygen radicals are able to suppress NMDA-induced arteriolar dilation.
Reduction in neuronal NOS activity after hypoxia could also account for the decrease in NMDA-evoked pial arteriolar dilation. However, we have not found any substantial reduction in NOS activity or neuronal NOS levels after complete ischemia in a global ischemia model,3 while NMDA-induced arterial dilatation was impaired significantly. Accordingly, Groenendaal et al33 showed that hypoxia did not alter NOS activity measured ex vivo in piglets.
Although the role of NMDA receptors in hypoxia-ischemia–associated brain damage has been intensively studied, there is little information about how functional changes depend on the duration of hypoxic exposure. In most experimental models the ischemic-hypoxic period was longer than 5 minutes. Early observations of Gill et al34 have shown that a brief period (5 minutes) of global ischemia already results in consistent neuronal injury.
In our experiments indomethacin pretreatment had minimal effects on arteriolar dilation to hypoxia. This finding is partly in conflict with recent observations of Coyle et al,35 who showed that indomethacin inhibited hypoxic cerebral vasodilation. In their study the lowest arterial Po2 level was 27 mm Hg, whereas in our study it decreased to 22±1 mm Hg. Hemoglobin O2 binding capacity increases sharply between 20 and 35 mm Hg. A relatively small shift in Po2 levels could mask considerable alterations in the tissue oxygen supply. It has been shown that under hypoxic conditions with an arterial oxygen tension of 35±5 mm Hg, there is an adequate oxygen supply in newborn animals.36
In conclusion, we found that arterial hypoxia but not extracellular acidosis affects the NMDA-dependent cerebral vasodilation. It is widely accepted that release of excitatory amino acids during hypoxic/anoxic stress is partly responsible for neurological sequelae and that decreased cerebrovascular reactivity to dilatory excitatory amino acids may limit damage. The present observations emphasize the potential beneficial effects of indomethacin or oxygen radical scavenger on the cerebral microcirculation during hypoxia and reperfusion.
Selected Abbreviations and Acronyms
|aCSF||=||artificial cerebrospinal fluid|
|NOS||=||nitric oxide synthase|
This study was supported by grants HL-30260, HL-46558, and HL-50587 from the National Institutes of Health. We thank Merck, Sharpe and Dohme for providing the indomethacin.
- Received April 11, 1996.
- Revision received June 6, 1996.
- Accepted June 10, 1996.
- Copyright © 1996 by American Heart Association
Busija DW, Meng W. Altered cerebrovascular responsiveness to N-methyl-D-aspartate after asphyxia in piglets. Am J Physiol. 1993;265:H389-H394.
Busija DW, Meng W, Bari F, McGough SP, Errico RA, Tobin JR, Louis TM. Effects of ischemia on cerebrovascular responses to N-methyl-D-aspartate in piglets. Am J Physiol. 1996;270:H1225-H1230.
Scheetz AJ, Constantine-Paton M. Modulation of NMDA receptor function: implications for vertebrate neural development. FASEB J.. 1994;8:745-752.
Traynelis SF, Hartley M, Heinemann SF. Control of proton sensitivity of the NMDA receptor by RNA splicing and polyamines. Science. 1995;268:873-876.
Armstead, WR, Mirro D, Zuckerman S, Busija DW, Leffler CW. Postischemic generation of superoxide anion by newborn brain. Am J Phys. 1988;H401-H403.
Faraci FM, Breese KR. Nitric oxide mediates vasodilatation in response to activation of N-methyl-d-aspartate receptors in the brain. Circ Res. 1993;72:476-480.
Meng W, Tobin JR, Busija DW. Glutamate-induced cerebral vasodilation is mediated by nitric oxide through N-methyl-d-aspartate receptors. Stroke. 1995;26:857-862.
Faraci FM, Brian JE. 7-Nitroindazole inhibits brain nitric oxide synthase and cerebral vasodilatation in response to N-methyl-d-aspartate. Stroke. 1995;26:2172-2176.
Louis TM, Meng W, Bari F, Errico RA, Busija DW. Ischemia reduces CGRP-induced cerebral vascular dilation in piglets. Stroke. 1966;27:134-139.
Leffler CW, Beasley DG, Busija DW. Cerebral ischemia alters cerebral microvascular reactivity in newborn pigs. Am J Physiol. 1989;257:H266-H271.
Astrup J, Heuser D, Lassen NA, Nilsson B, Norberg K, Siesjö BK. Evidence against H+ and K+ as main factors for the control of cerebral blood flow: a microelectrode study. In: Elliott K, O'Connor M, eds. Cerebral Vascular Smooth Muscle and its Control. New York, NY: Excerpta Medica; 1979:313-337.
Wagerle LC, Mishra OP. Mechanism of CO2 response in cerebral arteries of the newborn pig: role of phospholipase, cyclooxygenase, and lipoxygenase pathways. Circ Res. 1988;62:1019-1026.
Busija DW, Leffler CW. Dilator effects of amino acid neurotransmitters on piglet pial arterioles. Am J Physiol. 1989;257:H1200-H1203.
Dalkara T, Ayata C, Demirci M, Erdemli G, Onur R. Effects of cerebral ischemia on N-methyl-d-aspartate and dihydropyridine-sensitive calcium currents: an electrophysiological study in the rat hippocampus in situ. Stroke. 1996;27:127-133.
Kontos HA. Oxygen radicals in cerebral vascular injury. Circ Res. 1985;57:508-516.
Groenendaal F, Mishra OP, Hoffman DJ, Delivoria-Papadopoulos M. Cerebral nitric oxide synthase acting following hypoxia in newborn piglets. Pediatr Res. 1994;36(suppl):16A. Abstract.
Gill R, Foster AC, Woodruff GN. Systemic administration of MK-801 protects against ischemia induced hippocampal neurodegeneration in the gerbil. J Neurosci. 1987;7:3343-3349.
Coyle MG, Oh W, Stonestreet BS. Effects of indomethacin on brain blood flow and cerebral metabolism in hypoxic newborn piglets. Am J Physiol. 1993;264:H141-H149.
Koehler RC, Jones MD, Traystman RJ. Cerebral circulatory response to carbon monoxide and hypoxic hypoxia in the lamb. Am J Physiol. 1982;243:H27-H32.
Glutamate is the major excitatory neurotransmitter in the central nervous system of vertebrates. Glutamate and selective glutamate receptor agonists produce dilatation of cerebral blood vessels.1R 2R 3R 4R 5R 6R 7R 8R The response to glutamate and receptor agonists is dependent on neuronal activation1R 6R and production of nitric oxide,1R 2R 3R 4R 5R 6R a potent vasodilator. Thus, nitric oxide produced by neurons in response to activation of glutamate receptors appears to couple neuronal activity with local cerebral blood flow.1R
The cerebral vascular response to glutamate may be impaired under some pathophysiological conditions including ischemia and asphyxia.7R 8R In the present study Bari et al examined effects of hypoxia and hypercapnia on responses of cerebral arterioles to the glutamate receptor agonist NMDA. After relatively brief periods of hypoxia (5 to 15 minutes), vasodilator responses to NMDA were impaired. Impaired vasodilatation in response to NMDA could be prevented with indomethacin or SOD, which suggests that superoxide anion, produced via the cyclooxygenase pathway, was the mediator of vascular dysfunction. In contrast to impairment after hypoxia, responses of cerebral arterioles to NMDA were not inhibited by hypercapnia. These findings suggest that hypoxia, but not hypercapnia with accompanying moderate respiratory acidosis, impairs cerebral vasodilatation in response to NMDA.
Thus, hypoxia can profoundly impair responses of cerebral arterioles to NMDA. The implication of this finding is that hypoxia might also impair a major mechanism to link increases in neuronal activity with blood flow. The findings of the present study do not exclude the possibility that more severe acidosis, such as that which may occur during ischemia, may also alter vascular responses to NMDA.
Selected Abbreviations and Acronyms
|aCSF||=||artificial cerebrospinal fluid|
|NOS||=||nitric oxide synthase|
Faraci FM, Breese KR. Nitric oxide mediates vasodilatation in response to activation of N-methyl-d-aspartate receptors in brain. Circ Res.. 1993;72:476-480.
Meng W, Tobin JR, Busija DW. Glutamate-induced cerebral vasodilation is mediated by nitric oxide through N-methyl-d-aspartate receptors. Stroke.. 1995;26:857-863.
Faraci FM, Brian JE. 7-Nitroindazole inhibits brain nitric oxide synthase and cerebral vasodilatation in response to N-methyl-d-aspartate. Stroke.. 1995;26:2172-2176.
Faraci FM, Breese KR, Heistad DD. Responses of cerebral arterioles to kainate. Stroke.. 1994;25:2080-2084.
Mayhan WG, Didion SP. Glutamate-induced disruption of the blood-brain barrier in rats: role of nitric oxide. Stroke.. 1996;27:965-970.
Yang G, Iadecola C. Glutamate microinjections in cerebellar cortex reproduce cerebrovascular effects of parallel fiber stimulation. Am J Physiol. In press.
Busija DW, Meng W. Altered cerebrovascular responsiveness to N-methyl-D-aspartate after asphyxia in piglets. Am J Physiol.. 1993;265:H389-H394.
Busija DW, Meng W, Bari F, McGough SP, Errico RA, Tobin JR, Louis TM. Effects of ischemia on cerebrovascular responses to N-methyl-D-aspartate in piglets. Am J Physiol.. 1996;270:H1225-H1230.