Nitric oxide and prostaglandins interact to mediate arteriolar dilation during cortical spreading depression

We examined whether blockade of prostaglandin synthesis by indomethacin could attenuate the effect of nitric oxide synthase (NOS) inhibition on cerebral arteriolar dilation during cortical spreading depression (CSD). CSD was induced by microinjection of 5% (670 mM) KCl onto the cerebral cortex of anesthetized adult rabbits. A closed cranial window and intravital microscopy were used to measure pial arteriolar diameter, and NOS activity was determined by the conversion assay of [14C]arginine to [14C]citrulline. CSD dilated pial arterioles by 47 +/- 3% (baseline = 80-88 microns) (n = 21, P < 0.05), and inhibition of NOS by NG-nitro-L-arginine (L-NNA) (15 mg/kg iv) reduced dilation during CSD by over one-half (n = 8, P < 0.05) without altering the onset latency to CSD. After indomethacin administration (15 mg/kg iv), CSD dilated arterioles from 73 +/- 2 to 152 +/- 6 microns (n = 4, P < 0.05). However, after administration of both indomethacin and L-NNA (n = 5), CSD-induced arteriolar dilation was not different from the situation where indomethacin alone was given. Thus indomethacin completely abolished the inhibitory effect of L-NNA on CSD-induced dilation. Administration of L-NNA inhibited NOS activity in brain cortex almost completely (n = 8, P < 0.05), whereas indomethacin itself had no effect (n = 8). In addition, L-NNA inhibited topical acetylcholine (10(-5) M)-induced arteriolar dilation (n = 3, P < 0.05), and this effect was not altered by indomethacin (n = 4). In summary, L-NNA reduced arteriolar dilation during CSD. However, after administration of indomethacin, L-NNA does not reduce CSD-induced arteriolar dilation.

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Effect of cross-linked hemoglobin transfusion on endothelial-dependent dilation in cat pial arterioles

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1998.275.4.h1313 ◽

1998 ◽

Vol 275 (4) ◽

pp. H1313-H1321 ◽

Cited By ~ 23

Author(s):

Yoshio Asano ◽

Raymond C. Koehler ◽

John A. Ulatowski ◽

Richard J. Traystman ◽

Enrico Bucci

Keyword(s):

Nitric Oxide ◽

Hemoglobin Concentration ◽

Nitric Oxide Donor ◽

Nitric Oxide Synthase Inhibitor ◽

Cranial Window ◽

Dilatory Response ◽

Pial Arterioles ◽

Synthase Inhibitor ◽

Oxide Synthase ◽

Arteriolar Diameter

We determined whether addition of hemoglobin to the plasma would inhibit endothelial-dependent dilation in brain where tight endothelial junctions limit hemoglobin extravasation. Pial arteriolar diameter was measured by intravital microscopy through closed cranial windows in anesthetized cats either without transfusion (hematocrit = 32%) or after exchange transfusion with an albumin or sebacyl-cross-linked human hemoglobin solution (hematocrit = 18%). Dilation of small, medium, and large arterioles to acetylcholine and ADP was not significantly altered by hemoglobin transfusion. The dilatory responses were inhibited by the nitric oxide synthase inhibitor N G-nitro-l-arginine, although significant dilation to 30 μM acetylcholine persisted in small arterioles in the control and albumin-transfused group but not in the hemoglobin-transfused group. The dilatory response to the nitric oxide donor 3-morpholinosydnonimine was unaffected by albumin or hemoglobin transfusion, but the response to nitroprusside was reduced by one-third after hemoglobin transfusion. When cross-linked hemoglobin was superfused through the cranial window, the acetylcholine response became inhibited at a hemoglobin concentration of 0.1 μM and was completely blocked at 10 μM. Because this concentration is substantially less than the 500 μM hemoglobin concentration in plasma after transfusion when there was no inhibition of the acetylcholine response, hemoglobin permeation of the blood-brain barrier was considered negligible. We conclude that exchange of red cell-based hemoglobin with plasma-based hemoglobin does not produce a more effective sink for endothelial-derived nitric oxide evoked by agonist receptor-mediated activation. Furthermore, decreased hematocrit does not affect agonist-evoked endothelial-dependent dilation.

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Cortical spreading depression confounds concentration-dependent pial arteriolar dilation during N-methyl-d-aspartate superfusion

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01102.2005 ◽

2006 ◽

Vol 290 (5) ◽

pp. H1837-H1841 ◽

Cited By ~ 19

Author(s):

Cenk Ayata ◽

Michael A. Moskowitz

Keyword(s):

Nmda Receptors ◽

Cortical Spreading Depression ◽

Spreading Depression ◽

Slow Potential ◽

Mk 801 ◽

Potential Shift ◽

Cranial Window ◽

Cortical Areas ◽

Pial Arterioles ◽

Arteriolar Diameter

Pial arterioles do not express N-methyl-d-aspartate (NMDA) receptors but dilate in response to topical NMDA application. We explored the mechanism underlying NMDA-mediated responses in murine pial arterioles (11–31 μm), using a closed cranial window preparation, and found that arteriolar dilation was not concentration dependent. Pial arteriolar diameter abruptly increased within 3 min of superfusing 50 or 100 μM NMDA. Dilation reached a peak within 1 min (46 ± 14%) and then declined to a plateau (28 ± 13%) for the duration of superfusion. Whereas a higher concentration (200 μM) did not produce further dilation, lower concentrations (1–10 μM) did not dilate the arterioles at all. MK-801 (10 μM) abrogated the dilation response, whereas Nω-nitro-l-arginine (1 mM) attenuated the peak and abolished the sustained dilation during NMDA superfusion. We determined that NMDA-induced pial arteriolar responses were evoked by cortical spreading depression, because abrupt vasodilation during 50 or 100 μM NMDA superfusion was associated with a large negative slow potential shift and electrocorticogram suppression that spread from the superfusion window to distant cortical areas. Our data suggest that the responses of pial arterioles to NMDA are caused in part by neurovascular coupling due to cortical spreading depression.

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Nitric Oxide Scavenging by Hemoglobin or Nitric Oxide Synthase Inhibition by N-Nitro-L-Arginine Induces Cortical Spreading Ischemia When K+ Is Increased in the Subarachnoid Space

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-199809000-00007 ◽

1998 ◽

Vol 18 (9) ◽

pp. 978-990 ◽

Cited By ~ 184

Author(s):

Jens P. Dreier ◽

Katrin Körner ◽

Nathalie Ebert ◽

Astrid Görner ◽

Inger Rubin ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Cortical Spreading Depression ◽

Spreading Depression ◽

Transient Ischemia ◽

Cranial Window ◽

Radical Production ◽

Oxide Synthase ◽

Ischemic Events

We investigated the combined effect of increased brain topical K+ concentration and reduction of the nitric oxide(NO.) level caused by nitric oxide scavenging or nitric oxide synthase (NOS) inhibition on regional cerebral blood flow and subarachnoid direct current (DC) potential. Using thiopental-anesthetized male Wistar rats with a closed cranial window preparation, brain topical superfusion of a combination of the NO. scavenger hemoglobin(Hb; 2 mmol/L) and increased K+ concentration in the artificial cerebrospinal fluid ([K+]ACSF) at 35 mmol/L led to sudden spontaneous transient ischemic events with a decrease of CBF to 14 ± 7% (n = 4) compared with the baseline (100%). The ischemic events lasted for 53 ± 17 minutes and were associated with a negative subarachnoid DC shift of −7.3 ± 0.6 mV of 49 ± 12 minutes' duration. The combination of the NOS inhibitor N-nitro-L-arginine(L-NA, 1 mmol/L) with [K+]ACSF at 35 mmol/L caused similar spontaneous transient ischemic events in 13 rats. When cortical spreading depression was induced by KCl at a 5-mm distance, a typical cortical spreading hyperemia (CSH) and negative DC shift were measured at the closed cranial window during brain topical superfusion with either physiologic artificial CSF (n = 5), or artificial CSF containing increased [K+]ACSF at 20 mmol/L (n = 4), [K+]ACSF at 3 mmol/L combined with L-NA (n = 10), [K+]ACSF at 10 mmol/L combined with L-NA (five of six animals) or [K+]ACSF at 3 mmol/L combined with Hb (three of four animals). Cortical spreading depression induced long-lasting transient ischemia instead of CSH, when brain was superfused with either[K+]ACSF at 20 mmol/L combined with Hb (CBF decrease to 20± 20% duration 25 ± 21 minutes, n = 4), or [K+]ACSF at 20 mmol/L combined with L-NA (n = 19). Transient ischemia induced by NOS inhibition and [K+]ACSF at 20 mmol/L propagated at a speed of 3.4 ± 0.6 mm/min, indicating cortical spreading ischemia (CSI). Although CSH did not change oxygen free radical production, as measured on-line by in vivo lucigenin-enhanced chemiluminescence, CSI resulted in the typical radical production pattern of ischemia and reperfusion suggestive of brain damage (n = 4). Nimodipine (2 μg/kg body weight/min intravenously) transformed CSI back to CSH (n = 4). Vehicle had no effect on CSI(n = 4). Our data suggest that the combination of decreased NO. levels and increased subarachnoid K+ levels induces spreading depression with acute ischemic CBF response. Thus, a disturbed coupling of metabolism and CBF can cause ischemia. We speculate that CSI may be related to delayed ischemic deficits after subarachnoid hemorrhage, a clinical condition in which the release of Hb and K+ from erythrocytes creates a microenvironment similar to the one investigated here.

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Calcitonin gene-related peptide promotes cerebrovascular dilation during cortical spreading depression in rabbits

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1994.266.3.h1095 ◽

1994 ◽

Vol 266 (3) ◽

pp. H1095-H1102 ◽

Cited By ~ 4

Author(s):

D. M. Colonna ◽

W. Meng ◽

D. D. Deal ◽

D. W. Busija

Keyword(s):

Cortical Spreading Depression ◽

Spreading Depression ◽

Topical Administration ◽

Competitive Inhibitor ◽

Calcitonin Gene Related Peptide ◽

Cranial Window ◽

Related Peptide ◽

Brain Surface ◽

Calcitonin Gene ◽

Pial Arterioles

We examined the role of calcitonin gene-related peptide (CGRP) in cortical spreading depression (CSD)-induced dilation of rabbit pial arterioles. In urethan-anesthetized rabbits instrumented with a closed cranial window, CSD induction with KCl dilated pial arterioles from 86 +/- 10 to 132 +/- 13 (mean +/- SE, n = 6) microns (a 54 +/- 9% increase). Topical administration of 12.8 microM CGRP-(8-37), a competitive inhibitor of the CGRP receptor, reduced CSD-induced pial dilation from 54 +/- 9% baseline to 33 +/- 9% (P < 0.05). Removal of the receptor antagonist from the brain surface restored CSD-induced dilation to 59 +/- 11% (P < 0.05, compared with the response with the antagonist present). In other animals, we showed that this dose of the CGRP antagonist attenuated arteriolar dilation to topically applied 10(-7) M CGRP (n = 5), but it did not alter arteriolar dilation to arterial hypercapnia. We also evaluated the dilator potency of substance P (SP) compared with CGRP. Dilation with 10(-7) M SP was only 22 +/- 11%, whereas arterioles dilated to 57 +/- 7% above baseline diameter with 10(-7) M CGRP. We conclude that CGRP contributes to the transient arteriolar dilation that is characteristic of CSD.

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Arginine-nitric oxide pathway and cerebrovascular regulation in cortical spreading depression

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1995.269.1.h23 ◽

1995 ◽

Vol 269 (1) ◽

pp. H23-H29 ◽

Cited By ~ 11

Author(s):

M. Fabricius ◽

N. Akgoren ◽

M. Lauritzen

Keyword(s):

Nitric Oxide ◽

Cortical Spreading Depression ◽

Vascular Reactivity ◽

Spreading Depression ◽

Clinical Importance ◽

Receptor Activation ◽

Marked Rise ◽

Doppler Flowmetry ◽

Pial Arterioles ◽

Cerebrovascular Regulation

Nerve cells release nitric oxide (NO) in response to activation of glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype. We explored the hypothesis that NO influences the changes of cerebral blood flow (CBF) during cortical spreading depression (CSD), which is known to be associated with NMDA receptor activation. CBF was monitored in parietal cortex by laser-Doppler flowmetry in halothane-anesthetized rats. Under control conditions, CSD induced regular changes of CBF, which consisted of four phases: a brief hypoperfusion before the direct current (DC) shift; a marked CBF rise during the DC shift; followed by a smaller, but protracted increase of CBF; and a prolonged CBF reduction (the oligemia). NO synthase inhibition by intravenous and/or topical application of NG-nitro-L-arginine enhanced the brief initial hypoperfusion, but the CBF increases and the oligemia were unchanged. L-Arginine prevented the development of the prolonged oligemia after CSD but had no influence on the marked rise of CBF during CSD. Animals treated with L-arginine recovered the reduced vascular reactivity to hypercapnia after CSD much faster than control rats. Functional denervation of cortical and pial arterioles by tetrodotoxin accentuated the pre-CSD hypoperfusion and the oligemia but did not affect the CBF increases. The results suggest that NO is important for the changes of cerebrovascular regulation following CSD. The observations may have clinical importance, since CBF changes during migraine may be triggered by CSD.

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Systemic Nitric Oxide Synthase Inhibition Does Not Affect Brain Oxygenation during Cortical Spreading Depression in Rats: A Noninvasive Near-Infrared Spectroscopy and Laser-Doppler Flowmetry Study

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-199611000-00003 ◽

1996 ◽

Vol 16 (6) ◽

pp. 1100-1107 ◽

Cited By ~ 39

Author(s):

Tilo Wolf ◽

Ute Lindauer ◽

Hellmuth Obrig ◽

Jens Dreier ◽

Tobias Back ◽

...

Keyword(s):

Nitric Oxide ◽

Infrared Spectroscopy ◽

Nitric Oxide Synthase ◽

Near Infrared Spectroscopy ◽

Laser Doppler Flowmetry ◽

Cortical Spreading Depression ◽

Near Infrared ◽

Spreading Depression ◽

Doppler Flowmetry ◽

Oxide Synthase

Cortical spreading depression (CSD) has been implicated in the migraine aura and in stroke. This study demonstrates near-infrared spectroscopy (NIRS) for the first time as capable of noninvasive on-line detection of CSD in the pentobarbital-anesthetized rat. CSD was accompanied by a brief and rapid increase of regional CBF (by laser-Doppler flowmetry) to 200–400% baseline. NIRS demonstrates that this hyperperfusion is associated with concentration increases of oxyhemoglobin, while deoxyhemoglobin decreases. Simultaneously, oxygen partial pressure, measured on the brain surface with a solid-state Polarographic probe, was shown to be raised by at least 14 mm Hg during CSD. Oxygen-dependent phosphorescence life-time quenching measurements confirmed this finding. NIRS data on cytochrome aa3, however, showed a CSD-related shift toward a more reduced state, despite raised blood oxygenation. This may suggest either limited O2 transport from the blood to mitochondria or decreased oxygen utilization during CSD as supposed by theories about compartmentalization of energy metabolism favoring glycolytic rather than aerobic energy supply during CSD. However, the data on cytochrome aa3, warrant caution and are discussed critically. Nitric oxide synthase inhibition by systemic application of N′-nitro-l-arginine had no significant effect on the perfusion response or the tissue Po2 during CSD. During most CSD episodes, a brief decrease in MABP by 4–8 mm Hg was noted that might be caused by functional decortication during CSD.

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Prostanoids attenuate pial arteriolar dilation induced by cortical spreading depression in rabbits

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1991.261.4.r828 ◽

1991 ◽

Vol 261 (4) ◽

pp. R828-R834 ◽

Cited By ~ 2

Author(s):

M. Shibata ◽

C. W. Leffler ◽

D. W. Busija

Keyword(s):

Cerebrospinal Fluid ◽

Cortical Spreading Depression ◽

Spreading Depression ◽

Brain Vessels ◽

Cranial Window ◽

Baseline Levels ◽

Fluid Levels ◽

The Brain ◽

Arteriolar Diameter

The role of prostanoids in mediating cerebrovascular responses to cortical spreading depression (CSD) was examined in anesthetized rabbits. CSD was elicited by KCl microinjection, and its propagation was monitored electrophysiologically. Pial arterial diameter was determined using a closed cranial window and intravital microscopy, and regional cerebral blood flow (rCBF) was determined using laser flowmetry. Levels of peri-arachnoid cerebrospinal fluid prostanoids were determined by radioimmunoassay. CSF increased pial arteriolar diameter 62% and rCBF 354% over the baseline levels. Locations of propagating CSD, dilating pial arteriole, and increased rCBF were always closely associated spatiotemporally. Cerebrospinal fluid prostanoid levels increased during single CSD-induced arteriolar dilation, and they were further augmented during multiple CSDs. Indomethacin enhanced both CSD-induced vasodilation (88%) and rCBF increase (580%), but it decreased the cerebrospinal fluid levels of prostanoids below the baseline levels and prevented their increase during CSD-induced vasodilation. These results indicate that prostanoids are synthesized from neurons or glial cells and/or the brain vessels and, as the net result, counteract pial arteriolar dilation and rCBF increase during CSD. In addition, they support the hypothesis that the vasodilation is caused primarily by neurogenic factors associated with CSD.

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Oxygen Radicals Do Not Play a Role in Arteriolar Dilation during Cortical Spreading Depression

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-199601000-00021 ◽

1996 ◽

Vol 16 (1) ◽

pp. 175-179 ◽

Cited By ~ 5

Author(s):

Wei Meng ◽

David W. Busija

Keyword(s):

Superoxide Dismutase ◽

Cortical Spreading Depression ◽

Oxygen Radicals ◽

Spreading Depression ◽

Oxygen Radical ◽

Onset Latency ◽

Radical Scavengers ◽

Cranial Window ◽

Cerebral Arterioles

This study examined the role of oxygen radicals in pial arteriolar changes during cortical spreading depression (CSD). CSD was induced by microinjection of 5% KCl in anesthetized adult rabbits. Pial diameter was measured with a closed cranial window and intravital microscopy. During control CSD (n = 12), the dilation amplitude and area were 55 ± 14% and 693 ± 69 mm2 (baseline = 76 ± 14 μm), respectively. Oxygen radical scavengers, superoxide dismutase (SOD; 105 U/ml, topical application; n = 5) or oxypurinol (50 mg/kg i.v.; n = 7), did not alter the dilation amplitude and area or change onset latency during CSD. Further, SOD and oxypurinol did not prevent NG-nitro-L-arginine from attenuating arteriolar dilation during CSD (n = 12). We conclude that oxygen radicals do not play a role in the transient dilation of cerebral arterioles during CSD.

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