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

Jens P. Dreier; Katrin Körner; Nathalie Ebert; Astrid Görner; Inger Rubin; Tobias Back; Ute Lindauer; Tilo Wolf; Arno Villringer; Karl Max Einhäupl; Martin Lauritzen; Ulrich Dirnagl

doi:10.1097/00004647-199809000-00007

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

Jens P. Dreier^*, Katrin Körner, Nathalie Ebert, Astrid Görner, Inger Rubin, Tobias Back, Ute Lindauer, Tilo Wolf, Arno Villringer, Karl Max Einhäupl, Martin Lauritzen, Ulrich Dirnagl

^*Corresponding author for this work

Neuronal Signalling

202 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Journal of Cerebral Blood Flow and Metabolism
Volume	18
Issue number	9
Pages (from-to)	978-990
Number of pages	13
ISSN	0271-678X
DOIs	https://doi.org/10.1097/00004647-199809000-00007
Publication status	Published - 1 Jan 1998

Keywords

Cerebral blood flow
Delayed ischemic deficits
Ischemia
Migraine
Migrainous stroke
Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS)
Nitric oxide
Potassium
Spreading depression
Subarachnoid hemorrhage
Vasospasm

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10.1097/00004647-199809000-00007

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Dreier, J. P., Körner, K., Ebert, N., Görner, A., Rubin, I., Back, T., Lindauer, U., Wolf, T., Villringer, A., Einhäupl, K. M., Lauritzen, M., & Dirnagl, U. (1998). 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 and Metabolism, 18(9), 978-990. https://doi.org/10.1097/00004647-199809000-00007

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. / Dreier, Jens P.; Körner, Katrin; Ebert, Nathalie et al.

In: Journal of Cerebral Blood Flow and Metabolism, Vol. 18, No. 9, 01.01.1998, p. 978-990.

Research output: Contribution to journal › Journal article › Research › peer-review

Dreier, JP, Körner, K, Ebert, N, Görner, A, Rubin, I, Back, T, Lindauer, U, Wolf, T, Villringer, A, Einhäupl, KM, Lauritzen, M & Dirnagl, U 1998, '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 and Metabolism, vol. 18, no. 9, pp. 978-990. https://doi.org/10.1097/00004647-199809000-00007

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title = "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",

abstract = "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.",

keywords = "Cerebral blood flow, Delayed ischemic deficits, Ischemia, Migraine, Migrainous stroke, Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), Nitric oxide, Potassium, Spreading depression, Subarachnoid hemorrhage, Vasospasm",

author = "Dreier, {Jens P.} and Katrin K{\"o}rner and Nathalie Ebert and Astrid G{\"o}rner and Inger Rubin and Tobias Back and Ute Lindauer and Tilo Wolf and Arno Villringer and Einh{\"a}upl, {Karl Max} and Martin Lauritzen and Ulrich Dirnagl",

year = "1998",

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day = "1",

doi = "10.1097/00004647-199809000-00007",

language = "English",

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pages = "978--990",

journal = "Journal of Cerebral Blood Flow and Metabolism",

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TY - JOUR

T1 - 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

AU - Dreier, Jens P.

AU - Körner, Katrin

AU - Ebert, Nathalie

AU - Görner, Astrid

AU - Rubin, Inger

AU - Back, Tobias

AU - Lindauer, Ute

AU - Wolf, Tilo

AU - Villringer, Arno

AU - Einhäupl, Karl Max

AU - Lauritzen, Martin

AU - Dirnagl, Ulrich

PY - 1998/1/1

Y1 - 1998/1/1

N2 - 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.

AB - 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.

KW - Cerebral blood flow

KW - Delayed ischemic deficits

KW - Ischemia

KW - Migraine

KW - Migrainous stroke

KW - Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS)

KW - Nitric oxide

KW - Potassium

KW - Spreading depression

KW - Subarachnoid hemorrhage

KW - Vasospasm

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U2 - 10.1097/00004647-199809000-00007

DO - 10.1097/00004647-199809000-00007

M3 - Journal article

C2 - 9740101

AN - SCOPUS:0031723199

SN - 0271-678X

VL - 18

SP - 978

EP - 990

JO - Journal of Cerebral Blood Flow and Metabolism

JF - Journal of Cerebral Blood Flow and Metabolism

IS - 9

ER -

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

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