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

Summary: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 mmollL) and increased K+ concentration in the artificial cerebrospinal fluid ([K+1A csF) at 35 mmollL 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 min utes and were associated with a negative subarachnoid DC shift of -7.3 ± 0.6 mV of 49 ± 12 minutes' duration. The combina tion of the NOS inhibitor N-nitro-L-arginine (L-NA, I mmollL) with [K+1A csF at 35 mmollL caused similar spontaneous tran sient ischemic events in 13 rats. When cortical spreading de pression was induced by KCI at a 5-mm distance, a typical cortical spreading hyperemia (CSH) and negative DC shift were measured at the closed cranial window during brain topi cal superfusion with either physiologic artificial CSF (n = 5), 20 mmollL propagated at a speed of 3. 4 ± 0.6 mmlmin, indi cating cortical spreading ischemia (CSI). Although CSH did not change oxygen free radical production, as measured on-line by in vivo lucigenin-enhanced chemiluminescence, CSI re sulted in the typical radical production pattern of ischemia and reperfusion suggestive of brain damage (n = 4). Nimodipine (2 j-Lg/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 subarach noid hemorrhage, a clinical condition in which the release of Hb and K+ from erythrocytes creates a microenvironment simi lar to the one investigated here. Key Words: Cerebral blood flow-Nitric oxide-Potassium-Spreading depression Vasospasm-Migraine-Migrainous stroke-Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like epi sodes (MELAS)-Ischemia-Delayed ischemic deficits Subarachnoid hemorrhage.

Nimodipine accelerates the restoration of functional hyperemia during spreading oligemia

“…Of note, the early hypoperfusion component of the CBF response to SD is quite prominent in the mouse cortex as compared to the rat and other species, possibly because of a higher sensitivity of mouse cerebral vessels to vasoconstrictive potassium concentrations (Ayata et al, 2004; Ayata & Lauritzen, 2015). The attenuation of the hypoperfusion seen here is consistent with previous observations made in experimental rat models of subarachnoid hemorrhage that nimodipine antagonized the early and dominating vasoconstrictive element of the CBF response to arising SD (Dreier et al, 1998; Dreier et al, 2002). Furthermore, nimodipine reduced the SD‐related early hypoperfusion potentiated with high extracellular K + concentration in the optimally perfused rat cortex (Menyhárt et al, 2018).…”

Nimodipine accelerates the restoration of functional hyperemia during spreading oligemia

“…Of note, the early hypoperfusion component of the CBF response to SD is quite prominent in the mouse cortex as compared to the rat and other species, possibly because of a higher sensitivity of mouse cerebral vessels to vasoconstrictive potassium concentrations (Ayata et al, 2004; Ayata & Lauritzen, 2015). The attenuation of the hypoperfusion seen here is consistent with previous observations made in experimental rat models of subarachnoid hemorrhage that nimodipine antagonized the early and dominating vasoconstrictive element of the CBF response to arising SD (Dreier et al, 1998; Dreier et al, 2002). Furthermore, nimodipine reduced the SD‐related early hypoperfusion potentiated with high extracellular K + concentration in the optimally perfused rat cortex (Menyhárt et al, 2018).…”

Ischaemia triggered by spreading neuronal activation is inhibited by vasodilators in rats

“…The CBF response to CSD was not normal but was characterised by a sharp and short initial hypoperfusion. This was similar to that reported from NOS inhibition with physiological [K + ] ACSF (Duckrow, 1993; Fabricius et al 1995; Dreier et al 1998). The data indicate that the rise of baseline [K + ] ACSF directly altered the vascular reactivity to CSD.…”

“…5). This was similar to that known from NOS inhibition with normal [K + ] ACSF (Duckrow, 1993; Fabricius et al 1995; Dreier et al 1998) but started from a higher level of CBF. On average, CBF decreased from 140 ± 59 % to 110 ± 41 %.…”

Spreading depolarization and angiographic spasm are separate mediators of delayed infarcts

“… 4 , 16 , 22 In 2018, using neuromonitoring in combination with longitudinal neuroimaging, the entire sequence of infarct development after aSAH with SD-induced persistent activity depression, SD-induced spreading ischaemia and transition from clustered SDs to NUP was demonstrated in a small patient population where the recording devices were located directly in the area of newly developing infarcts. 16 The concept that local factors at the cortex surface suffice to initiate the mechanism of spreading ischaemia 21 is also consistent with observations in DISCHARGE-1 that 14.5% of patients with delayed infarcts had no angiographic vasospasm and 50% had only relatively mild angiographic vasospasm. 4 The often extreme hyperaemia typically observed in aSAH patients immediately following severe spreading ischaemia also argues against sustained upstream restriction of rCBF as the principal cause of spreading ischaemia, as sustained upstream restriction of rCBF would not allow hyperaemia of such high amplitude to occur (compare figure 7 in Dreier et al .…”

Nimodipine accelerates the restoration of functional hyperemia during spreading oligemia

“…Of note, the early hypoperfusion component of the CBF response to SD is quite prominent in the mouse cortex as compared to the rat and other species, possibly because of a higher sensitivity of mouse cerebral vessels to vasoconstrictive potassium concentrations (Ayata et al, 2004; Ayata & Lauritzen, 2015). The attenuation of the hypoperfusion seen here is consistent with previous observations made in experimental rat models of subarachnoid hemorrhage that nimodipine antagonized the early and dominating vasoconstrictive element of the CBF response to arising SD (Dreier et al, 1998; Dreier et al, 2002). Furthermore, nimodipine reduced the SD‐related early hypoperfusion potentiated with high extracellular K + concentration in the optimally perfused rat cortex (Menyhárt et al, 2018).…”

Ischaemia triggered by spreading neuronal activation is inhibited by vasodilators in rats

“…The CBF response to CSD was not normal but was characterised by a sharp and short initial hypoperfusion. This was similar to that reported from NOS inhibition with physiological [K + ] ACSF (Duckrow, 1993; Fabricius et al 1995; Dreier et al 1998). The data indicate that the rise of baseline [K + ] ACSF directly altered the vascular reactivity to CSD.…”

“…5). This was similar to that known from NOS inhibition with normal [K + ] ACSF (Duckrow, 1993; Fabricius et al 1995; Dreier et al 1998) but started from a higher level of CBF. On average, CBF decreased from 140 ± 59 % to 110 ± 41 %.…”

Spreading depolarization and angiographic spasm are separate mediators of delayed infarcts

“… 4 , 16 , 22 In 2018, using neuromonitoring in combination with longitudinal neuroimaging, the entire sequence of infarct development after aSAH with SD-induced persistent activity depression, SD-induced spreading ischaemia and transition from clustered SDs to NUP was demonstrated in a small patient population where the recording devices were located directly in the area of newly developing infarcts. 16 The concept that local factors at the cortex surface suffice to initiate the mechanism of spreading ischaemia 21 is also consistent with observations in DISCHARGE-1 that 14.5% of patients with delayed infarcts had no angiographic vasospasm and 50% had only relatively mild angiographic vasospasm. 4 The often extreme hyperaemia typically observed in aSAH patients immediately following severe spreading ischaemia also argues against sustained upstream restriction of rCBF as the principal cause of spreading ischaemia, as sustained upstream restriction of rCBF would not allow hyperaemia of such high amplitude to occur (compare figure 7 in Dreier et al .…”

Nimodipine accelerates the restoration of functional hyperemia during spreading oligemia

“…Of note, the early hypoperfusion component of the CBF response to SD is quite prominent in the mouse cortex as compared to the rat and other species, possibly because of a higher sensitivity of mouse cerebral vessels to vasoconstrictive potassium concentrations (Ayata et al, 2004; Ayata & Lauritzen, 2015). The attenuation of the hypoperfusion seen here is consistent with previous observations made in experimental rat models of subarachnoid hemorrhage that nimodipine antagonized the early and dominating vasoconstrictive element of the CBF response to arising SD (Dreier et al, 1998; Dreier et al, 2002). Furthermore, nimodipine reduced the SD‐related early hypoperfusion potentiated with high extracellular K + concentration in the optimally perfused rat cortex (Menyhárt et al, 2018).…”

Ischaemia triggered by spreading neuronal activation is inhibited by vasodilators in rats

“…The CBF response to CSD was not normal but was characterised by a sharp and short initial hypoperfusion. This was similar to that reported from NOS inhibition with physiological [K + ] ACSF (Duckrow, 1993; Fabricius et al 1995; Dreier et al 1998). The data indicate that the rise of baseline [K + ] ACSF directly altered the vascular reactivity to CSD.…”

“…5). This was similar to that known from NOS inhibition with normal [K + ] ACSF (Duckrow, 1993; Fabricius et al 1995; Dreier et al 1998) but started from a higher level of CBF. On average, CBF decreased from 140 ± 59 % to 110 ± 41 %.…”

Spreading depolarization and angiographic spasm are separate mediators of delayed infarcts

“… 4 , 16 , 22 In 2018, using neuromonitoring in combination with longitudinal neuroimaging, the entire sequence of infarct development after aSAH with SD-induced persistent activity depression, SD-induced spreading ischaemia and transition from clustered SDs to NUP was demonstrated in a small patient population where the recording devices were located directly in the area of newly developing infarcts. 16 The concept that local factors at the cortex surface suffice to initiate the mechanism of spreading ischaemia 21 is also consistent with observations in DISCHARGE-1 that 14.5% of patients with delayed infarcts had no angiographic vasospasm and 50% had only relatively mild angiographic vasospasm. 4 The often extreme hyperaemia typically observed in aSAH patients immediately following severe spreading ischaemia also argues against sustained upstream restriction of rCBF as the principal cause of spreading ischaemia, as sustained upstream restriction of rCBF would not allow hyperaemia of such high amplitude to occur (compare figure 7 in Dreier et al .…”