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.

Clinical Relevance of Cortical Spreading Depression in Neurological Disorders: Migraine, Malignant Stroke, Subarachnoid and Intracranial Hemorrhage, and Traumatic Brain Injury

“…These studies were restricted to the initial hours after the hemorrhage. The phenomenon of spreading ischemia was discovered in a rat model replicating the delayed conditions after subarachnoid hemolysis after SAH (Dreier et al, 1998). Spreading ischemia results from local microvascular dysfunction, which causes an inverse hemodynamic response to the cortical depolarization.…”

“…Severe spreading ischemia was sufficient to induce widespread cortical necrosis in rats (Dreier et al, 2000). Based on the experimental evidence, it was speculated that spreading ischemia is a phenomenon involved in DCI (Dreier et al, 1998).…”

“…The classic pattern of a brief, large hyperperfusion followed by a protracted hypoperfusion is changed in disease states. In subarachnoid hemorrhage (SAH), CSD may trigger a state of cortical spreading ischemia (Dreier et al, 1998(Dreier et al, , 2000, and the changes in cerebrovascular signature triggered by CSD differ greatly in the penumbra depending on the distance to the infarct core (Strong et al, 2007) as described in detail in the following sections. In normal rats, L-arginine pretreatment prevents the development of low CBF after CSD, and increases the rate of recovery of the cerebrovascular responsiveness after CSD (Gault et al, 1994;Fabricius et al, 1995).…”

“…The basis for this relationship may lie in the imbalance between metabolic workload and delivery of oxygen and glucose: metabolic workload is abnormally high because of restoration of cell membrane ion gradients after depolarization events, leading to depletion of the tissue glucose pool (Nedergaard and Astrup, 1986;Hopwood et al, 2005;Hashemi et al, 2009;Feuerstein et al, 2010) and insufficient oxygen delivery to the tissue . On the other hand, oxygen and glucose supply is reduced due to microvascular constriction in response to the depolarization (Dreier et al, 1998;Strong et al, 2007;Luckl et al, 2009). Early formation of vasogenic edema within the first 3 hours is another factor contributing to progressively disturbed tissue perfusion in the penumbra due to mechanical compression of adjacent microvessels and veins in hemispheric experimental stroke in rats (Walberer et al, 2008;Gerriets et al, 2009).…”

“…Spreading ischemia results from local microvascular dysfunction, which causes an inverse hemodynamic response to the cortical depolarization. With the inverse response, severe microvascular spasm instead of vasodilatation is coupled to the depolarization (Dreier et al, 1998;Petzold et al, 2005;Shin et al, 2006). Consequently, spreading ischemia delays the cortical repolarization.…”