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.

No abstract

Background and Purpose-We studied the risk of recurrent cerebrovascular events in patients who had a transient ischemic attack or ischemic stroke and who had evidence of microbleeds on MRI. Methods-A prospective follow-up study was performed on hospitalized patients who were at least 50 years old with a transient ischemic attack or an ischemic stroke. The presence and number of microbleeds were assessed on gradient echo MRI and the presence of white matter disease on fluid-attenuated inversion recovery imaging using a semiquantitative scale. Patients were followed up by phone every 6 months. End points were intracerebral hemorrhage, ischemic stroke, and unclassified stroke. Cerebral events were adjudicated by 2 independent neurologists blinded to the presence of microbleeds. Cox regression analysis was performed. Results-A total of 487 patients with a mean age of 72 years were followed up for a median of 2.2 years (25th to 75th percentile 1.9 to 2.7 years). Microbleeds were identified in 129 patients (25.6%). Two patients developed intracerebral hemorrhage during follow-up, 32 patients developed recurrent ischemic stroke, and 3 patients had unclassified strokes. Microbleeds were not independent predictors of recurrent stroke (Pϭ0.2) or intracerebral hemorrhage (Pϭ0.43). Lobar microbleeds or combined lobar and deep microbleeds were independently associated with recurrent stroke (Pϭ0.018). Conclusion-In this European cohort, patients with microbleeds who have had cerebral ischemia have a higher risk of developing new ischemic strokes than of intracerebral hemorrhage. Lobar microbleeds or combined lobar and deep microbleeds might be independent predictors of recurrent stroke.

Background and Purpose-Apolipoprotein E (apoE) alleles (2 and 4) are associated with cerebral amyloid angiopathy, in which white matter disease and microbleeds are prominent features. The role of apoE in patients with microbleeds or white matter disease but no evidence of cerebral amyloid angiopathy has not been elucidated. We studied apoE alleles in relation to white matter disease and microbleeds in patients with transient ischemic attack or ischemic stroke. Methods-We obtained brain MRI scans and apoE genotypes in 334 transient ischemic attack or ischemic stroke patients.Microbleeds were scored on a gradient echo MRI and white matter disease was examined on fluid attenuated inversion recovery MRI using a semiquantitative rating scale. Results-Patients with moderate to severe white matter disease more frequently carried apoE 2 alleles (25.2% versus 11.3%, Pϭ0.001), but not apoE 4 (26.6% in apoE 4 carriers versus 25.9%; Pϭ0.98). Adjustment for traditional risk factors did not modify this relationship (odds ratio, 2.9; 95% confidence interval, 1.5 to 5.3). There was no association between the presence of microbleeds and the apoE 4 or apoE 2 alleles. Conclusions-ApoE alleles do not exert a major influence on the development of microbleeds, but apoE 2 may be associated with development of moderate to severe white matter disease in transient ischemic attack and stroke patients.

Summary:The response of the regional cerebral blood flow (rCBF) to brain topical superfusion of 20 mM K + was characterized in a closed cranial window preparation in barbiturate anesthetized and ventilated rats: Increasing K + in the artificial cerebrospinal fluid (ACSF) induced a rCBF elevation (measured by laser-Doppler flowmetry) of + 85 ± 37% above baseline (n = 19), This elevation was stable for > 3 h with continuous superfusion of in creased K + (n = 5) and partially reversible to a level of + 18 ± 19% above baseline when returning to a physio logical K + concentration, Nitric oxide synthase (NOS) inhibition by brain topical superfusion with Nw-nitro-L arginine (L-NA) revealed (a) Addition of L-NA to high potassium ACSF reduced the rCBF increase from + 94 ± 36% to +21 ± 18%(p",, 0,01,n = 7). (b) When L-NA was superfused for 60 min before increasing K +, rCBF de creased to -17 ± 7% below baseline. Subsequent coap plication of L-NA and increased K + induced only an el evation of + 7 ± 4% above baseline (n = 4). (c) When the Potassium has long been discussed as a mediator of the coupling of cerebral metabolism and blood flow (Lubbers and Leniger-Follert, 1978;Iadecola and Kraig, 1991). K + is released by active neurons, transported through astrocytes, and released onto blood vessels (Paulson and Newman, 1987). Pial ar teries respond to moderate elevations (up to 20 mM) of the local K + concentration with vasodilation (Kuschinsky et aI., 1972). Regional cerebral blood flow (rCBF) increases with elevation of extracellu- 914NO donor S-nitroso-N-acetylpenicillamine (SNAP) was added during NOS inhibition to restore basal tissue NO levels, the resultant level of rCBF was + 28 ± 54% above baseline. Subsequent increase of K + in the presence of NOS inhibition and SNAP elevated rCBF to + 137 ± 89% above baseline (n = 4). Statistical analysis comparing K + -induced elevation of rCBF (a) without any added drugs, (b) in the presence of NOS inhibition with L-NA, and (c) in the presence of both NOS inhibition and SNAP revealed,that K + -induced elevation in the presence of NOS inhibition was significantly reduced (p "" 0.05) whereas no statistical difference was found between K + -induced elevation of rCBF without drugs compared with the K + -induced elevation of rCBF in the presence of L-NA and SNAP. We conclude that NO is a modulator of the rCBF elevation to increased extracellular K + concen tration. Key Words: Laser-Doppler flowmetry-Cranial window-Microcirculation-Coupling.lar potassium concentration ([K + ]0) in this range (Iadecola and Kraig, 1991). This vasodilation is probably mediated by the Na + -K + -ATPase and by inward rectifier K + channels of vascular smooth muscle (Edwards et aI., 1988; McCarron and Halp ern, 1990; Toda, 1976;Webb and Bohr, 1978). Apart from potassium, another important candi date in the coupling of cerebral metabolism and blood flow is nitric oxide (NO) (Dirnagl et aI., 1993;Iadecola, 1993; ladecola et aI., 1994a). Rapoport and Murad (1983) have demonstrated a synergistic relaxation of ...