Ischemia triggered by spreading neuronal activation is induced by endothelin-1 and hemoglobin in the subarachnoid space.
Delayed cerebral vasospasm has a major impact on the outcome of subarachnoid hemorrhage. Two important candidates to cause the arterial spasm are the red blood cell product oxyhemoglobin and the vasoconstrictor endothelin-1, although oxyhemoglobin alone is not sufficient to induce cerebral ischemia and endothelin-1 leads to ischemia only at relatively high concentrations. In this study, we demonstrated that the combination of oxyhemoglobin and endothelin-1 triggered spreading neuronal activation in rat cortex in vivo. In contrast with the expected transient increase of regional cerebral blood flow during spreading depression, however, cerebral blood flow decreased profoundly and was long-lasting, paralleled by delayed repolarization of the steady (direct current) potential. These changes are characteristic of cortical spreading ischemia. Replacing oxyhemoglobin for the nitric oxide synthase inhibitor Nomega-nitro-L-arginine mimicked these effects, implicating nitric oxide scavenging functions of oxyhemoglobin. Furthermore, the effect of endothelin-1 was related to a reduction of Na(+)-/K(+)-ATPase activity rather than solely to its vasoconstrictive properties. In conclusion, the threshold concentration of endothelin-1 that induces cerebral ischemia is profoundly reduced via a complex interaction between the neuronal/astroglial network and the cortical microcirculation if nitric oxide availability declines. The results may have implications for the understanding of subarachnoid hemorrhage-related cortical lesions.
Departments of Experimental Neurology, Charité Hospital, Humboldt University, Schumannstrasse 20/21, 10098 Berlin, Germany. gabor.petzold@charite.de
Gabor C
GC
Petzold
Karl M
KM
Einhäupl
Ulrich
U
Dirnagl
Jens P
JP
Dreier
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology*; D002540:Cerebral Cortex / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D013181:Cortical Spreading Depression / Q000187:drug effects*; D019332:Endothelin-1 / Q000008:administration & dosage / Q000494:pharmacology*; D016166:Free Radical Scavengers / Q000494:pharmacology; D006454:Hemoglobins / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D000254:Sodium-Potassium-Exchanging ATPase / Q000187:drug effects / Q000378:metabolism; D013346:Subarachnoid Space
D019332:Endothelin-1; D016166:Free Radical Scavengers; D006454:Hemoglobins; D000254:Sodium-Potassium-Exchanging ATPase