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(Hypertension. 2009;54:150.)
© 2009 American Heart Association, Inc.

Original Articles

Tumor Necrosis Factor- Mediates Hemolysis-Induced Vasoconstriction and the Cerebral Vasospasm Evoked by Subarachnoid Hemorrhage

Carmine Vecchione; Alessandro Frati; Alba Di Pardo; Giuseppe Cifelli; Daniela Carnevale; Maria Teresa Gentile; Rosa Carangi; Alessandro Landolfi; Pierluigi Carullo; Umberto Bettarini; Giovanna Antenucci; Giada Mascio; Carla Letizia Busceti; Antonella Notte; Angelo Maffei; Gian Paolo Cantore; Giuseppe Lembo

From the Departments of Angiocardioneurology (C.V., A.D.P., G.C., M.T.G., R.C., A.L., P.C., U.B., G.A., G.M., C.L.B., A.N., A.M., G.L.) and Neurosurgery (A.F., G.P.C.), IRCCS Neuromed, Pozzilli (IS), Italy; Department of Cell Biology and Neurosciences (D.C.), Istituto Superiore di Sanità, Rome, Italy; and Department of Experimental Medicine (G.L.), Sapienza University, Rome, Italy.

Correspondence to Giuseppe Lembo, Sapienza University of Rome and Department of Angiocardioneurology, Neuromed Institute IRCCS, Loc Camerelle, 86077 Pozzilli (IS), Italy. E-mail lembo{at}neuromed.it

Hypertension can lead to subarachnoid hemorrhage and eventually to cerebral vasospasm. It has been suggested that the latter could be the result of oxidative stress and an inflammatory response evoked by subarachnoid hemorrhage. Because an unavoidable consequence of hemorrhage is lysis of red blood cells, we first tested the hypothesis on carotid arteries that the proinflammatory cytokine tumor necrosis factor- contributes to vascular oxidative stress evoked by hemolysis. We observed that hemolysis induces a significant increase in tumor necrosis factor- both in blood and in vascular tissues, where it provokes Rac-1/NADPH oxidase–mediated oxidative stress and vasoconstriction. Furthermore, we extended our observations to cerebral vessels, demonstrating that tumor necrosis factor- triggered this mechanism on the basilar artery. Finally, in an in vivo model of subarachnoid hemorrhage obtained by the administration of hemolyzed blood in the cisterna magna, we demonstrated, by high-resolution ultrasound analysis, that tumor necrosis factor- inhibition prevented and resolved acute cerebral vasoconstriction. Moreover, tumor necrosis factor- inhibition rescued the hemolysis-induced brain injury, evaluated with the method of 2,3,5-triphenyltetrazolium chloride and by the histological analysis of pyknotic nuclei. In conclusion, our results demonstrate that tumor necrosis factor- plays a crucial role in the onset of hemolysis-induced vascular injury and can be used as a novel target of the therapeutic strategy against cerebral vasospasm.

Key Words: cytokines • cerebrovascular disease • oxidant stress • inflammation • subarachnoid hemorrhage