Authors: Kreipke, Christian¹; Schafer, Patrick¹; Rossi, Noreen²; Rafols, Jose³

Source: Neurological Research, Volume 32, Number 2, March 2010 , pp. 209-214(6)

Publisher: Maney Publishing

Abstract:

Objectives: Our laboratory has previously shown that endothelin 1 (ET-1), a powerful vasoconstrictor, and its receptors, A (ETrA) and B (ETrB), are up-regulated following trauma. This up-regulation coincides temporally with enhanced vasoreactivity in cerebral cortical microvessels, which leads to a state of chronic hypoperfusion for up to 48 hours following traumatic brain injury (TBI). However, the direct contribution of either receptor up-regulation to decreased cerebral blood flow (CBF) after closed head trauma has not been determined. Furthermore, how ET-1 blockade may affect histological outcome following TBI has not been explored. Therefore, the effects of ETrA and B antagonism on TBI induced hypoperfusion of CBF and cell injury in sensorimotor cortex (smCx) and hippocampus (Hipp) were assessed by arterial spin labeling magnetic resonance imaging and Fluoro-Jade staining, respectively.

Methods: Adult male rats were given intracerebroventricular injections of ETrA (BQ123) or ETrB antagonist (BQ788) before being subjected to TBI using a closed head acceleration impact model. Following TBI, CBF was measured and histological examination of cell integrity was carried out.

Results: ETrA blockade ameliorated TBI induced hypoperfusion in smCx and Hipp at 4 and 24 hours after TBI and caused a mild hyperemia in both centers by 48 hours after injury. Furthermore, ETrA antagonism reduced the extent of Fluoro-Jade labeled cells within smCx and Hipp as compared with TBI only. ETrB blockade had little effect on TBI induced hypoperfusion and did not change the extent of cell injury following TBI.

Discussion: These results suggest that decreased CBF following TBI may be caused by ETrA, but not ETrB, up-regulation. Furthermore, these results suggest that TBI induced hypoperfusion may contribute to poor neurologic outcome following TBI. In this work, we provide a rationale for studying the clinical relevancy of use of ETrA antagonists following TBI.

Keywords: VASCULAR REGULATION; BRAIN TRAUMA; ENDOTHELIN

Document Type: Research Article

DOI: http://dx.doi.org/10.1179/174313209X414515

Affiliations: 1: Department of Anatomy and Cell Biology, School of Medicine, Wayne State University, Detroit, MI, USA 2: Department of Internal Medicine, School of Medicine, Wayne State University, Detroit, MI, USA 3: Department of Anatomy and Cell Biology, School of Medicine, Wayne State University, Room 9312 Scott Hall, 540 East Canfield, Detroit, MI 48201, USA;, Email: jrafols@med.wayne.edu

Publication date: 2010-03-01

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