EDHF Following Traumatic Brain Injury

Baylor College Of Medicine, Houston TX

Investigators

Linked publications & trials

Abstract

The endothelium regulates the contractile state of cerebral arteries and arterioles through the release of[unreadable] relaxing factors. In recent years, an endothelial-dependent dilator process, other than nitric oxide (NO) or[unreadable] prostacyclin, has been discovered. This new process, termed "endothelium-derived hyperpolarizing factor" or[unreadable] EDHF, is upregulated to compensate for diminished endothelial-derived NO following traumatic brain injury.[unreadable] Thus, EDHF could be an important mechanism to maintain cerebral perfusion when the NO dilator[unreadable] mechanism is compromised. This proposal addresses the mechanism of the EDHF-mediated dilations in[unreadable] cerebral arteries following traumatic brain injury to the rat. In Specific Aim 1, studies are proposed to[unreadable] determine if the mechanism of EDHF-mediated dilations following traumatic brain injury involves the[unreadable] metabolism of arachidonic acid through the P450 epoxygenase pathway. In Specific Aim 2, studies are[unreadable] proposed to determine if the mechanism of EDHF-mediated dilations following traumatic brain injury involves[unreadable] an increased production of hydrogen peroxide (H2O2). In Specific Aim 3 studies are proposed to measure[unreadable] Ca2+ and membrane potential in endothelium and vascular smooth muscle during EDHF dilations following[unreadable] traumatic brain injury. Diameter changes of pressurized branches of middle cerebral arteries (bMCAs),[unreadable] isolated from injured (controlled cortical impact injury) and non-injured cortex, will be compared following[unreadable] agonist induced EDHF dilations. A combination of pharmacological interventions, optical methods for[unreadable] selectively measuring [Ca2+] and membrane potential of vascular smooth muscle and endothelium,[unreadable] electrophysiological techniques, and analytic methods to measure P450 epoxygenase metabolites and H2O2[unreadable] are proposed to address the aims. In Specific Aim 4 EDHF dilations will be studied in vivo during normal[unreadable] conditions and following traumatic brain injury. We propose to study the EDHF response using laser Doppler[unreadable] flowmetry and measurement of pial arteriole diameter. We speculate that EDHF upregulation is an important[unreadable] intrinsic mechanism to maintain cerebral perfusion. Understanding the mechanism of EDHF-mediated[unreadable] dilations following traumatic brain injury will allow better insight into the regulation of cerebral blood flow[unreadable] following brain injury. Further, it will allow us to test the hypothesis that the EDHF upregulation is protective[unreadable] and could lead to new therapeutic strategies for treatment of traumatic brain injury.