ln recent years, we and others have determined that at least one endothelial process, in addition to NO and cyclooxygenase metabolites, dilates cerebral vessels. This new process, termed """"""""endothelium-derived hyperpolarizing factor"""""""" or EDHF, is likely an important dilator mechanism in the cerebral circulation during normal physiological states and following pathological conditions. In the proposed studies, we will address the mechanism of EDHF in cerebral arteries. The major hypothesis to be tested is that tandem-pore domain potassium channels are involved with the EDHF-mediated dilations in cerebral vessels of the rat. In order for the above hypothesis to be valid then all of the following specific aims must be true. (Specific Aim 1) Tandem-pore domain potassium channels must be present in cerebral arteries; (Specific Aim 2) activation of tandem-pore domain potassium channels must elicit dilation in cerebral arteries, and (Specific Aim 3) inhibition of tandem-pore domain potassium channels must inhibit EDHF-mediated dilations.
In Specific Aim 1, we plan to use a combination of RT-PCR, Western analysis, immunohistochemistry, and electrophysiology to demonstrate the presence of the tandem pore domain potassium channels in cerebral arteries and, further, demonstrate that they are functional.
In specific Aim 2, we will use isolated perfused cerebral arteries to determine if activation of these channels produces dilation. Furthermore, we plan to determine if inhibition of channel expression (anti-sense) and inhibition by pharmacological blockers antagonizes dilations produced by these potassium channels.
In Specific Aim 3, we propose to determine if inhibition of tandem pore domain potassium channels inhibit EDHF-mediated dilations. Completion of the proposed studies will provide important insight into EDHF and its mechanism of circulatory control in brain. Furthermore, we anticipate that new information regarding tandem pore domain potassium channels will be a big step in the understanding of cerebral circulatory control. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS046666-02
Application #
6986072
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Jacobs, Tom P
Project Start
2004-12-01
Project End
2009-11-30
Budget Start
2005-12-01
Budget End
2006-11-30
Support Year
2
Fiscal Year
2006
Total Cost
$338,724
Indirect Cost
Name
Baylor College of Medicine
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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Schwingshackl, Andreas; Teng, Bin; Makena, Patrudu et al. (2014) Deficiency of the two-pore-domain potassium channel TREK-1 promotes hyperoxia-induced lung injury. Crit Care Med 42:e692-701
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Parelkar, Nikhil K; Silswal, Neerupma; Jansen, Kirsten et al. (2010) 2,2,2-trichloroethanol activates a nonclassical potassium channel in cerebrovascular smooth muscle and dilates the middle cerebral artery. J Pharmacol Exp Ther 332:803-10
Lloyd, Eric E; Marrelli, Sean P; Bryan Jr, Robert M (2009) cGMP does not activate two-pore domain K+ channels in cerebrovascular smooth muscle. Am J Physiol Heart Circ Physiol 296:H1774-80
Lloyd, Eric E; Marrelli, Sean P; Namiranian, Khodadad et al. (2009) Characterization of TWIK-2, a two-pore domain K+ channel, cloned from the rat middle cerebral artery. Exp Biol Med (Maywood) 234:1493-502

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