A novel endothelium-dependent dilator mechanism was identified in cerebral arteries and arterioles. This dilator mechanism has been called endothelium-derived hyperpolarizing factor (EDHF) or endothelium- dependent hyperpolarization (EDH).This mechanism, which does not involve nitric oxide (NO) or cyclooxygenase metabolites (i.e., prostacyclin), requires the activation of intermediate and/or small conductance calcium-activated K+ channels (IKCa and SKCa respectively) in cerebral vessels. Studies utilizing isolated cerebral arteries and arterioles provide circumstantial evidence that this dilator mechanism, involving IKCa and SKCa, may be as important as endothelium-derived NO in regulating cerebral blood flow (CBF). This idea is based on the key role of IKCa/SKCa in setting the resting diameter of cerebral arteries and arterioles, their contribution to endothelium-mediated dilations, and their relative importance compared to NO in penetrating arterioles, a site of major vascular resistance in the brain. In addition, dilations through IKCa/SKCa are enhanced following ischemia/reperfusion, traumatic brain injury, and other pathological states when NO bioavailability is diminished. Upregulation of IKCa/SKCa-mediated dilations may be an important protective strategy serving to compensate for decreased NO and ultimately limit reductions in CBF during pathological states. Although provocative, it is important to emphasize that studies to date involving IKCa/SKCa-mediated dilations have primarily used isolated cerebral vessels, which were removed from the brain and examined ex vivo in a vessel chamber. In order to fully understand the importance of IKCa and SKCa in controlling CBF, it is imperative that these studies are extended to the in vivo situation where arteries and arterioles function as a coordinated network in the cardiovascular system. Therefore, we propose to test the hypothesis that IKCa and/or SKCa channels regulate CBF in vivo. We propose to demonstrate that activation of IKCa and SKCa increase cerebral blood flow (Specific Aim 1). We will determine the contribution of IKCa and SKCa to resting CBF (Specific Aim 2). Finally, we will determine the contribution of IKCa and SKCa to increases in CBF elicited by ATP, an agonist released by red blood cells into the plasma (Specific Aim 3). Increases in CBF will be measured from the cortical surface using laser Doppler flowmetry following direct stimulation of IKCa and SKCa channels or indirectly through ATP, an agonist for endothelial P2Y2 receptors. For the specific aims, we will utilize selective pharmacological inhibitors to determine the relative contribution of IKCa and SKCa in controlling CBF. The need to conduct the proposed studies in vivo is amplified by the circumstantial evidence indicating an important role for IKCa/SKCa in regulating CBF. IKCa/SKCa channels could be of clinical relevance and a therapeutic target during pathological conditions where the bioavailability of NO is compromised. Furthermore, IKCa/SKCa channels could find their way into clinical practice in a manner similar to that of NO.

Public Health Relevance

The control of cerebral blood flow is an important clinical consideration for a number of pathological states such as stroke and traumatic brain injury. Intermediate and small conductance potassium channels, which allow only K+ to pass across the cell membrane, appear to be an important mechanism for endothelial control of cerebral blood flow. The proposed studies will determine the role of these intermediate and small conductance potassium channels in the regulation of cerebral blood flow.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS078773-02
Application #
8468226
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Koenig, James I
Project Start
2012-07-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$188,778
Indirect Cost
$68,153
Name
Baylor College of Medicine
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Crossland, Randy F; Durgan, David J; Lloyd, Eric E et al. (2013) A new rodent model for obstructive sleep apnea: effects on ATP-mediated dilations in cerebral arteries. Am J Physiol Regul Integr Comp Physiol 305:R334-42
Durgan, David J; Bryan, Robert M (2013) The same but different. J Cereb Blood Flow Metab 33:1485