Potassium (K) channel activation in vascular smooth muscle (VSM) promotes dilation of arteries to physiological stimuli. Our new finding is that insulin resistance (IR) impairs dilator responses of cerebral arteries to stimuli, which are dependent on opening of K channels in VSM. The underlying basis of K channel dysfunction in IR may involve increased production of reactive oxygen species (ROS). This vascular impairment may account for the increased incidence of and/or impaired recovery from cerebrovascular accidents such as subarachnoid hemorrhage (SAH). However, these issues have not been adequately investigated. We have created 2 specific aims to examine these issues in the in situ basilar artery of the Zucker Obese rat model of IR:
Specific Aim 1. Elucidation of mechanisms of deranged K function in VSM of the cerebral circulation. We will test the hypotheses that IR impairs K channel function of cerebral arteries in a subtype-specific fashion and that vascular production and actions of ROS mediate K channel dysfunction. First, we will examine effects of selective K channel agonists and antagonists on the basilar artery and its branches in vivo. Second, we will determine whether IR changes vascular levels of K channel subunits. Third, we will assess the role of ROS in K channel dysfunction in IR using pharmacological and gene transfer approaches. Fourth, we will determine the metabolic source of ROS. Fifth, we will determine whether impaired K channel-mediated dilation leads to enhance constrictor effects. And sixth, we will use electrophysiological approaches to characterize the relationship between VSM membrane potential and diameter in cerebral arteries from IR rats.
Specific Aim 2. Examination of effects of IR on cerebral arterial function following experimental SAH. We will test the hypothesis that underlying IR will potentiate adverse effects of SAH on baseline artery diameter and reverse augmented vascular responses to K channel-dependent dilator agents. First, we will examine the effects of SAH on baseline diameter and vascular responsiveness in IR. Second, we will explore the role of K channels in impairment of arterial function following SAH in IR. Third, we will determine whether gene transfer protects vascular responses against SAH in IR animals. And fourth, we will examine the relationship between membrane potential and diameter in cerebral VSM in IR and SAH.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL077731-02
Application #
6905649
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Goldman, Stephen
Project Start
2004-09-01
Project End
2009-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
2
Fiscal Year
2005
Total Cost
$358,750
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Physiology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Sure, Venkata N; Sakamuri, Siva S V P; Sperling, Jared A et al. (2018) A novel high-throughput assay for respiration in isolated brain microvessels reveals impaired mitochondrial function in the aged mice. Geroscience 40:365-375
Merdzo, Ivan; Rutkai, Ibolya; Sure, Venkata N L R et al. (2017) Impaired Mitochondrial Respiration in Large Cerebral Arteries of Rats with Type 2 Diabetes. J Vasc Res 54:1-12
Merdzo, Ivan; Rutkai, Ibolya; Tokes, Tunde et al. (2016) The mitochondrial function of the cerebral vasculature in insulin-resistant Zucker obese rats. Am J Physiol Heart Circ Physiol 310:H830-8
Rutkai, Ibolya; Dutta, Somhrita; Katakam, Prasad V et al. (2015) Dynamics of enhanced mitochondrial respiration in female compared with male rat cerebral arteries. Am J Physiol Heart Circ Physiol 309:H1490-500
Dutta, Somhrita; Rutkai, Ibolya; Katakam, Prasad V G et al. (2015) The mechanistic target of rapamycin (mTOR) pathway and S6 Kinase mediate diazoxide preconditioning in primary rat cortical neurons. J Neurochem 134:845-56
Rutkai, Ibolya; Katakam, Prasad V G; Dutta, Somhrita et al. (2014) Sustained mitochondrial functioning in cerebral arteries after transient ischemic stress in the rat: a potential target for therapies. Am J Physiol Heart Circ Physiol 307:H958-66
Katakam, Prasad V G; Gordon, Angellica O; Sure, Venkata N L R et al. (2014) Diversity of mitochondria-dependent dilator mechanisms in vascular smooth muscle of cerebral arteries from normal and insulin-resistant rats. Am J Physiol Heart Circ Physiol 307:H493-503
Busija, David W; Katakam, Prasad V (2014) Mitochondrial mechanisms in cerebral vascular control: shared signaling pathways with preconditioning. J Vasc Res 51:175-89
Carvalho, Cristina; Katz, Paige S; Dutta, Somhrita et al. (2014) Increased susceptibility to amyloid-? toxicity in rat brain microvascular endothelial cells under hyperglycemic conditions. J Alzheimers Dis 38:75-83
Katakam, Prasad V G; Wappler, Edina A; Katz, Paige S et al. (2013) Depolarization of mitochondria in endothelial cells promotes cerebral artery vasodilation by activation of nitric oxide synthase. Arterioscler Thromb Vasc Biol 33:752-9

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