Potassium Channel Dysfunction in Cerebral Arteries

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DESCRIPTION (provided by applicant): 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.