Abstract SNACC-14

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Ability to Prevent K channel Mediated Vasodilator Impairment As a Determinant in Sex Dependent Pressor Choice To Protect Cerebral Autoregulation After TBI.

1Armstead W, 1Riley J, 2Vavilala M
1University of Pennsylvania, Philadelphia, PA, USA; 2University of Washington, Seattle, WA, USA

Introduction: Hypotension and low cerebral perfusion pressure (CPP) are associated with low cerebral blood flow (CBF), cerebral ischemia, and poor outcomes after traumatic brain injury (TBI). TBI is the leading cause of death in children, and boys and younger children have particularly poor outcomes compared to girls and older children. Cerebral autoregulation is impaired after TBI, contributing to poor outcome. CPP is often normalized by use of inotropes and vasopressors to increase MAP and optimize CBF. Clinically, current vasopressor use is variable, empiric, and may be related to variability in mortality. Since ethical considerations constrain mechanistic studies in children, we use an established porcine model of fluid percussion brain injury (FPI) to understand this pathology. We observed that phenylephrine (Phe) prevented in female but exacerbated impairment of autoregulation in male newborn pigs after FPI. In contrast, dopamine (DA) prevented impairment of autoregulation in both sexes after FPI, suggesting that pressor choice impacts outcome. Activation of Katp and Kca channels is an important mechanism for cerebral vasodilation, including autoregulation. K channel mediated dilation, an index of K channel function, is blunted after FPI via upregulation of the ERK isoform of mitogen activated protein kinase (MAPK). Phe protected impairment of K channel mediated dilation in females but aggravated impairment in male piglets after FPI. We hypothesized that DA protected autoregulation in both males and females because it equally protected K channel mediated dilation in both sexes after FPI.
Methods: Lateral FPI was produced in anesthetized piglets. Pial artery reactivity was measured via a closed cranial window. ERK MAPK was quantified by ELISA. Data (n=5) were analyzed by repeated measures ANOVA, with significance determined at p less than 0.05.
Results: Cromakalim and calcitonin gene related peptide (CGRP) (Katp agonists) and NS 1619 (Kca agonist) produced pial artery dilation which was blunted by FPI in both male and female piglets. DA (15 µg/kg/min iv, 30 min post FPI) elevated MAP and CPP equally in male and female piglets after FPI. DA protected cromakalim, CGRP, and NS 1619 induced dilation and blocked upregulation of ERK MAPK equivalently in male and female pigs after FPI.
Discussion: These data indicate that DA protects K channel mediated cerebrovasodilation equally in both male and female piglets because of equivalent blockade of ERK MAPK upregulation in both sexes after FPI. Identification of a therapeutic which protects K channel function equally in males and females is an approach to limit sex dependent differences in outcome when systemic pressors are used to normalize CPP after TBI.

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