Phenylephrine Infusion Prevents Impairment of ATP- and Calcium-Sensitive Potassium Channel-Mediated Cerebrovasodilation after Brain Injury in Female, but Aggravates Impairment in Male, Piglets through Modulation of ERK MAPK Upregulation

Abstract

Traumatic brain injury (TBI) contributes to morbidity in children and boys, and hypotension worsens outcome. Extracellular signal-related kinase (ERK) mitogen-activated protein kinase (MAPK) is upregulated more in males and reduces cerebral blood flow (CBF) after fluid percussion injury (FPI). Increased cerebral perfusion pressure (CPP) via phenylephrine (Phe) sex-dependently improves impairment of the cerebral autoregulation seen after FPI through modulation of ERK MAPK upregulation, which is aggravated in males, but is blocked in females. Activation of ATP-and calcium-sensitive (Katp and Kca) channels produces cerebrovasodilation and contributes to autoregulation, both of which are impaired after FPI. Using piglets equipped with a closed cranial window, we hypothesized that potassium channel functional impairment after FPI is prevented by Phe in a sexdependent manner through modulation of ERK MAPK upregulation. The Katp and Kca agonists cromakalim and NS 1619 produced vasodilation that was impaired after FPI more in males than in females. Phe prevented reductions in cerebrovasodilation after cromakalim and NS 1619 in females, but reduced dilation after these potassium channel agonists were given to males after FPI. Co-administration of U 0126, an ERK antagonist, and Phe fully restored dilation to cromakalim, calcitonin gene-related peptide (CGRP), and NS 1619, in males after FPI. These data indicate that Phe sex-dependently prevents impairment of Katp and Kca channel-mediated cerebrovasodilation after FPI in females, but aggravates impairment in males, through modulation of ERK MAPK upregulation. Since autoregulation of CBF is dependent on intact functioning of potassium channels, these data suggest a role for sex-dependent mechanisms in the treatment of cerebral autoregulation impairment after pediatric TBI.

RETRACTED: Dopamine protects cerebral autoregulation and prevents hippocampal necrosis after traumatic brain injury via block of ERK MAPK in juvenile pigs

“…We also showed that the ET-1 antagonist BQ 123 blunted while the free radical scavenger SODCAT blocked ERK MAPK release after FPI, supportive of the sequential pathway wherein FPI releases ET-1 to increase superoxide which in turn releases ERK MAPK to impair K channel mediated cerebrovasodilation and thereby cerebral autoregulation (Armstead and Vavilala 2013). More ET-1, activated oxygen, and ERK MAPK are released in males compared to females to sequentially impair K channel mediated cerebrovasodilation, contributing to greater impairment of autoregulation after TBI (Armstead 2000; Armstead et al 2011; Armstead and Vavilala 2013). New data in the present study show that DA equivalently blocks upregulation of ERK MAPK in male and female newborn and juvenile pigs.…”

Cerebral Blood Flow Autoregulation and Dysautoregulation

“…Therefore, Phe augments impairment of autoregulation in males after TBI both because it promotes release of a spasmogen and subsequent block of Katp and Kca channels as well because it simultaneously limits release of an endogenous neuroprotectant (Fig 1). 66 In contrast, DA completely blocked ET-1 and ERK MAPK upregulation in both newborn male and female piglets after FPI (Fig 1), 61 serving as an explanation for equivalent protection of autoregulation post injury in male and female piglets.…”

Optimizing Cerebral Autoregulation May Decrease Neonatal Regional Hypoxic-Ischemic Brain Injury

“…These covariates were selected due to their potential influence on cerebral autoregulation and neurologic injury. [6–8, 23–25] Relationships between perinatal insult score and brain injury were estimated with polytomous regression for ordered categorical outcomes. Finally, we examined the neonates’ blood pressures in relation to MAP OPT as they progressed through hypothermia, rewarming, and normothermia using a Pearson’s correlation coefficient to compare the percentages of the autoregulation monitoring period with blood pressure below, within, or above MAP OPT between hypothermia vs. rewarming; hypothermia vs. normothermia; and rewarming vs. normothermia.…”

“…However, these studies were too small to control for confounders that affect autoregulation, such as the arterial partial pressure of carbon dioxide (PaCO 2 ) [6] and vasopressors. [7, 8] Here, we studied a larger cohort to evaluate autoregulation independent of PaCO 2 , vasopressors, perinatal insult severity, and seizures.…”