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

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 sex-dependent 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.