Impaired cerebral blood flow autoregulation during posttraumatic arterial hypotension after fluid percussion brain injury is prevented by phenylephrine in female but exacerbated in male piglets by extracellular signal-related kinase mitogen-activated protein kinase upregulation

Abstract

Objective Traumatic brain injury (TBI) contributes to morbidity and mortality in children and boys are disproportionately represented. Hypotension is common and worsens outcome after TBI. Extracellular signal-related kinase (ERK) mitogen activated protein kinase (MAPK) is upregulated and reduces CBF after fluid percussion brain injury (FPI) in piglets. We hypothesized that increased CPP via phenylephrine (PHE) sex dependently reduces impairment of cerebral autoregulation during hypotension after FPI through modulation of ERK MAPK. Design Prospective, randomized animal study. Setting University laboratory. Subjects Newborn (1–5 day old) pigs. Interventions CBF, pial artery diameter, ICP and autoregulatory index (ARI) were determined before and after FPI in untreated, pre- and post-injury PHE (1 μg/kg/min iv) treated male and female pigs during normotension and hemorrhagic hypotension. CSF ERK MAPK was determined by ELISA. Measurements and Main Results Reductions in pial artery diameter, CBF, CPP and elevated ICP after FPI were greater in males, which were blunted by PHE pre- or post-FPI. During hypotension and FPI, pial artery dilation was impaired more in males. PHE decreased impairment of hypotensive pial artery dilation after FPI in females, but paradoxically caused vasoconstriction after FPI in males. Papaverine induced pial artery vasodilation was unchanged by FPI and PHE. CBF, CPP, and ARI decreased markedly during hypotension and FPI in males but less in females. PHE prevented reductions in CBF, CPP, and ARI during hypotension in females but increased reductions in males. CSF ERK MAPK was increased more in males than females after FPI. PHE blunted ERK MAPK upregulation in females, but increased ERK MAPK upregulation in males after FPI. Conclusions These data indicate that elevation of CPP with PHE sex dependently prevents impairment of cerebral autoregulation during hypotension after FPI through modulation of ERK MAPK. These data suggest the potential role for sex dependent mechanisms in cerebral autoregulation after pediatric TBI.

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

“…Similar observations were made in pial arterioles. Phenylephrine produced comparable increases in MAP in male and female piglets (Armstead et al, 2010b). Phenylephrine increased CPP more in the female than in male piglets, both after FPI and combined hypotension and FPI, a result similar to that of our prior study (Armstead et al, 2010b).…”

“…CSF adrenomedullin concentrations are increased after FPI in the female, but these concentrations are unchanged after FPI in the male (Fig. 4), as reported previously (Armstead et al, 2010b). Phenylephrine decreases CSF adrenomedullin concentrations after FPI in the male, which is contrary to the increases in adrenomedullin seen with combined phenylephrine and U 0126 (Fig.…”

“…Recent studies have shown that systemic pressor support with phenylephrine also profoundly protects cerebral autoregulation in the setting of FPI in the female, but not the male, newborn pig (Armstead et al, 2010b). In prior unrelated studies, it was observed that pial artery dilation in response to hypotension is dependent on the activation of Katp and Kca channels (Armstead, 1999).…”

“…Our previous recent studies also showed that FPI produces greater increases in intracranial pressure (ICP) and reductions in parietal cortical blood flow and CPP in male compared to female newborn piglets (Armstead et al, 2010a(Armstead et al, , 2010b. Phenylephrine blunted FPI-associated increases in ICP postinjury in male and female piglets (Armstead et al, 2010b).…”

“…4). In the female, however, phenylephrine increases CSF adrenomedullin after FPI (Armstead et al, 2010b), and combined phenylephrine and U 0126 have only a minimal additional effect on CSF adrenomedullin concentrations after FPI (Fig. 4).…”