Chloride/bicarbonate exchange adversely modifies cardiovascular responses to traumatic brain injury

Physical trauma, psychosocial stress, and oxidative stress increase the neuronal transcription ratio of genes encoding the sodium-potassium chloride cotransporter (<i>Nkcc1, Slc12a2</i>) and the potassium chloride cotransporter (<i>Kcc2, Slc12a5</i>), which leads to neuronal depolarization and excitability. We hypothesized that increases in the <i>Nkcc1:Kcc2</i> ratio of gene transcription in these injuries would be countered with downregulation of the gene encoding the cardiac and neuronal isoform of the chloride/bicarbonate exchanger (<i>Ae3, Slc4a3</i>). We found a reflex decrease in cardiac and neuronal <i>Ae3</i> transcription that was associated with diminished traumatic brain injury (TBI)-induced increases in systolic blood pressure and decrements in heart rate and posttraumatic stress disorder (PTSD)-induced anxiety. We also observed pronounced sex differences in <i>Nkcc1:Kcc2</i> expression, with female control and <i>Ae3</i> knockout mice exhibiting significantly higher brain <i>Nkcc1:Kcc2</i> ratios compared with males. Administration of testosterone after injury reduced the excessive cardiovascular reactivity induced by TBI. We suggest that pharmacologic antagonism of the cardiac/neuronal isoform of <i>Ae3</i>, perhaps with testosterone supplementation, may prove salutary in reducing the adverse cardiovascular and behavioral sequelae of TBI or psychological stress.<b>NEW & NOTEWORTHY</b> Our findings may lead to a new way to effectively treat the chronic stress, anxiety, and excessive cardiovascular reactivity that frequently follow head injuries, such as sports concussion.