Inhaled nitric oxide protects cerebral autoregulation through prevention of impairment of ATP and calcium sensitive K channel mediated cerebrovasodilation after traumatic brain injury.

Hypotension and low cerebral perfusion pressure are associated with low cerebral blood flow, cerebral ischemia, and poor outcomes after traumatic brain injury (TBI). Cerebral autoregulation is impaired after TBI, contributing to poor outcome. In prior studies, ERK mitogen activated protein kinase (MAPK) and ET-1 had been observed to be upregulated and contribute to impairment of cerebral autoregulation and histopathology after fluid percussion brain injury (FPI). Activation of ATP and Calcium sensitive (Katp and Kca) channels produce cerebrovasodilation and contribute to autoregulation, both impaired after TBI. Upregulation of ERK MAPK and endothelin-1 (ET-1) produces K channel function impairment after CNS injury. Inhaled nitric oxide (iNO) has recently been observed to prevent impairment of cerebral autoregulation and hippocampal CA1 and CA3 neuronal cell necrosis after FPI via block of upregulation of ERK MAPK and ET-1. We presently investigated whether iNO prevented impairment of Katp and Kca-mediated cerebrovasodilation after FPI in pigs equipped with a closed cranial window. Results show that pial artery dilation in response to the Katp agonist cromakalim, the Kca agonist NS1619, PGE2 and the NO releaser sodium nitroprusside (SNP) were blocked by FPI, but such impairment was prevented by iNO administered at 2 h post injury. Protection lasted for at least 1 h after iNO administration was stopped. Using vasodilaton as an index of function, these data indicate that iNO prevents impairment of cerebral autoregulation and limits histopathology after TBI through protection of K channel function via blockade of ERK MAPK and ET-1.