Protein tyrosine kinase and mitogen-activated protein kinase activation contribute to KATP and Kca channel impairment after brain injury

Previous studies have observed that pial artery dilation to activators of the ATP sensitive K (K-ATP) and calcium sensitive K (K-ca) channel was blunted following fluid percussion brain injury (FPI) in the piglet. In recent studies in the rat. protein tyrosine kinase (PTK) activation was observed to contribute to K-ATP Channel impairment after FPI, but such a role in K-ca channel impairment was unclear. This study investigated the role of PTK and mitogen activated protein kinase (MAPK) activation in blunted pial dilation to K-ATP and K-ca channel agonists following FPI in pi.-lets equipped with a closed cranial window. Cromakalim and NS 1619 (10(-8), 10(-6) M) induced pial artery dilation was blunted after FPI, but partially restored by the PTK inhibitors gemstein (10(-6) M) and tyrphostin A23 (10(-5) M) (10+/-1 and 19+/-1%, sham control; 2+/-1 and 4+/-1%, FPI; and 7+/-1 and 11-1% FPI-genistein pretreated for NS 1619 10(-)8, 10-6 M, respectively). Cromakalim- and NS1619-induced pial dilation was also partially restored after FPI by pretreatment with the MAPK inhibitors U0126 (10(-6) M) and PD98059 (10(-5) M) (12+/-1 and 21+/-1%, sham control; 2 +/- 1 and 4 +/- 1%, FPI; and 6 +/- 1 and 10 +/- 2%, FPI-U0126 pretreated for NS 1619 10(-8), 10(-6) M, respectively). These data suggest that PTK and MAPK activation contribute to K-ATP and K-ca channel impairment following FPI. (C) 2002 Elsevier Science B.V. All rights reserved.