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The blood-brain tumor barrier (BTB) significantly limits delivery of effective concentrations of chemotherapeutic drugs to brain tumors. Previous studies suggest that BTB permeability may be modulated via alteration in the activity of potassium channels. In this study, we studied the relationship of BTB permeability increase mediated by potassium channel agonists to channel expression in two rat brain tumor models. Intravenous infusion of KCO912 (K(ATP) agonist), minoxidil sulfate (K(ATP) agonist) or NS1619 (K(Ca) agonist) increased tumor permeability more in the 9L allogeneic brain tumor model than in the syngeneic brain tumor model. Consistently, expression of both K(ATP) and K(Ca) channels in 9L tumors was increased to a significantly greater extent in Wistar rats (allogeneic) as compared to Fischer rats (syngeneic). Furthermore, as a preliminary effort to understand clinical implication of potassium channels in brain tumor treatment, we determined the expression of K(ATP) in surgical specimens. K(ATP) mRNA was detected in glioblastoma multiforme (GBM) from nineteen patients examined, with a wide range of expression levels. Interestingly, in paired GBM tissues from seven patients before and after vaccination therapy, increased levels of K(ATP) were detected in five patients after vaccination that had positive response to chemotherapy after vaccination. The present study indicates that the effects of potassium channel agonists on BTB permeability are different between syngeneic and allogeneic models which have different expression levels of potassium channels. The expression of potassium channels in brain tumors is variable, which may be associated with different tumor permeability to therapeutic agents among patients.

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 piglets equipped with a closed cranial window. Cromakalim and NS1619 (10(-8), 10(-6) M) induced pial artery dilation was blunted after FPI, but partially restored by the PTK inhibitors genistein (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 NS1619 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 NS1619 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.