Endothelin impairs ATP-sensitive K+ channel function after brain injury.

In piglets, pial arteries constrict, ATP-sensitive K+(KATP) channel function is impaired, and cerebrospinal fluid endothelin-1 (ET-1) increases to 10-10 M after brain injury [fluid percussion injury (FPI)]. Nitric oxide (NO) elicits dilation via guanosine 3',5'-cyclic monophosphate (cGMP) and KATP channel activation. This study was designed to characterize the relationship between ET-1 and impaired function of KATP channels after FPI. Injury was produced via the lateral FPI technique in piglets equipped with a closed cranial window. Cromakalim, a KATP agonist, produced dilation that was attenuated by FPI and partially restored by BQ-123, an ET-1 antagonist (11 ± 1 and 23 ± 2 vs. 2 ± 1 and 4 ± 1 vs. 8 ± 1 and 17 ± 2% for responses to 10-8 and 10-6 M cromakalim before FPI, after FPI, and after FPI with BQ-123, respectively). Because ET-1 constriction may antagonize dilation, separate experiments were conducted under conditions of equivalent baseline diameter in the absence and presence of ET-1 (10-10 M). Cromakalim dilation was attenuated by ET-1 and partially restored by the protein kinase C (PKC) inhibitor staurosporine (12 ± 1 and 28 ± 1 vs. 2 ± 1 and 21 ± 3 vs. 9 ± 1 and 29 ± 2% for 10-8 and 10-6 M cromakalim, cromakalim with ET-1, and cromakalim with ET-1+staurosporine, respectively). Similar interactions were observed with calcitonin gene-related peptide, 8-bromoguanosine 3',5'-cyclic monophosphate, and the NO releasers sodium nitroprusside and S-nitroso- N-acetylpenicillamine. These data show that ET-1 blunts KATP channel-, NO-, and cGMP-mediated dilation. These data suggest that ET-1 contributes to altered cerebral hemodynamics after FPI through impairment of KATP channel function via PKC activation.