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

• Published in: American journal of physiology. Heart and circulatory physiology 1997-12, Vol.273 (6), p.H2639-H2647
• Main Authors: Kasemsri, T, Armstead, W. M
• Format: Article
• Language: English
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.1997.273.6.h2639

Departments of Anesthesia and Pharmacology, University of Pennsylvania, and The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104 In piglets, pial arteries constrict, ATP-sensitive K + (K ATP ) 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 K ATP channel activation. This study was designed to characterize the relationship between ET-1 and impaired function of K ATP channels after FPI. Injury was produced via the lateral FPI technique in piglets equipped with a closed cranial window. Cromakalim, a K ATP 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 K ATP channel-, NO-, and cGMP-mediated dilation. These data suggest that ET-1 contributes to altered cerebral hemodynamics after FPI through impairment of K ATP channel function via PKC activation. newborn; cerebral circulation; nitric oxide; cyclic nucleotides