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.
Kasemsri
T
T
Department of Anesthesia, University of Pennsylvania, Philadelphia, USA.
Armstead
W M
WM
D000818:Animals; D000831:Animals, Newborn; D001160:Arterioles / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D001930:Brain Injuries / Q000503:physiopathology*; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D002536:Cerebral Arteries / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D019806:Cromakalim / Q000494:pharmacology*; D019332:Endothelin-1 / Q000494:pharmacology*; D005260:Female; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D009599:Nitroprusside / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D010841:Pia Mater / Q000098:blood supply; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D026423:S-Nitroso-N-Acetylpenicillamine; D013552:Swine
D019332:Endothelin-1; D015221:Potassium Channels; D019806:Cromakalim; D009599:Nitroprusside; D026423:S-Nitroso-N-Acetylpenicillamine; D010396:Penicillamine; D015740:Calcitonin Gene-Related Peptide