Global Ischemia Impairs ATP-Sensitive K + Channel Function in Cerebral Arterioles in Piglets

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Abstract
Background and Purpose Indirect evidence from studies in which calcitonin gene–related peptide was used indicates that anoxic stress suppresses functioning of cerebral vascular ATP-sensitive K + channels. The purpose of this study was to directly examine effects of total global ischemia on cerebral arteriolar dilator responses to activators of ATP-sensitive K + channels. Methods We measured pial arteriolar diameters in anesthetized piglets using a closed cranial window and intravital microscopy. Baseline diameters were approximately 100 μm. Arteriolar responses to aprikalim (10 −8 and 10 −6 mol/L), a pharmacological activator of ATP-sensitive K + channels, and iloprost (0.1 and 1 μg/mL), a physiological activator of these channels, were determined before and 1, 2, and 4 hours after a 10-minute period of total global ischemia. Ischemia was caused by increasing intracranial pressure. Results Before ischemia, aprikalim dilated cerebral arterioles by 7±2% at 10 −8 mol/L and by 25±4% at 10 −6 mol/L (n=5). At 1 hour after ischemia, aprikalim did not cause significant dilation at either dose (3±2% at 10 −8 mol/L and 7±4% at 10 −6 mol/L; P <.05 compared with corresponding preischemic response). Arteriolar dilation returned toward normal values at 2 and 4 hours. Similar results were found with iloprost. Furthermore, prior treatment with indomethacin (5 mg/kg) preserved normal arteriolar dilation to aprikalim and iloprost after ischemia. In contrast, arteriolar dilator responses to prostaglandin E 2 were intact after ischemia. Conclusions Ischemia transiently eliminates cerebral arteriolar dilation to activation of ATP-sensitive K + channels; arteriolar responses are suppressed at 1 hour and return toward normal over 2 to 4 hours. In addition, reduced responsiveness can be prevented by prior treatment with indomethacin.