Selective impairment of response to acetylcholine after ischemia/reperfusion in mice.
OBJECTIVE
We previously reported that the endothelium-dependent dilation of pial arterioles by either topical acetylcholine (ACh) or bradykinin (BK) was markedly inhibited after 10 minutes of near total ischemia after bilateral carotid occlusion. The present study tests the responses after 10 minutes of reperfusion and investigates the effect of either oxygen or oxygen radical scavengers on the results.


METHODS
Mice were subjected to bilateral carotid ligation or sham ligation. Pial arteriolar diameters were monitored by an image-splitting technique at a craniotomy site. In separate studies, the responses to topically suffused ACh, BK, or sodium nitroprusside (SNP) were tested before ischemia. After 10 minutes of ischemia and 10 minutes of reperfusion, the response was assessed again. Sham-operated mice were observed in each study. Cerebral blood flow was continuously monitored with a laser-Doppler technique. Additional separate studies were conducted as follows: presence of superoxide dismutase plus catalase during ischemia and reperfusion, or increase in the inspired oxygen (arterial oxygen) and oxygen in suffusate.


RESULTS
The response to ACh was significantly impaired after 10 minutes of reperfusion. The responses to BK and SNP were unaffected. Radical scavengers failed to influence the impaired response to ACh. Elevations of arterial and suffusate oxygen levels to over 300 mm Hg failed to prevent the impairment.


CONCLUSIONS
After 10 minutes of reperfusion, a selective impairment of the response to ACh remains. The response to another endothelium-dependent dilator, BK, recovered, and the response to endothelium-independent SNP was unaffected. Because neither radical scavengers nor oxygen altered the outcome with respect to ACh, I suggest that neither radical generation nor hypoxia accounts for the selective impairment of dilation by ACh. Rather, I hypothesize that reduced shear during ischemia diminishes the ability of the endothelium to synthesize and/or release the endothelium-derived relaxing factor for ACh. I hypothesize further that this impaired release or synthesis persists throughout the 10-minute period of reperfusion.
Rosenblum
W I
WI
Department of Pathology (Neuropathology), Medical College of Virginia/Virginia Commonwealth University Richmond, USA.
D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D001160:Arterioles / Q000187:drug effects; D001920:Bradykinin / Q000494:pharmacology*; D002545:Brain Ischemia / Q000378:metabolism*; D002374:Catalase / Q000494:pharmacology; D004351:Drug Resistance; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009599:Nitroprusside / Q000494:pharmacology*; D018384:Oxidative Stress; D010100:Oxygen / Q000097:blood / Q000494:pharmacology; D010313:Partial Pressure; D010841:Pia Mater / Q000098:blood supply*; D017382:Reactive Oxygen Species; D015427:Reperfusion Injury / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000494:pharmacology; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; D009599:Nitroprusside; D002374:Catalase; D013482:Superoxide Dismutase; D000109:Acetylcholine; D010100:Oxygen; D001920:Bradykinin