Ischemia Reduces CGRP-Induced Cerebral Vascular Dilation in Piglets

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Abstract
Background and Purpose Effects of anoxic stress on cerebrovascular responses to calcitonin gene–related peptide (CGRP) have not been examined previously. We determined the effects of total global ischemia on cerebral arteriolar responses to CGRP in newborn pigs. Methods Piglets were anesthetized and ventilated with a respirator. Pial arteriolar diameter was determined using a closed cranial window and intravital microscopy. Baseline arteriolar diameters ranged from 80 to 100 μm. Arteriolar responses to 10 −9 and 10 −8 mmol/L CGRP applied topically 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, CGRP dilated arterioles by 14±2% (n=6) and 24±3% (n=7) at 10 −9 and 10 −8 mmol/L, respectively. However, after ischemia, arteriolar responses to 10 −9 mmol/L CGRP were reduced at 1 hour to 4±1%, at 2 hours to 3±2%, and at 4 hours to 5±4% ( P <.05 for all comparisons). Similarly, arteriolar responses to 10 −8 mmol/L CGRP were reduced to 5±2% at 1 hour, 5±2% at 2 hours, and 10±6% at 4 hours ( P <.05 for all comparisons). In time control animals, arteriolar responses to CGRP did not change over time. In other animals, we examined effects of pretreatment with indomethacin (5 mg/kg IV) on ischemia-induced decreases in arteriolar responses to CGRP. Indomethacin administration did not preserve arteriolar dilation to CGRP at 1 hour after ischemia, but responses were normal at 2 hours. Conclusions Total global ischemia leads to prolonged attenuated dilator responses of cerebral arterioles to CGRP. In addition, indomethacin treatment alters effects of ischemia on CGRP-induced dilation.

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