Effects of Ischemia on Cerebral Arteriolar Dilation to Arterial Hypoxia in Piglets

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Abstract
Background and Purpose —Arterial hypoxia mediates cerebral arteriolar dilation primarily via mechanisms involving activation of ATP-sensitive K + channels (K ATP ), which we have shown to be sensitive to ischemic stress. In this study, we determined whether ischemia/reperfusion alters cerebral arteriolar responses to arterial hypoxia in anesthetized piglets. Since adenosine plays an important role in cerebrovascular responses to hypoxia, we also determined whether adenosine-induced arteriolar dilation is affected by ischemic stress. We tested the hypothesis that reductions in cerebral arteriolar dilator responses after ischemia would be proportional to the contribution of K ATP to hypoxia and adenosine. Methods —Pial arteriolar diameters were measured using a cranial window and intravital microscopy. We examined arteriolar responses to arterial hypoxia (inhalation of 8.5% and 7.5% O 2 ), to topical adenosine (10 –5 and 10 –4 mol/L) and to arterial hypercapnia (inhalation of 5% and 10% CO 2 in air) before and after 10 minutes of global ischemia. Ischemia was achieved by increasing intracranial pressure. Arterial hypercapnia was used as a positive control for the effectiveness of the ischemic insult. In addition, we evaluated cerebral arteriolar responses to 10 –5 and 10 –4 mol/L adenosine applied topically with or without glibenclamide, a selective inhibitor of K ATP (10 –5 and 10 –6 mol/L). Finally, we administered theophylline (20 mg/kg, IV) to assess the contribution of adenosine to cerebral arteriolar dilation to arterial hypoxia. Results —Before ischemia, cerebral arterioles dilated by 19±3% to moderate and 29±4% to severe hypoxia (n=7; P <.05); 13±2% to 10 –5 and 20±1% to 10 –4 mol/L adenosine (n=9; P <.05); and by 17±2% to moderate and 28±3% to severe hypercapnia (n=6; P <.05). After ischemia, cerebral arteriolar responses to hypoxia and adenosine were unchanged. In contrast, cerebral arteriolar dilation to hypercapnia was impaired by ischemia (1±1% and 2±1% at 1 hour; n=6). Glibenclamide reduced cerebral arteriolar dilation to adenosine by approximately one half (n=7). In addition, blockade of adenosine receptors by theophylline (20 mg/kg, IV) almost totally suppressed cerebral arteriolar dilation to arterial hypoxia (n=6). Conclusions —Cerebrovascular responsiveness is selectively affected by anoxic stress. In addition, cerebral arteriolar dilation to hypoxia and adenosine is maintained after ischemia despite the expected impairment in K ATP function.