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

Abstract

Background and Purpose—Arterial hypoxia mediates cerebral arteriolar dilation primarily via mechanisms involving activation of ATP-sensitive K+channels (KATP), 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 KATPto 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% O2), to topical adenosine (10–5and 10–4mol/L) and to arterial hypercapnia (inhalation of 5% and 10% CO2in 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 10–5and 10–4mol/L adenosine applied topically with or without glibenclamide, a selective inhibitor of KATP(10–5and 10–6mol/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 10–5and 20±1% to 10–4mol/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 KATPfunction.