From the Department of Physiology and Pharmacology (F.B., D.W.B), Bowman
Gray School of Medicine, Wake Forest University, Winston-Salem, NC; the
Department of Physiology (F.B.), Albert Szent-Györgyi Medical University,
Szeged, Hungary; and the Department of Anatomy and Cell Biology (T.M.L.), East
Carolina University, Medical School, Greenville, NC.
Correspondence to David W. Busija, PhD, Department of Physiology and Pharmacology, Bowman Gray School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1083. E-mail dbusija{at}bgsm.edu
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
KATP 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%
O2), to topical adenosine (10–5 and
10–4 mol/L) and to arterial hypercapnia
(inhalation of 5% and 10% CO2 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 KATP (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 KATP
function.
Departments
of Physiology, Pharmacology, and Biochemistry and Center
for Perinatal Biology,
Loma Linda University School of Medicine,
Loma Linda, California
© 1998 American Heart Association, Inc.
Original Contributions
Effects of Ischemia on Cerebral Arteriolar Dilation to Arterial Hypoxia in Piglets
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