Poor Hemodynamic and Metabolic Recovery after Global Incomplete Cerebral Ischemia Associated with Short-Term Diabetes in Dogs

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Abstract
We determined the effect of 4–5 weeks of diabetes on ATP recovery following global incomplete cerebral ischemia. 31P magnetic resonance spectra of ATP, intracellular pH (pHi), and CBF (radiolabeled microspheres) were measured in three groups of anesthetized dogs (n = 8/group): chronic hyperglycemic diabetes (pancreatectomy followed by blood glucose of >10 m M for 4–5 weeks); acute hyperglycemia (blood glucose of >10 m M) during ischemia and reperfusion in nondiabetic dogs; and normoglycemic controls. Twenty minutes of incomplete ischemia was produced by ventricular fluid infusion to keep cerebral perfusion pressure (CPP) at 10 mm Hg during spontaneous variations in MABP. Intracranial pressure was increased initially to similar levels, resulting in a similar Cushing response among the groups. However, during the final 8 min of ischemia, MABP decreased to a greater extent in diabetic (86 ± 42 mm Hg) than in hyperglycemic (162 ± 30 mm Hg) and normoglycemic (135 ± 54 mm Hg) groups and remained lower throughout 3 h of reperfusion. CPP was kept constant during ischemia, but was lower throughout reperfusion in diabetic dogs. During ischemia CBF was reduced similarly among groups: 5 ± 3 ml · min−1 · 100 g−1 in hyperglycemic and normoglycemic and 4 ± 3 ml · min−1 · 100 g−1 in diabetic dogs. During reperfusion early hyperemia was attenuated and delayed hypoperfusion was augmented (7 ± 17 ml · min−1 · 100 g−1 by 180 min) as a result of low perfusion pressure in diabetics. However, medullary blood flow was similar among groups. Endischemic ATP was similar among groups (25 ± 34, 30 ± 25, and 4 ± 11% of baseline in normoglycemic, hyperglycemic and diabetic dogs, respectively). Following 180 min of reperfusion ATP was 87 ± 15, 45 ± 38, and 7 ± 19% of control in normoglycemic, hyperglycemic and diabetic dogs, respectively. End-ischemic pHi was lower in hyperglycemic (5.94 ± 0.16) and diabetic (5.96 ± 0.08) than normoglycemic (6.32 ± 0.04) groups. By 45 min of reperfusion, pHi recovered in normoglycemic (7.02 ± 0.09) but not in diabetic (6.13 ± 0.38) or hyperglycemic dogs (6.44 ± 0.28). This study shows that MABP, CBF, ATP, and pHi following global incomplete ischemia did not recover in diabetic dogs. In diabetics poor metabolic recovery was related to the MABP decreases during ischemia and reperfusion. These results contrast with previous studies from our laboratory showing good metabolic recovery with longer-term diabetes (3–4 months). Our findings indicate that in this diabetic model, the cerebral ischemic response is dependent on duration of diabetes.