Chronic Hyperglycemic Diabetes in the Rat is Associated with a Selective Impairment of Cerebral Vasodilatory Responses

Abstract

Diabetes has been reported to impair vasodilatory responses in the peripheral vascular tissue. However, little is known about vasodilatory function in the diabetic brain. We therefore studied, in the N₂O-sedated, paralyzed, and artificially ventilated rat, the effects of chronic hyperglycemic diabetes on the cerebral blood flow (CBF) responses to 3 acutely imposed vasodilatory stimuli: Hypoglycemia (HG) (plasma glucose = 1.6–1.9 μmol ml⁻¹), hypoxia (HX) (P_aO₂ = 35–38 mm Hg), or hypercarbia HC) (P_aCO₂ = 75–78 mm Hg). In addition, we evaluated the somatosensory evoked potential (SSEP) and plasma catecholamine changes in rats exposed to acute glycemic reductions. Diabetes was induced via streptozotocin (STZ, 60 mg kg⁻¹ i.p.). All results in diabetic rats were compared to those obtained in age-matched nondiabetic controls. The animals were studied at 6–8 weeks (HG experiments) or 4–6 months (HG, HX, and HC experiments) post-STZ. Values for CBF were obtained for the cortex (CX), subcortex (SC), brainstem (BS), and cerebellum (CE) employing radiolabeled microspheres. Up to three CBF determinations were made in each animal. In 6–8 week diabetics vs. controls, CBF increased to a lesser value in the CX, SC, and BS (p < 0.05). Thus, in the diabetics, going from chronic hyperglycemia to acute hypoglycemia, CBF values (in ml 100 g⁻¹ min¹ ± SD) increased (p < 0.05) from 89 ± 22 to 221 ± 57 in the CX, from 82 ± 21 to 160 ± 52 in the SC, and from 79 ± 34 to 237 ± 125 in the BS. In controls, going from normoglycemia to acute hypoglycemia, the CBF changes (p < 0.05) were 128 ± 27 to 350 ±219 (CX), 117 ± 11 to 358 ± 206 (SC), and 130 ± 29 to 452 ± 254 (BS). CBF changes and absolute values in the CE were similar in the two groups. At 4–6 months post-STZ, a complete loss of the hypoglycemic CBF response was found in the CX, SC, and CE. In the BS, a CBF response to hypoglycemia was seen in the diabetic rats, with the CBF increasing from 114 ± 28 (hyperglycemia) to 270 ± 204 ml 100 g⁻¹ min⁻¹ (p < 0.05), compared to a change from 147 ± 36 (normoglycemia) to 455 ± 299 ml 100 g⁻¹ min⁻¹ (p < 0.05) in the control group. The hypoglycemic CBF values in these two groups were not statistically different. The hypoglycemic SSEP amplitudes were ∼50% lower in diabetic (6–8 week and 4–6 month) vs. nondiabetic rats (p < 0.05). Hypoglycemic plasma catecholamine responses were significantly suppressed in diabetics compared to controls. Plasma epinephrine (E) and norepinephrine (NE) (in ng ml⁻¹ ± SD), in 6–8 week diabetics, increased from 0.23 ± 0.18 and 0.77 ± 0.29, respectively, in hyperglycemia, to 2.3 ± 1.0 and 1.3 ± 0.5 in normoglycemia (p < 0.05 for both E and NE), with no further changes in hypoglycemia. On the other hand, in controls, E and NE increased (p < 0.05) from 0.36 ± 0.09 and 0.84 ± 0.31 ng ml⁻¹ (normoglycemia) to 8.5 ± 2.2 and 2.9 ± 1.0 ng ml⁻¹ (hypoglycemia). No differences in the CBF increases accompanying hypoxia or hypercarbia were seen in diabetics vs. controls. These data suggest a selective suppression of the cerebral vasodilatory capacity in the chronically hyperglycemic diabetic. The CBF results are discussed with respect to the possible contributions of a sympathetic/cerebral β-adrenoeeptor dysfunction. The SSEP findings indicate the importance of CBF increases during hypoglycemia in acting to attenuate the reduction in glucose supply and the severity of the functional disturbance.