Increased glucose availability does not restore prolonged spreading depression durations in hypotensive rats without brain injury

Abstract

Maintenance of transmembrane ionic gradients and their restoration after cortical spreading depression (CSD) are energy dependent. We recently showed an inverse relationship between blood pressure and CSD duration that is independent of tissue oxygenation. Here, we tested the alternative hypothesis that glucose availability becomes rate-limiting for CSD recovery upon reduced blood pressure in anesthetized rats under full systemic physiological monitoring. Hypotension induced by controlled exsanguination significantly prolonged CSD durations, reduced propagation speeds, and diminished the blood flow response. Hyperglycemia failed to restore the prolonged CSD durations in hypotensive rats and did not significantly alter the propagation speed or the blood flow response. These data suggest that prolonged CSD durations during reduced cerebral perfusion pressure are independent of tissue energy status, and implicate alternative mechanisms of CSD recovery such as vascular clearance of extracellular K+.

Spreading Depression, Spreading Depolarizations, and the Cerebral Vasculature

“…In contrast, mild systemic hypoxia (PO 2 ϳ45 mmHg) did not significantly prolong the DC shift as long as the arterial pressure and cerebral perfusion were maintained within a normal range (456,457). Indeed, there was no correlation between tissue PO 2 and the duration of the DC shift, and excess tissue O 2 or glucose availability by systemic hyperoxia (arterial PO 2 ϳ400 mmHg) or hyperglycemia (blood glucose ϳ400 mg/dl) did not restore prolonged DC shift durations to normal during hypotension (198,457). Similarly, SD recovery in isolated retinal preparation is independent of O 2 availability, albeit with substantially elevated glucose levels (501).…”

“…Systemic hypotension in rats, even when it is relatively mild within the autoregulatory range, brings out and augments the initial hypoperfusion (component I) during the DC shift, and diminishes the peak hyperemia (component II), while prolonging both components; systemic hypoxia has a similar effect, albeit milder (FIGURE 7A) (123,198,445,456,457). Systemic hypercapnia has also been reported to diminish the peak hyperemia, possibly because SD was superimposed on an elevated resting CBF (523).…”

Multifaceted roles for astrocytes in spreading depolarization: A target for limiting spreading depolarization in acute brain injury?

“…In the context of ischemic injuries, CBF responses to SD can be transformed, such that the initial vasoconstrictive phase becomes prolonged and the hyperemic phase is diminished (Dreier et al, ; Hoffmann et al, ). The resulting “spreading ischemia” that can be seen under these conditions is obviously a dangerous set of conditions, as it occurs just when brain tissue is experiencing unusually severe metabolic demands.…”

“…The resulting “spreading ischemia” that can be seen under these conditions is obviously a dangerous set of conditions, as it occurs just when brain tissue is experiencing unusually severe metabolic demands. The mechanism(s) underlying this conversion of CBF responses in injured tissue are not fully identified, but it is noted that reduced baseline perfusion further exacerbates hypoperfusion responses and limits hyperemia (Feuerstein et al, ; Hoffmann et al, ), and elevated extracellular K + also leads to a more pronounced and prolonged CBF decrease (Dreier et al, ). In addition, reduction in the availability of the endogenous vasodilator nitric oxide (NO) can transform the normal hyperemic response to a pronounced hypoperfusion (Dreier et al, ).…”

Subarachnoid Hemorrhage, Spreading Depolarizations and Impaired Neurovascular Coupling

“…Although hypotension appears to be more potent than hypoxia in this regard, combined hypoxia and hypotension, most closely mimicking ischemic penumbra, transforms the predominantly dilator response into a biphasic one. Neither induced hyperoxia nor hyperglycemia restores the CBF response [55, 62], suggesting that cerebral perfusion pressure affects SD-mediated vascular responses by a mechanism unrelated to tissue energy status. …”