Cerebral vasodilating capacity during forebrain ischemia

Abstract

THE effects of chronic 17β-estradiol (E₂) depletion, via ovariectomy (OVX), and its repletion, on cortical cerebral blood flow (CBF) and EEG activities during forebrain ischemia, as well as post-ischemic recovery and neuropathology, were assessed and compared with results obtained in normal female rats. We also examined whether neuronal nitric oxide synthase (nNOS) activity is affected by OVX and E₂ replacement and whether NOS-derived NO supports vasodilation during ischemia. OVX females displayed a significantly lower CBF during ischemia (10% of baseline) than did normal females (23% of baseline). In OVX rats, given chronic low-dose E₂ treatment (0.1 mg kg⁻¹ day⁻¹), intra-ischemic CBF was similar to normal females (25% of baseline). However, at supraphysiologic E₂ doses (≥ 0.5 mg kg⁻¹ day⁻¹), that benefit was diminished or lost. Intra-ischemic EEG power reductions and post-ischemic survival rates, neurological dysfunction, and histopathology displayed similar relative differences among groups as the CBF findings. Intra-ischemic CBF was reduced by nNOS inhibition, with ARL 17477, in normal and low-dose E₂-treated OVX rats (4–8% baseline). The repressed intra-ischemic vasodilating function in OVX rats may be due to reductions in nNOS activity, because untreated OVX rats showed a 50% lower cortical nNOS activity than that in normal rats and in rats treated with low or high dose (5 mg kg⁻¹ day⁻¹) E₂. However, the inability to restore vasodilating function despite normalization of nNOS activity indicates that another mechanism is responsible for the repression of vasodilatory function in the high-dose group. These findings suggest that E₂, at levels within the physiological range, promotes ischemic neuroprotection via improving vasodilating capacity. One possible mechanism may relate to E₂ enhancing brain nNOS expression and activity.