CEREBRAL VASODILATING CAPACITY DURING FOREBRAIN ISCHEMIA - EFFECTS OFCHRONIC ESTROGEN DEPLETION AND REPLETION AND THE ROLE OF NEURONAL NITRIC-OXIDE SYNTHASE
Da. Pelligrino et al., CEREBRAL VASODILATING CAPACITY DURING FOREBRAIN ISCHEMIA - EFFECTS OFCHRONIC ESTROGEN DEPLETION AND REPLETION AND THE ROLE OF NEURONAL NITRIC-OXIDE SYNTHASE, NeuroReport, 9(14), 1998, pp. 3285-3291
THE effects of chronic 17 beta-estradiol (E-2) depletion, via ovariect
omy (OVX), and its repletion, on cortical cerebral blood flow (CBF) an
d EEG activities during forebrain ischemia, as well as post-ischemic r
ecovery and neuropathology, were assessed and compared with results ob
tained in normal female rats. We also examined whether neuronal nitric
oxide synthase (nNOS) activity is affected by OVX and E-2 replacement
and whether NOS-derived NO supports vasodilation during ischemia. OVX
females displayed a significantly lower CBF during ischemia (10% of b
aseline) than did normal females (23% of baseline). In OVX rats, given
chronic low-dose E-2 treatment (0.1 mg kg(-1) day(-1)), intra-ischemi
c CBF was similar to normal females (25% of baseline). However, at sup
raphysiologic E-2 doses (greater than or equal to 0.5 mg kg(-1) day(-1
)), that benefit was diminished or lost. Intra-ischemic EEG power redu
ctions 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 E-2-treated OVX rats (4-8% base
line). 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)) E-2. Howe
ver, the inability to restore vasodilating function despite normalizat
ion of nNOS activity indicates that another mechanism is responsible f
or the repression of vasodilatory function in the high-dose group. The
se findings suggest that E,, at levels within the physiological range,
promotes ischemic neuroprotection via improving vasodilating capacity
. One possible mechanism may relate to E, enhancing brain nNOS express
ion and activity. (C) 1998 Lippincott Williams & Wilkins.