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little is known about the effects of estrogen on postischemic cerebral
vasomotor dynamics after ischemic injury. Emerging hypotheses suggest that the
timing after menopause at which hormone replacement is initiated might be
important and might modulate the potential benefits of estrogen on brain rescue once a cerebral ischemic event occurs.
Therefore, we sought to determine if protracted hypoestrogenicity
modifies estrogen’s protective effects on postischemic pial artery dilatory
dysfunction and if the arachidonic acid metabolite 20-hydroxyeicosatetraeonic
(20-HETE) contributes to the dysfunction. Pial artery dilation to acetylcholine
was examined before and 1 hour after 15 minutes forebrain ischemia. The rat
study groups included: sexually mature males (M), naive (N), OVX (OV),
estrogen-treated OVX females (E1; estrogen started 1 week post ovariectomy) and
delayed estrogen-treated (E10; started 10 weeks post ovariectomy) females.
Postischemic responses were assessed before and after superfusion of the
20-HETE synthesis inhibitor N-hydroxy-N’-(4-butyl-2-methylphenyl)-formamidine
(HET0016). Postischemic acetylcholine dilation was depressed in M, OV and E10
compared to N and E1 rats. Compared to E1, delayed estrogen replacement
worsened acetylcholine-induced dilation. Postischemic microvascular estrogen
receptor alpha (ERα) density was
similar in the OV, E1 and E10 rats. Postischemic application of HET0016 failed
to improve acetylcholine dilation. Continuous infusion of HET0016 during and
after ischemia did not reverse postischemic pial vasodilatory dysfunction.
Timing of estrogen replacement may be critical for vascular health after cerebral ischemic injury.
Postischemic loss of acetylcholine reactivity does not appear to involve
mechanisms related to 20-HETE synthesis or microvascular ERα expression.