Effects of delayed estrogen treatment and 20-HETE synthesis inhibition on postischemic pial artery response to acetylcholine in rats


Relatively 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.

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Miyazaki, C. , N. Zeynalov, E. , C. Koehler, R. and T. Littleton-Kearney, M. (2014) Effects of delayed estrogen treatment and 20-HETE synthesis inhibition on postischemic pial artery response to acetylcholine in rats. Open Journal of Molecular and Integrative Physiology, 4, 1-10. doi: 10.4236/ojmip.2014.41001.

Conflicts of Interest

The authors declare no conflicts of interest.


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