Estrogen increases cGMP in selected brain regions and in cerebral microvessels.
We have previously reported that exogenous and endogenous estrogen can amplify residual cerebral blood flow during experimental cerebral ischemia. Because estrogen has been linked to nitric oxide and cyclic guanosine monophosphate (cGMP) signaling in noncerebral tissue, we tested the hypothesis that long-term 17beta-estradiol treatment increases basal cGMP in brain homogenates and cerebral microvessels in female rabbits. We also determined whether there are important baseline gender-specific differences in regional cGMP. Adult female rabbits were implanted with 17beta-estradiol pellets, 10 mg (F10, n = 10) or 50 mg (F50, n = 13), and compared with untreated females (F, n = 19) and males with negligible estrogen (M, n = 19) (plasma 17beta-estradiol levels of 4+/-4 pg/mL in M, 7+/-5 pg/mL in F, 141+/-74 pg/mL in F10, and 289 +/-10 pg/mL in F50). Cyclic GMP was determined by radioimmunoassay in cerebellum, hypothalamus, caudate nucleus, hippocampus, and cortex. Cerebral microvessels were harvested from additional cohorts of untreated males and females or estradiol-implanted females (n = 6 per group). Basal cGMP was higher in F versus M only in cerebellum. Estrogen-induced increases in regional cGMP were prominent in hippocampus at all doses (M = 43+/-26, F = 43+/-21, F10 = 84+/-24, F50 = 117+/-55 fmol/mg protein) and in cortex at the high dose (M = 78+/-55, F = 88+/-51, F10 = 69+/-34, F50 = 143+/-52 fmol/mg protein). Similarly, microvascular cGMP increased only in females treated with the 50 mg dose (M = 77+/-13, F = 86+/-25, F10O = 106+/-35, F50 = 192+/-88 fmol/mg protein). Therefore, 17beta-estradiol increases cGMP content in parenchymal regions that are known physiologic targets for reproductive steroids but are also areas of selective vulnerability to ischemic insult. Further, high doses of estrogenic steroids could amplify cGMP signaling within the cerebral microvasculature.
Palmon
S C
SC
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287-4961, USA.
Williams
M J
MJ
Littleton-Kearney
M T
MT
Traystman
R J
RJ
Kosk-Kosicka
D
D
Hurn
P D
PD
D000818:Animals; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D002421:Caudate Nucleus / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D006152:Cyclic GMP / Q000378:metabolism*; D004343:Drug Implants; D004958:Estradiol / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism; D008297:Male; D008833:Microcirculation / Q000187:drug effects / Q000378:metabolism*; D009928:Organ Specificity; D011817:Rabbits; D012727:Sex Characteristics
D004343:Drug Implants; D004958:Estradiol; D006152:Cyclic GMP