Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, U.S.A.

Correspondence: Patricia D Hurn, Anesthesiology/Critical Care Medicine, Johns Hopkins Medical Institutions, 600 N. Wolfe Street, Blalock 1404, Baltimore, MD 21287-4961, U.S.A.

Received 12 January 1998; Revised 5 March 1998; Accepted 9 March 1998.

Abstract

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 17-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 17-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 17-estradiol levels of 4 4 pg/mL in M, 7 5 pg/mL in F, 141 74 pg/mL in F10, and 289 110 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, F10 = 106 35, F50 = 192 88 fmol/mg protein). Therefore, 17-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.