Altered Calcium Dynamics Do Not Account for Attenuation of Endothelium-Derived Hyperpolarizing Factor–Mediated Dilations in the Female Middle Cerebral Artery

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Abstract
Background and Purpose— The contribution of endothelium-derived hyperpolarizing factor (EDHF) to ATP-mediated dilations is significantly attenuated in the rat middle cerebral artery of intact and estrogen-treated ovariectomized (OVX) females compared with males and vehicle-treated OVX females. Since an increase in endothelial calcium appears to be a critical prerequisite in the EDHF response, we tested the hypothesis that endothelial cell intracellular calcium ([Ca 2+ ] i ) fails to reach sufficient levels to elicit robust EDHF-mediated dilations in females and that this effect is mediated by estrogen. Methods— Vascular diameter and [Ca 2+ ] i were measured concomitantly in perfused middle cerebral artery segments with the use of videomicroscopy and fura 2 fluorescence, respectively. Results— In the presence of N G -nitro- l -arginine methyl ester and indomethacin, the dilation to 10 −5 mol/L ATP was significantly reduced ( P 2+ ] i increased to comparable levels in intact females (461±116 nmol/L), estrogen-treated OVX females (417±50 nmol/L), intact males (421±77 nmol/L), and vehicle-treated OVX females (530±92 nmol/L). In response to luminal ATP (10 −5 mol/L), smooth muscle cell [Ca 2+ ] i decreased to a greater degree in males (37±4%; n=8) compared with females (21±5%; n=7) and in vehicle-treated OVX females (18±7%; n=7) compared with estrogen-treated OVX females (3±5%; n=9). Conclusions— Our data suggest that loss of a factor coupling EDHF to reduction of ionized smooth muscle cell [Ca 2+ ] i accounts for the attenuated EDHF-mediated dilations in the female middle cerebral artery.

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