Women rarely suffer cardiovascular dysfunction before menopause, but by the age of 65 a woman becomes as vulnerable to cardiovascular mortality as a man. It has been proposed that estrogens protect against cardiovascular disease; however, the physiological basis of estrogen protection is unknown. In the present study the mechanism of estrogen-induced relaxation of coronary arteries was investigated at the tissue, cellular, and molecular levels. Tissue studies demonstrate that 17 beta-estradiol relaxes porcine coronary arteries by an endothelium-independent mechanism involving K+ efflux, and subsequent studies employing the patch-clamp technique confirmed that estrogen stimulates K+ channel gating in coronary smooth muscle. Perforated-patch recordings from metabolically intact coronary myocytes revealed that 17 beta-estradiol more than doubles steady state outward currents in these cells at positive voltages. Studies of on-cell patches demonstrated a potent stimulatory effect of 17 beta-estradiol on the gating of the large-conductance, Ca(2+)- and voltage-activated K+ (BKCa) channels, while 17 alpha-estradiol had no effect. Furthermore, blocking BKCa channels in intact arteries inhibited estrogen-induced relaxation. The effect of 17 beta-estradiol on BKCa channels was blocked by inhibiting cGMP-dependent protein kinase (PKG) activity and was mimicked by exogenous cGMP or by stimulating PKG activity. Therefore, we propose that 17 beta-estradiol relaxes coronary arteries by opening BKCa channels via cGMP-dependent phosphorylation. This novel mechanism could account for the hypotensive effect of estrogens and help explain, at least in part, why postmenopausal estrogen therapy lowers the risk of cardiovascular disease.
Estrogens are proposed to exert protection against cardiovascular disease, and evidence now suggests that this protection involves a direct vasodilatory effect. We have shown previously that estrogen relaxes endothelium-denuded porcine coronary arteries by opening the large-conductance calcium- and voltage-activated potassium (BKCa) channel of myocytes through guanosine 3',5'-cyclic monophosphate (cGMP)-dependent phosphorylation (35). The present study confirms these results and now demonstrates that this mechanism involves production of nitric oxide (NO). S-nitroso-N-acetylpenicillamine (SNAP), an NO donor, or 8-bromo-cGMP mimicked the effect of estrogen on BKCa channels. Furthermore, inhibition of NO synthase (NOS) attenuated estrogen- or tamoxifen-induced BKCa-channel activity, and this effect was disinhibited by L-arginine. Inhibition of guanylyl cyclase activity blocked the stimulatory effect of estrogen, SNAP, or L-arginine on BKCa channels. Furthermore, 17 beta-estradiol stimulated accumulation of nitrite and cGMP in coronary myocytes. Therefore, we propose that the vasodilatory effect of estrogen on the coronary circulation is mediated by NO. A portion of the beneficial cardiovascular effects of estrogen may be attributed to relaxation of vascular smooth muscle by a process that involves NO- and cGMP-dependent stimulation of BKCa channels.
Advanced displays for military and other user-interaction intensive systems need objective measures of merit for analyzing the information transfer from the displays to the user. A usable objective metric for display interface designers needs to be succinct, modular and scaleable. The authors have combined the concepts of weighted Signal to Noise Ratio (SNR) and multidimensional correlation to calculate a novel index of display complexity. Preliminary data supporting the development of this metric for complex visual, auditory and mixed auditory and visual displays will be presented. Analysis of the human subject data indicates the coefficients for the algorithm are easily determined. Furthermore, the metric can predict reaction-times and accuracy rates for complex displays. This combination of semi-automated reduction of display information and calculation of a single complexity index makes this algorithm a potentially convenient tool for designers of complex display interfaces.
The True Depth Display (TDD) employs two display surfaces in the same visual space but separated in depth. Users see both displays simultaneously, so information can be presented to exploit the overlayed images. Information density can be increased without the debilitating effects of clutter. A hardware prototype of the TDD will demonstrate how this display technology can enhance user interface design.
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